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Zhou Z, Moore TM, Strumwasser AR, Ribas V, Iwasaki H, Morrow N, Ma A, Tran PH, Wanagat J, de Aguiar Vallim TQ, Clifford B, Zhang Z, Sallam T, Parks BW, Reue K, Shirihai O, Acin-Perez R, Morselli M, Pellegrini M, Mahata SK, Norheim F, Zhou M, Seldin MM, Lusis AJ, Lee CC, Goodarzi MO, Rotter JI, Hansen JR, Drucker B, Sagendorf TJ, Adkins JN, Sanford JA, DeMayo FJ, Hewitt SC, Korach KS, Hevener AL. Muscle metabolic resilience and enhanced exercise adaptation by Esr1-induced remodeling of mitochondrial cristae-nucleoid architecture in males. Cell Rep Med 2025; 6:102116. [PMID: 40328250 DOI: 10.1016/j.xcrm.2025.102116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 06/26/2024] [Accepted: 04/09/2025] [Indexed: 05/08/2025]
Abstract
Reduced estrogen action is associated with obesity and insulin resistance. However, the cell and tissue-specific actions of estradiol in maintaining metabolic health remain inadequately understood, especially in men. We observed that skeletal muscle ESR1/Esr1 (encodes estrogen receptor α [ERα]) is positively correlated with insulin sensitivity and metabolic health in humans and mice. Because skeletal muscle is a primary tissue involved in oxidative metabolism and insulin sensitivity, we generated muscle-selective Esr1 loss- and gain-of-expression mouse models. We determined that Esr1 links mitochondrial DNA replication and cristae-nucleoid architecture with metabolic function and insulin action in the skeletal muscle of male mice. Overexpression of human ERα in muscle protected male mice from diet-induced disruption of metabolic health and enhanced mitochondrial adaptation to exercise training intervention. Our findings indicate that muscle expression of Esr1 is critical for the maintenance of mitochondrial function and metabolic health in males and that tissue-selective activation of ERα can be leveraged to combat metabolic-related diseases in both sexes.
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Affiliation(s)
- Zhenqi Zhou
- David Geffen School of Medicine, Department of Medicine, Division of Endocrinology and Metabolism, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Timothy M Moore
- David Geffen School of Medicine, Department of Medicine, Division of Endocrinology and Metabolism, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Alexander R Strumwasser
- David Geffen School of Medicine, Department of Medicine, Division of Endocrinology and Metabolism, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Vicent Ribas
- David Geffen School of Medicine, Department of Medicine, Division of Endocrinology and Metabolism, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Hirotaka Iwasaki
- David Geffen School of Medicine, Department of Medicine, Division of Endocrinology and Metabolism, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Noelle Morrow
- David Geffen School of Medicine, Department of Medicine, Division of Endocrinology and Metabolism, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Alice Ma
- David Geffen School of Medicine, Department of Medicine, Division of Endocrinology and Metabolism, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Peter H Tran
- David Geffen School of Medicine, Department of Medicine, Division of Endocrinology and Metabolism, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Jonathan Wanagat
- Division of Geriatrics, David Geffen School of Medicine, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Thomas Q de Aguiar Vallim
- Division of Cardiology, David Geffen School of Medicine, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Bethan Clifford
- Division of Cardiology, David Geffen School of Medicine, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Zhengyi Zhang
- Division of Cardiology, David Geffen School of Medicine, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Tamer Sallam
- Division of Cardiology, David Geffen School of Medicine, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Brian W Parks
- David Geffen School of Medicine, Department of Medicine, Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Karen Reue
- David Geffen School of Medicine, Department of Medicine, Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Orian Shirihai
- David Geffen School of Medicine, Department of Medicine, Division of Endocrinology and Metabolism, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Rebeca Acin-Perez
- David Geffen School of Medicine, Department of Medicine, Division of Endocrinology and Metabolism, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Marco Morselli
- Department of Molecular, Cell and Developmental Biology and UCLA-DOE Institute for Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA 900095, USA
| | - Matteo Pellegrini
- Department of Molecular, Cell and Developmental Biology and UCLA-DOE Institute for Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA 900095, USA
| | - Sushil K Mahata
- Department of Medicine and VA, University of California, San Diego, La Jolla, CA 92037, USA
| | - Frode Norheim
- David Geffen School of Medicine, Department of Medicine, Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; University Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway
| | - Mingqi Zhou
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA
| | - Marcus M Seldin
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA
| | - Aldons J Lusis
- Division of Cardiology, David Geffen School of Medicine, Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; David Geffen School of Medicine, Department of Medicine, Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Cathy C Lee
- Department of Medicine and VA, Greater Los Angeles Healthcare System GRECC, Los Angeles, CA 90073, USA
| | - Mark O Goodarzi
- Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Jerome I Rotter
- Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Joshua R Hansen
- Chemical and Biological Signature Sciences Group, Pacific Northwest National Laboratory, Richland, WA 99354, USA
| | - Ben Drucker
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA
| | - Tyler J Sagendorf
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA
| | - Joshua N Adkins
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA
| | - James A Sanford
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA
| | - Francesco J DeMayo
- Reproductive Developmental Biology Laboratory, NIEHS, NIH, Research Triangle Park, NC 27709, USA
| | - Sylvia C Hewitt
- Reproductive Developmental Biology Laboratory, NIEHS, NIH, Research Triangle Park, NC 27709, USA
| | - Kenneth S Korach
- Reproductive Developmental Biology Laboratory, NIEHS, NIH, Research Triangle Park, NC 27709, USA
| | - Andrea L Hevener
- David Geffen School of Medicine, Department of Medicine, Division of Endocrinology and Metabolism, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine and VA, Greater Los Angeles Healthcare System GRECC, Los Angeles, CA 90073, USA; Iris Cantor-UCLA Women's Health Research Center, Los Angeles, CA 90095, USA.
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Ganguly S, Chattopadhyay T, Kazi R, Das S, Malik B, Ml U, Iyer PS, Kashiv M, Singh A, Ghadge A, Nair SD, Sonawane MS, Kolthur-Seetharam U. Consumption of sucrose-water rewires macronutrient uptake and utilization mechanisms in a tissue specific manner. J Nutr Biochem 2025; 139:109850. [PMID: 39889860 DOI: 10.1016/j.jnutbio.2025.109850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 10/31/2024] [Accepted: 01/25/2025] [Indexed: 02/03/2025]
Abstract
Consumption of sugar-sweetened beverages (SSBs) have been linked to metabolic dysfunction, obesity, diabetes and enhanced risk of cardiovascular diseases across all age-groups globally. Decades of work that have provided insights into pathophysiological manifestations of sucrose overfeeding have employed paradigms that rarely mimic human consumption of SSBs. Thus, our understanding of multiorgan cross-talk and molecular and/or cellular mechanisms, which operate across scales and drive physiological derangement is still poor. By employing a paradigm of sucrose water feeding in mice that closely resembles chronic SSB consumption in humans (10% sucrose in water), we have unraveled hitherto unknown tissue-specific mechanistic underpinnings, which contribute towards perturbed physiology. Our findings illustrate that systemic impaired glucose homeostasis, mediated by hepatic gluconeogenesis and insulin resistance, does not involve altered gene expression programs in the liver. We have discovered the pivotal role of the small intestine, which in conjunction with liver and muscles, drives dyshomeostasis. Importantly, we have uncovered rewiring of molecular mechanisms in the proximal intestine that is either causal or consequential to systemic ill-effects of chronic sucrose water consumption including dysfunction of liver and muscle mitochondria. Tissue-specific molecular signatures, which we have unveiled as the primary outcome, clearly indicate that inefficient utilization of glucose is exacerbated by enhanced uptake by the gut. Besides providing systems-wide mechanistic insights, we propose that consumption of SSBs causes intestinal 'molecular addiction' for deregulated absorption of hexose-sugars, and drives diseases such as diabetes and obesity.
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Affiliation(s)
- Saptarnab Ganguly
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India
| | - Tandrika Chattopadhyay
- Centre for innovation in molecular and pharmaceutical sciences, Dr. Reddy's Institute of Life Sciences, Hyderabad, Telangana, India
| | - Rubina Kazi
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Souparno Das
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Bhavisha Malik
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Uthpala Ml
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India
| | - Padmapriya S Iyer
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India
| | - Mohit Kashiv
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India
| | - Anshit Singh
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Amita Ghadge
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Shyam D Nair
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India
| | - Mahendra S Sonawane
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India; Development and Aging (ARUMDA), Advanced Research Unit on Metabolism, Tata Institute of Fundamental Research, Hyderabad, Telangana, India.
| | - Ullas Kolthur-Seetharam
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India; Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India; Development and Aging (ARUMDA), Advanced Research Unit on Metabolism, Tata Institute of Fundamental Research, Hyderabad, Telangana, India; Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
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Ungvari Z, Fekete M, Varga P, Munkácsy G, Fekete JT, Lehoczki A, Buda A, Kiss C, Ungvari A, Győrffy B. Exercise and survival benefit in cancer patients: evidence from a comprehensive meta-analysis. GeroScience 2025:10.1007/s11357-025-01647-0. [PMID: 40220151 DOI: 10.1007/s11357-025-01647-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 04/01/2025] [Accepted: 04/02/2025] [Indexed: 04/14/2025] Open
Abstract
Cancer remains a major global health challenge, and growing evidence suggests that physical activity is a key modifiable factor that may improve survival outcomes in cancer patients. However, a comprehensive, large-scale synthesis of the effects of post-diagnosis physical activity across multiple cancer types remains lacking. This meta-analysis aims to systematically evaluate the association between physical activity and survival in patients diagnosed with breast, lung, prostate, colorectal, and skin cancers. We conducted a comprehensive search in PubMed, Web of Science, Scopus, and Cochrane Library for studies on physical activity and cancer survival. Eligible studies (January 2000-November 2024) included adults (≥ 18 years) with breast, lung, prostate, colorectal, or skin cancer. Only prospective cohort and case-control studies reporting hazard ratios (HRs) with 95% confidence intervals (CIs) for overall or cancer-specific mortality were included, with a minimum sample size of 100 and at least six months of follow-up. Meta-analysis was performed using metaanalysisonline.com, applying random-effects models and assessing heterogeneity via the I2 statistic. Sensitivity analyses and publication bias (Egger's test, funnel plots) were evaluated. The meta-analysis included 151 cohorts with almost 1.5 million cancer patients. Post-diagnosis physical activity was associated with significantly lower cancer-specific mortality across all five cancer types. The greatest benefit was observed in breast cancer, with a pooled hazard ratio (HR) of 0.69 (95% CI: 0.63-0.75), followed by prostate cancer (HR: 0.73, 95% CI: 0.62-0.87). Lung cancer patients who engaged in physical activity had a 24% lower risk of cancer-specific death (HR: 0.76, 95% CI: 0.69-0.84), while colorectal cancer patients experienced a similar benefit (HR: 0.71, 95% CI: 0.63-0.80). In skin cancer, physical activity was associated with a non-significant reduction in mortality (HR: 0.86, 95% CI: 0.71-1.05). These findings provide robust evidence supporting the survival benefits of post-diagnosis physical activity in cancer patients, particularly for breast, prostate, lung, and colorectal cancers. The results underscore the potential for incorporating structured physical activity interventions into oncological care to improve long-term patient outcomes.
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Affiliation(s)
- Zoltan Ungvari
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral College, Health Sciences Division/Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary
| | - Mónika Fekete
- Institute of Preventive Medicine and Public Health, Semmelweis University, Semmelweis University, Budapest, Hungary
- Jozsef Fodor Center for Prevention and Healthy Aging, Semmelweis University, Budapest, Hungary
| | - Péter Varga
- Institute of Preventive Medicine and Public Health, Semmelweis University, Semmelweis University, Budapest, Hungary
- Jozsef Fodor Center for Prevention and Healthy Aging, Semmelweis University, Budapest, Hungary
- Doctoral College, Health Sciences Division, Semmelweis University, Budapest, Hungary
| | - Gyöngyi Munkácsy
- Dept. Of Bioinformatics, Semmelweis University, H- 1094, Budapest, Hungary
- Cancer Biomarker Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, H- 1117, Budapest, Hungary
| | - János Tibor Fekete
- Dept. Of Bioinformatics, Semmelweis University, H- 1094, Budapest, Hungary
- Cancer Biomarker Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, H- 1117, Budapest, Hungary
| | - Andrea Lehoczki
- Institute of Preventive Medicine and Public Health, Semmelweis University, Semmelweis University, Budapest, Hungary
- Jozsef Fodor Center for Prevention and Healthy Aging, Semmelweis University, Budapest, Hungary
- Doctoral College, Health Sciences Division, Semmelweis University, Budapest, Hungary
| | - Annamaria Buda
- Institute of Preventive Medicine and Public Health, Semmelweis University, Semmelweis University, Budapest, Hungary
- Jozsef Fodor Center for Prevention and Healthy Aging, Semmelweis University, Budapest, Hungary
- Doctoral College, Health Sciences Division, Semmelweis University, Budapest, Hungary
| | - Csaba Kiss
- Dept. Of Bioinformatics, Semmelweis University, H- 1094, Budapest, Hungary
- Cancer Biomarker Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, H- 1117, Budapest, Hungary
| | - Anna Ungvari
- Institute of Preventive Medicine and Public Health, Semmelweis University, Semmelweis University, Budapest, Hungary.
| | - Balázs Győrffy
- Dept. Of Bioinformatics, Semmelweis University, H- 1094, Budapest, Hungary
- Cancer Biomarker Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, H- 1117, Budapest, Hungary
- Dept. Of Biophysics, Medical School, University of Pecs, H- 7624, Pecs, Hungary
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Yang L, Peng T, Yan X, Lin P. Effect of midlife exercise on lipid metabolism in aging mice: comparable to lifelong exercise, better than ceasing midlife exercise. Sci Rep 2025; 15:12531. [PMID: 40216894 PMCID: PMC11992076 DOI: 10.1038/s41598-025-97140-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 04/02/2025] [Indexed: 04/14/2025] Open
Abstract
This study examines the effects of continuous versus interrupted lifelong exercise on lipid metabolism in naturally aging male BALB/c mice. Five-week-old male BALB/c mice were randomly assigned to five groups: young control group (YC), natural ageing control group (AC), exercise cessation group (DE), middle-aged commencing exercise group (ME), and lifelong exercise group (LE). Moderate Intensity Continuous Training exercise sessions were conducted three times per week, with each session lasting 50 min; after exercise interventions until 72 weeks of age, the following parameters were measured: body morphology, exercise capacity, blood lipid, liver fat content, liver function, expression of liver lipid metabolism-related genes and endoplasmic reticulum stress-related genes, and activities of liver metabolism enzymes. The results suggest that advancing age leads to disrupted lipid processing, reduced hepatic performance, and increased endoplasmic reticular tension. Compared with the AC group, the ME and LE cohorts showed reduced serum lipids, whereas the LE group exhibited elevated high-density lipoprotein cholesterol (HDL-C) levels (P < 0.05). Post-exercise reductions were observed in hepatic total cholesterol and free fatty acid (FFA). Moreover, the exercises mitigated age-related hepatic impairments and diminished susceptibility towards cirrhosis despite higher aspartate aminotransferase (AST) and lower albumin (ALB) levels being evident within the DE cohort (P < 0.05). Exercise demonstrates the potential to mitigate age-related abnormalities in lipid metabolism. Middle-aged commencing and lifelong exercise interventions are more effective in alleviating lipid abnormalities than exercise cessation in middle age. This disparity in efficacy can be attributed to differences in regulating endoplasmic reticulum stress, enhancing liver lipid oxidation capacity, and reducing lipid synthesis ability. Notably, middle-aged individuals commencing exercise yield similar outcomes in regulating aging-associated abnormal lipid metabolism compared to the lifelong exercise group. This highlights the importance of initiating exercise in middle age, as it remains beneficial even if lifelong commitment is unfeasible, so exercise initiation in midlife is still beneficial. However, to prevent liver lipid metabolism disorders later in life, the earlier exercise initiation, the better.
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Affiliation(s)
- Ling Yang
- School of Physical Education, Shaoguan University, Shaoguan, 512000, Guangdong, China
- Institute for Health and Sport, Victoria University, Melbourne, VIC, 8001, Australia
| | - Tuanhui Peng
- Luohe Institute of Technology, Henan University of Technology, Luohe, 462000, Henan, China
| | - Xu Yan
- Institute for Health and Sport, Victoria University, Melbourne, VIC, 8001, Australia
| | - Pengjie Lin
- Guang Dong Polytechnic of Industry and Commerce, Guangzhou, 510000, Guangdong, China.
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Von Ruff ZD, Miller MJ, Moro T, Reidy PT, Ebert SM, Volpi E, Adams CM, Rasmussen BB. Resistance exercise training in older men reduces ATF4-activated and senescence-associated mRNAs in skeletal muscle. GeroScience 2025:10.1007/s11357-025-01564-2. [PMID: 40011348 DOI: 10.1007/s11357-025-01564-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 02/10/2025] [Indexed: 02/28/2025] Open
Abstract
Sarcopenia increases the risk of frailty, morbidity, and mortality in older adults. Resistance exercise training improves muscle size and function; however, the response to exercise training is variable in older adults. The objective of our study was to determine both the age-independent and age-dependent changes to the transcriptome following progressive resistance exercise training. Skeletal muscle biopsies were obtained before and after 12 weeks of resistance exercise training in 8 young (24 ± 3.3 years) and 10 older (72 ± 4.9 years) men. RNA was extracted from each biopsy and prepared for analysis via RNA sequencing. We performed differential mRNA expression, gene ontology, and gene set enrichment analyses. We report that when comparing post-training vs pre-training 226 mRNAs and 959 mRNAs were differentially expressed in the skeletal muscle of young and older men, respectively. Additionally, 94 mRNAs increased, and 17 mRNAs decreased in both young and old, indicating limited overlap in response to resistance exercise training. Furthermore, the differential gene expression was larger in older skeletal muscle. Finally, we report three novel findings: 1) resistance exercise training decreased the abundance of ATF4-activated and senescence-associated skeletal muscle mRNAs in older men; 2) resistance exercise-induced increases in lean mass correlate with increased mRNAs encoding mitochondrial proteins; and 3) increases in muscle strength following resistance exercise positively correlate with increased mRNAs involved in translation, rRNA processing, and polyamine metabolism. We conclude that resistance exercise training elicits a differential gene expression response in young and old skeletal muscle, including reduced ATF-4 activated and senescence-associated gene expression.
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Affiliation(s)
| | - Matthew J Miller
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA
- University of Iowa, Iowa City, IA, USA
| | - Tatiana Moro
- Department of Biomedical Sciences, University of Padova, Padua, Italy
| | - Paul T Reidy
- Department of Kinesiology, Nutrition, and Health, Miami University, Oxford, OH, USA
| | - Scott M Ebert
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA
| | - Elena Volpi
- Barshop Institute for Longevity & Aging Studies, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7756, San Antonio, TX, 78229, USA
| | - Christopher M Adams
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA
| | - Blake B Rasmussen
- Barshop Institute for Longevity & Aging Studies, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7756, San Antonio, TX, 78229, USA.
- Department of Cellular & Integrative Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7756, San Antonio, TX, 78229, USA.
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Blackwell JEM, Gharahdaghi N, Deane CS, Brook MS, Williams JP, Lund JN, Atherton PJ, Smith K, Wilkinson DJ, Phillips BE. Molecular mechanisms underpinning favourable physiological adaptations to exercise prehabilitation for urological cancer surgery. Prostate Cancer Prostatic Dis 2024; 27:749-755. [PMID: 38110544 PMCID: PMC11543602 DOI: 10.1038/s41391-023-00774-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 11/26/2023] [Accepted: 11/30/2023] [Indexed: 12/20/2023]
Abstract
BACKGROUND Surgery for urological cancers is associated with high complication rates and survivors commonly experience fatigue, reduced physical ability and quality of life. High-intensity interval training (HIIT) as surgical prehabilitation has been proven effective for improving the cardiorespiratory fitness (CRF) of urological cancer patients, however the mechanistic basis of this favourable adaptation is undefined. Thus, we aimed to assess the mechanisms of physiological responses to HIIT as surgical prehabilitation for urological cancer. METHODS Nineteen male patients scheduled for major urological surgery were randomised to complete 4-weeks HIIT prehabilitation (71.6 ± 0.75 years, BMI: 27.7 ± 0.9 kg·m2) or a no-intervention control (71.8 ± 1.1 years, BMI: 26.9 ± 1.3 kg·m2). Before and after the intervention period, patients underwent m. vastus lateralis biopsies to quantify the impact of HIIT on mitochondrial oxidative phosphorylation (OXPHOS) capacity, cumulative myofibrillar muscle protein synthesis (MPS) and anabolic, catabolic and insulin-related signalling. RESULTS OXPHOS capacity increased with HIIT, with increased expression of electron transport chain protein complexes (C)-II (p = 0.010) and III (p = 0.045); and a significant correlation between changes in C-I (r = 0.80, p = 0.003), C-IV (r = 0.75, p = 0.008) and C-V (r = 0.61, p = 0.046) and changes in CRF. Neither MPS (1.81 ± 0.12 to 2.04 ± 0.14%·day-1, p = 0.39) nor anabolic or catabolic proteins were upregulated by HIIT (p > 0.05). There was, however, an increase in phosphorylation of AS160Thr642 (p = 0.046) post-HIIT. CONCLUSIONS A HIIT surgical prehabilitation regime, which improved the CRF of urological cancer patients, enhanced capacity for skeletal muscle OXPHOS; offering potential mechanistic explanation for this favourable adaptation. HIIT did not stimulate MPS, synonymous with the observed lack of hypertrophy. Larger trials pairing patient-centred and clinical endpoints with mechanistic investigations are required to determine the broader impacts of HIIT prehabilitation in this cohort, and to inform on future optimisation (i.e., to increase muscle mass).
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Affiliation(s)
- James E M Blackwell
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research and National Institute for Health Research Nottingham Biomedical Research Centre, School of Medicine, University of Nottingham, Derby, UK
- Department of Surgery & Anaesthetics, Royal Derby Hospital, Derby, UK
| | - Nima Gharahdaghi
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research and National Institute for Health Research Nottingham Biomedical Research Centre, School of Medicine, University of Nottingham, Derby, UK
| | - Colleen S Deane
- Human Development & Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Matthew S Brook
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - John P Williams
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research and National Institute for Health Research Nottingham Biomedical Research Centre, School of Medicine, University of Nottingham, Derby, UK
- Department of Surgery & Anaesthetics, Royal Derby Hospital, Derby, UK
| | - Jonathan N Lund
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research and National Institute for Health Research Nottingham Biomedical Research Centre, School of Medicine, University of Nottingham, Derby, UK
- Department of Surgery & Anaesthetics, Royal Derby Hospital, Derby, UK
| | - Philip J Atherton
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research and National Institute for Health Research Nottingham Biomedical Research Centre, School of Medicine, University of Nottingham, Derby, UK
| | - Ken Smith
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research and National Institute for Health Research Nottingham Biomedical Research Centre, School of Medicine, University of Nottingham, Derby, UK
| | - Daniel J Wilkinson
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research and National Institute for Health Research Nottingham Biomedical Research Centre, School of Medicine, University of Nottingham, Derby, UK
| | - Bethan E Phillips
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research and National Institute for Health Research Nottingham Biomedical Research Centre, School of Medicine, University of Nottingham, Derby, UK.
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Kunutsor SK, Kaminsky LA, Lehoczki A, Laukkanen JA. Unraveling the link between cardiorespiratory fitness and cancer: a state-of-the-art review. GeroScience 2024; 46:5559-5585. [PMID: 38831183 PMCID: PMC11493895 DOI: 10.1007/s11357-024-01222-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 05/24/2024] [Indexed: 06/05/2024] Open
Abstract
Cardiorespiratory fitness (CRF) not only reflects an individual's capacity to perform physical activities but also encapsulates broader effects on the basic biology of aging. This review aims to summarize the evidence on the influence of CRF on overall and site-specific cancer risks. It delves into the biological mechanisms through which CRF may exert its effects, explores the clinical implications of these findings, identifies gaps in the current evidence base, and suggests directions for future research. The synthesis of findings reveals that higher CRF levels (general threshold of > 7 METs) are consistently associated with a reduced risk of a range of cancers, including head and neck, lung, breast, gastrointestinal, particularly pancreatic and colorectal, bladder, overall cancer incidence and mortality, and potentially stomach and liver, bile duct, and gall bladder cancers. These inverse associations between CRF and cancer risk do not generally differ across age groups, sex, race, or adiposity, suggesting a universal protective effect of CRF. Nonetheless, evidence linking CRF with skin, mouth and pharynx, kidney, and endometrial cancers is limited and inconclusive. Conversely, higher CRF levels may be potentially linked to an increased risk of prostate cancer and hematological malignancies, such as leukemia and myeloma, although the evidence is still not conclusive. CRF appears to play a significant role in reducing the risk of several cancers through various biological mechanisms, including inflammation reduction, immune system enhancement, hormonal regulation, and metabolic improvements. Overall, enhancing CRF through regular physical activity offers a vital, accessible strategy for reducing cancer risk and extending the health span. Future research should aim to fill the existing evidence gaps regarding specific cancers and elucidate the detailed dose-response relationships between CRF levels and cancer risk. Studies are also needed to elucidate the causal relationships and mechanistic pathways linking CRF to cancer outcomes.
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Affiliation(s)
- Setor K Kunutsor
- Diabetes Research Centre, Leicester General Hospital, University of Leicester, Leicester, LE5 4WP, UK.
| | - Leonard A Kaminsky
- Clinical Exercise Physiology, College of Health, Ball State University, Muncie, IN, USA
| | - Andrea Lehoczki
- Department of Public Health, Semmelweis University, Budapest, Hungary
- Doctoral College, Health Sciences Program, Semmelweis University, Budapest, Hungary
- Department of Haematology and Stem Cell Transplantation, National Institute for Haematology and Infectious Diseases, South Pest Central Hospital, 1097, Budapest, Hungary
| | - Jari A Laukkanen
- Institute of Clinical Medicine, Department of Medicine, University of Eastern Finland, Kuopio, Finland
- Department of Medicine, Wellbeing Services County of Central Finland, Jyväskylä, Finland
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8
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Molnar T, Lehoczki A, Fekete M, Varnai R, Zavori L, Erdo-Bonyar S, Simon D, Berki T, Csecsei P, Ezer E. Mitochondrial dysfunction in long COVID: mechanisms, consequences, and potential therapeutic approaches. GeroScience 2024; 46:5267-5286. [PMID: 38668888 PMCID: PMC11336094 DOI: 10.1007/s11357-024-01165-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 04/15/2024] [Indexed: 08/22/2024] Open
Abstract
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has introduced the medical community to the phenomenon of long COVID, a condition characterized by persistent symptoms following the resolution of the acute phase of infection. Among the myriad of symptoms reported by long COVID sufferers, chronic fatigue, cognitive disturbances, and exercise intolerance are predominant, suggesting systemic alterations beyond the initial viral pathology. Emerging evidence has pointed to mitochondrial dysfunction as a potential underpinning mechanism contributing to the persistence and diversity of long COVID symptoms. This review aims to synthesize current findings related to mitochondrial dysfunction in long COVID, exploring its implications for cellular energy deficits, oxidative stress, immune dysregulation, metabolic disturbances, and endothelial dysfunction. Through a comprehensive analysis of the literature, we highlight the significance of mitochondrial health in the pathophysiology of long COVID, drawing parallels with similar clinical syndromes linked to post-infectious states in other diseases where mitochondrial impairment has been implicated. We discuss potential therapeutic strategies targeting mitochondrial function, including pharmacological interventions, lifestyle modifications, exercise, and dietary approaches, and emphasize the need for further research and collaborative efforts to advance our understanding and management of long COVID. This review underscores the critical role of mitochondrial dysfunction in long COVID and calls for a multidisciplinary approach to address the gaps in our knowledge and treatment options for those affected by this condition.
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Affiliation(s)
- Tihamer Molnar
- Department of Anaesthesiology and Intensive Care, Medical School, University of Pecs, Pecs, Hungary
| | - Andrea Lehoczki
- Doctoral College, Health Sciences Program, Semmelweis University, Budapest, Hungary
- Department of Haematology and Stem Cell Transplantation, National Institute for Haematology and Infectious Diseases, South Pest Central Hospital, 1097, Budapest, Hungary
- Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Monika Fekete
- Department of Public Health, Semmelweis University, Budapest, Hungary
| | - Reka Varnai
- Department of Primary Health Care, Medical School University of Pecs, Pecs, Hungary
| | | | - Szabina Erdo-Bonyar
- Department of Immunology and Biotechnology, Medical School, University of Pecs, Pecs, Hungary
| | - Diana Simon
- Department of Immunology and Biotechnology, Medical School, University of Pecs, Pecs, Hungary
| | - Tímea Berki
- Department of Immunology and Biotechnology, Medical School, University of Pecs, Pecs, Hungary
| | - Peter Csecsei
- Department of Neurosurgery, Medical School, University of Pecs, Ret U 2, 7624, Pecs, Hungary.
| | - Erzsebet Ezer
- Department of Anaesthesiology and Intensive Care, Medical School, University of Pecs, Pecs, Hungary
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9
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Szilágyi A, Takács B, Szekeres R, Tarjányi V, Nagy D, Priksz D, Bombicz M, Kiss R, Szabó AM, Lehoczki A, Gesztelyi R, Juhász B, Szilvássy Z, Varga B. Effects of voluntary and forced physical exercise on the retinal health of aging Wistar rats. GeroScience 2024; 46:4707-4728. [PMID: 38795184 PMCID: PMC11336036 DOI: 10.1007/s11357-024-01208-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 05/13/2024] [Indexed: 05/27/2024] Open
Abstract
Aging is accompanied by an increased prevalence of degenerative conditions, including those affecting ocular health, which significantly impact quality of life and increase the burden on healthcare systems. Among these, retinal aging is of particular concern due to its direct link to vision impairment, a leading cause of disability in the elderly. Vision loss in the aging population is associated with heightened risks of cognitive decline, social isolation, and morbidity. This study addresses the critical gap in our understanding of modifiable lifestyle factors, such as physical exercise, that may mitigate retinal aging and its related pathologies. We investigated the effects of different exercise regimens-voluntary (recreational-type) and forced (high-intensity)-on the retinal health of aging Wistar rats (18-month-old), serving as a model for studying the translational potential of exercise interventions in humans. Male Wistar rats were divided into four groups: a young control (3-month-old) for baseline comparison, an aged sedentary control, an aged group engaging in voluntary exercise via a running wheel in their cage, and an aged group subjected to forced exercise on a treadmill for six sessions of 20 min each per week. After a 6-month experimental period, we assessed retinal function via electroretinography (ERG), measured retinal thickness histologically, and analyzed protein expression changes relevant to oxidative stress, inflammation, and anti-aging mechanisms. Our findings reveal that voluntary exercise positively impacts retinal function and morphology, reducing oxidative stress and inflammation markers while enhancing anti-aging protein expression. In contrast, forced exercise showed diminished benefits. These insights underscore the importance of exercise intensity and preference in preserving retinal health during aging. The study highlights the potential of recreational physical activity as a non-invasive strategy to counteract retinal aging, advocating for further research into exercise regimens as preventative therapies for age-related ocular degenerations.
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Affiliation(s)
- Anna Szilágyi
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei Krt 98., 4032, Debrecen, Hungary
| | - Barbara Takács
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei Krt 98., 4032, Debrecen, Hungary
| | - Réka Szekeres
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei Krt 98., 4032, Debrecen, Hungary
| | - Vera Tarjányi
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei Krt 98., 4032, Debrecen, Hungary
| | - Dávid Nagy
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei Krt 98., 4032, Debrecen, Hungary
| | - Dániel Priksz
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei Krt 98., 4032, Debrecen, Hungary
| | - Mariann Bombicz
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei Krt 98., 4032, Debrecen, Hungary
| | - Rita Kiss
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei Krt 98., 4032, Debrecen, Hungary
| | - Adrienn Mónika Szabó
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei Krt 98., 4032, Debrecen, Hungary
| | - Andrea Lehoczki
- Departments of Hematology and Stem Cell Transplantation, South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Saint Ladislaus Campus, Budapest, Hungary
- Department of Public Health, Semmelweis University, Budapest, Hungary
- Doctoral College, Health Sciences Program, Semmelweis University, Budapest, Hungary
| | - Rudolf Gesztelyi
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei Krt 98., 4032, Debrecen, Hungary
| | - Béla Juhász
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei Krt 98., 4032, Debrecen, Hungary
| | - Zoltán Szilvássy
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei Krt 98., 4032, Debrecen, Hungary
| | - Balázs Varga
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Debrecen, Nagyerdei Krt 98., 4032, Debrecen, Hungary.
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10
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Pabla P, Jones E, Piasecki M, Phillips B. Skeletal muscle dysfunction with advancing age. Clin Sci (Lond) 2024; 138:863-882. [PMID: 38994723 PMCID: PMC11250095 DOI: 10.1042/cs20231197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 06/15/2024] [Accepted: 06/20/2024] [Indexed: 07/13/2024]
Abstract
As a result of advances in medical treatments and associated policy over the last century, life expectancy has risen substantially and continues to increase globally. However, the disconnect between lifespan and 'health span' (the length of time spent in a healthy, disease-free state) has also increased, with skeletal muscle being a substantial contributor to this. Biological ageing is accompanied by declines in both skeletal muscle mass and function, termed sarcopenia. The mechanisms underpinning sarcopenia are multifactorial and are known to include marked alterations in muscle protein turnover and adaptations to the neural input to muscle. However, to date, the relative contribution of each factor remains largely unexplored. Specifically, muscle protein synthetic responses to key anabolic stimuli are blunted with advancing age, whilst alterations to neural components, spanning from the motor cortex and motoneuron excitability to the neuromuscular junction, may explain the greater magnitude of function losses when compared with mass. The consequences of these losses can be devastating for individuals, their support networks, and healthcare services; with clear detrimental impacts on both clinical (e.g., mortality, frailty, and post-treatment complications) and societal (e.g., independence maintenance) outcomes. Whether declines in muscle quantity and quality are an inevitable component of ageing remains to be completely understood. Nevertheless, strategies to mitigate these declines are of vital importance to improve the health span of older adults. This review aims to provide an overview of the declines in skeletal muscle mass and function with advancing age, describes the wide-ranging implications of these declines, and finally suggests strategies to mitigate them, including the merits of emerging pharmaceutical agents.
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Affiliation(s)
- Pardeep Pabla
- Centre of Metabolism, Ageing and Physiology (COMAP), School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, DE22 3DT, U.K
| | - Eleanor J. Jones
- Centre of Metabolism, Ageing and Physiology (COMAP), School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, DE22 3DT, U.K
| | - Mathew Piasecki
- Centre of Metabolism, Ageing and Physiology (COMAP), School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, DE22 3DT, U.K
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research (CMAR), U.K
- NIHR Nottingham Biomedical Research Centre (BRC), U.K
| | - Bethan E. Phillips
- Centre of Metabolism, Ageing and Physiology (COMAP), School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, DE22 3DT, U.K
- MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research (CMAR), U.K
- NIHR Nottingham Biomedical Research Centre (BRC), U.K
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11
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Miller MJ, Gries KJ, Marcotte GR, Ryan Z, Strub MD, Kunz HE, Arendt BK, Dasari S, Ebert SM, Adams CM, Lanza IR. Human myofiber-enriched aging-induced lncRNA FRAIL1 promotes loss of skeletal muscle function. Aging Cell 2024; 23:e14097. [PMID: 38297807 PMCID: PMC11019130 DOI: 10.1111/acel.14097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 01/11/2024] [Accepted: 01/13/2024] [Indexed: 02/02/2024] Open
Abstract
The loss of skeletal muscle mass during aging is a significant health concern linked to adverse outcomes in older individuals. Understanding the molecular basis of age-related muscle loss is crucial for developing strategies to combat this debilitating condition. Long noncoding RNAs (lncRNAs) are a largely uncharacterized class of biomolecules that have been implicated in cellular homeostasis and dysfunction across a many tissues and cell types. To identify lncRNAs that might contribute to skeletal muscle aging, we screened for lncRNAs whose expression was altered in vastus lateralis muscle from older compared to young adults. We identified FRAIL1 as an aging-induced lncRNA with high abundance in human skeletal muscle. In healthy young and older adults, skeletal muscle FRAIL1 was increased with age in conjunction with lower muscle function. Forced expression of FRAIL1 in mouse tibialis anterior muscle elicits a dose-dependent reduction in skeletal muscle fiber size that is independent of changes in muscle fiber type. Furthermore, this reduction in muscle size is dependent on an intact region of FRAIL1 that is highly conserved across non-human primates. Unbiased transcriptional and proteomic profiling of the effects of FRAIL1 expression in mouse skeletal muscle revealed widespread changes in mRNA and protein abundance that recapitulate age-related changes in pathways and processes that are known to be altered in aging skeletal muscle. Taken together, these findings shed light on the intricate molecular mechanisms underlying skeletal muscle aging and implicate FRAIL1 in age-related skeletal muscle phenotypes.
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Affiliation(s)
- Matthew J. Miller
- Division of EndocrinologyMayo ClinicRochesterMinnesotaUSA
- University of IowaIowa CityIowaUSA
| | | | - George R. Marcotte
- Division of EndocrinologyMayo ClinicRochesterMinnesotaUSA
- University of IowaIowa CityIowaUSA
| | - Zachary Ryan
- Division of EndocrinologyMayo ClinicRochesterMinnesotaUSA
| | | | - Hawley E. Kunz
- Division of EndocrinologyMayo ClinicRochesterMinnesotaUSA
| | | | - Surendra Dasari
- Department of Quantitative Health SciencesMayo ClinicRochesterMinnesotaUSA
| | - Scott M. Ebert
- Division of EndocrinologyMayo ClinicRochesterMinnesotaUSA
- Emmyon, Inc.RochesterMinnesotaUSA
| | - Christopher M. Adams
- Division of EndocrinologyMayo ClinicRochesterMinnesotaUSA
- Emmyon, Inc.RochesterMinnesotaUSA
| | - Ian R. Lanza
- Division of EndocrinologyMayo ClinicRochesterMinnesotaUSA
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12
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Gonzalez-Armenta JL, Bergstrom J, Lee J, Furdui CM, Nicklas BJ, Molina AJA. Serum factors mediate changes in mitochondrial bioenergetics associated with diet and exercise interventions. GeroScience 2024; 46:349-365. [PMID: 37368157 PMCID: PMC10828137 DOI: 10.1007/s11357-023-00855-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 06/15/2023] [Indexed: 06/28/2023] Open
Abstract
Mitochondrial improvements resulting from behavioral interventions, such as diet and exercise, are systemic and apparent across multiple tissues. Here, we test the hypothesis that factors present in serum, and therefore circulating throughout the body, can mediate changes in mitochondrial function in response to intervention. To investigate this, we used stored serum from a clinical trial comparing resistance training (RT) and RT plus caloric restriction (RT + CR) to examine effects of blood borne circulating factors on myoblasts in vitro. We report that exposure to dilute serum is sufficient to mediate bioenergetic benefits of these interventions. Additionally, serum-mediated bioenergetic changes can differentiate between interventions, recapitulate sex differences in bioenergetic responses, and is linked to improvements in physical function and inflammation. Using metabolomics, we identified circulating factors associated with changes in mitochondrial bioenergetics and the effects of interventions. This study provides new evidence that circulating factors play a role in the beneficial effects of interventions that improve healthspan among older adults. Understanding the factors that drive improvements in mitochondrial function is a key step towards predicting intervention outcomes and developing strategies to countermand systemic age-related bioenergetic decline.
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Affiliation(s)
- Jenny L Gonzalez-Armenta
- Section On Gerontology and Geriatrics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Jaclyn Bergstrom
- Division of Geriatrics, Gerontology, and Palliative Care, Department of Medicine, University of California San Diego School of Medicine, 9500 Gilman Drive, MC 0665, La Jolla, CA, 92093-0665, USA
| | - Jingyun Lee
- Proteomics and Metabolomics Shared Resource, Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Cristina M Furdui
- Section On Molecular Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Barbara J Nicklas
- Section On Gerontology and Geriatrics, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Anthony J A Molina
- Division of Geriatrics, Gerontology, and Palliative Care, Department of Medicine, University of California San Diego School of Medicine, 9500 Gilman Drive, MC 0665, La Jolla, CA, 92093-0665, USA.
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13
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Ungvari Z, Fazekas-Pongor V, Csiszar A, Kunutsor SK. The multifaceted benefits of walking for healthy aging: from Blue Zones to molecular mechanisms. GeroScience 2023; 45:3211-3239. [PMID: 37495893 PMCID: PMC10643563 DOI: 10.1007/s11357-023-00873-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 07/11/2023] [Indexed: 07/28/2023] Open
Abstract
Physical activity, including walking, has numerous health benefits in older adults, supported by a plethora of observational and interventional studies. Walking decreases the risk or severity of various health outcomes such as cardiovascular and cerebrovascular diseases, type 2 diabetes mellitus, cognitive impairment and dementia, while also improving mental well-being, sleep, and longevity. Dose-response relationships for walking duration and intensity are established for adverse cardiovascular outcomes. Walking's favorable effects on cardiovascular risk factors are attributed to its impact on circulatory, cardiopulmonary, and immune function. Meeting current physical activity guidelines by walking briskly for 30 min per day for 5 days can reduce the risk of several age-associated diseases. Additionally, low-intensity physical exercise, including walking, exerts anti-aging effects and helps prevent age-related diseases, making it a powerful tool for promoting healthy aging. This is exemplified by the lifestyles of individuals in Blue Zones, regions of the world with the highest concentration of centenarians. Walking and other low-intensity physical activities contribute significantly to the longevity of individuals in these regions, with walking being an integral part of their daily lives. Thus, incorporating walking into daily routines and encouraging walking-based physical activity interventions can be an effective strategy for promoting healthy aging and improving health outcomes in all populations. The goal of this review is to provide an overview of the vast and consistent evidence supporting the health benefits of physical activity, with a specific focus on walking, and to discuss the impact of walking on various health outcomes, including the prevention of age-related diseases. Furthermore, this review will delve into the evidence on the impact of walking and low-intensity physical activity on specific molecular and cellular mechanisms of aging, providing insights into the underlying biological mechanisms through which walking exerts its beneficial anti-aging effects.
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Affiliation(s)
- Zoltan Ungvari
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary.
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
| | | | - Anna Csiszar
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Setor K Kunutsor
- Diabetes Research Centre, University of Leicester, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4WP, UK.
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14
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Ruegsegger GN, Pataky MW, Simha S, Robinson MM, Klaus KA, Nair KS. High-intensity aerobic, but not resistance or combined, exercise training improves both cardiometabolic health and skeletal muscle mitochondrial dynamics. J Appl Physiol (1985) 2023; 135:763-774. [PMID: 37616334 PMCID: PMC10642518 DOI: 10.1152/japplphysiol.00405.2023] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 08/26/2023] Open
Abstract
This study investigated how different exercise training modalities influence skeletal muscle mitochondrial dynamics. Healthy [average body mass index (BMI): 25.8 kg/m2], sedentary younger and older participants underwent 12 wk of supervised high-intensity aerobic interval training (HIIT; n = 13), resistance training (RT; n = 14), or combined training (CT; n = 11). Mitochondrial structure was assessed using transmission electron microscopy (TEM). Regulators of mitochondrial fission and fusion, cardiorespiratory fitness (V̇o2peak), insulin sensitivity via a hyperinsulinemic-euglycemic clamp, and muscle mitochondrial respiration were assessed. TEM showed increased mitochondrial volume, number, and perimeter following HIIT (P < 0.01), increased mitochondrial number following CT (P < 0.05), and no change in mitochondrial abundance after RT. Increased mitochondrial volume associated with increased mitochondrial respiration and insulin sensitivity following HIIT (P < 0.05). Increased mitochondrial perimeter associated with increased mitochondrial respiration, insulin sensitivity, and V̇o2peak following HIIT (P < 0.05). No such relationships were observed following CT or RT. OPA1, a regulator of fusion, was increased following HIIT (P < 0.05), whereas FIS1, a regulator of fission, was decreased following HIIT and CT (P < 0.05). HIIT also increased the ratio of OPA1/FIS1 (P < 0.01), indicative of the balance between fission and fusion, which positively correlated with improvements in respiration, insulin sensitivity, and V̇o2peak (P < 0.05). In conclusion, HIIT induces a larger, more fused mitochondrial tubular network. Changes indicative of increased fusion following HIIT associate with improvements in mitochondrial respiration, insulin sensitivity, and V̇o2peak supporting the idea that enhanced mitochondrial fusion accompanies notable health benefits of HIIT.NEW & NOTEWORTHY We assessed the effects of 12 wk of supervised high-intensity interval training (HIIT), resistance training, and combined training (CT) on skeletal muscle mitochondrial abundance and markers of fission and fusion. HIIT increased mitochondrial area and size and promoted protein changes indicative of increased mitochondrial fusion, whereas lessor effects were observed after CT and no changes were observed after RT. Furthermore, increased mitochondrial area and size after HIIT associated with improved mitochondrial respiration, cardiorespiratory fitness, and insulin sensitivity.
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Affiliation(s)
- Gregory N Ruegsegger
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, United States
- Department of Health and Human Performance, University of Wisconsin-River Falls, River Falls, Wisconsin, United States
| | - Mark W Pataky
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, United States
| | - Suvyaktha Simha
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, United States
| | - Matthew M Robinson
- School of Biological and Population Health Sciences, College of Public Health and Human Sciences, Oregon State University, Corvallis, Oregon, United States
| | - Katherine A Klaus
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, United States
| | - K Sreekumaran Nair
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, United States
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15
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Lindner R, Raj IS, Yang AWH, Zaman S, Larsen B, Denham J. Moderate to Vigorous-intensity Continuous Training versus High-intensity Interval Training for improving VO2max in women: A systematic review and meta-analysis. Int J Sports Med 2023. [PMID: 37084758 DOI: 10.1055/a-2044-8952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/23/2023]
Abstract
Traditional continuous training and high-intensity interval training (HIIT) can increase maximal oxygen uptake (V̇O2max). However, there is conflicting evidence regarding which form of training demonstrates the greatest improvements to V̇O2max, and data in women is sparse. We conducted a systematic review and meta-analyses to assess whether moderate to vigorous-intensity continuous training (MVICT) or HIIT was superior at improving V̇O2max in women. Randomised controlled and parallel studies examined the influence of MVICT and/or HIIT on V̇O2max in women. There was no statistical difference in V̇O2max improvements after training between women in the MVICT and HIIT cohorts (mean difference [MD]: -0.42, 95%CI: -1.43 to 0.60, p>0.05). Both MVICT and HIIT increased V̇O2max from baseline (MD: 3.20, 95% CI: 2.73 to 3.67 and MD: 3.16, 95% CI 2.09 to 4.24, respectively, p<0.001). Greater improvements in V̇O2max were observed in women who participated in more training sessions in both training formats. Long-HIIT was superior to short-HIIT protocols at increasing V̇O2max. Although MVICT and long-HIIT sessions elicited greater increases in V̇O2max in younger women compared to short-HIIT protocols, these differences were negligible in older women. Our findings suggest MVICT and HIIT are equally effective strategies for improving V̇O2max and indicate an effect of age on its response to training in women.
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Affiliation(s)
- Robert Lindner
- School of Health and Biomedical Sciences, RMIT University, Melbourne, Australia
| | - Isaac Selva Raj
- School of Health and Biomedical Sciences, RMIT University, Melbourne, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia
| | | | - Shadman Zaman
- School of Health and Biomedical Sciences, RMIT University, Melbourne, Australia
| | - Brianna Larsen
- School of Health and Medical Sciences, University of Southern Queensland, Toowoomba, Australia
- Institute for Resilient Regions Centre, Centre for Health Research, Toowoomba, Queensland, Australia
| | - Joshua Denham
- School of Health and Biomedical Sciences, RMIT University, Melbourne, Australia
- School of Health and Medical Sciences, University of Southern Queensland, Toowoomba, Australia
- Institute for Resilient Regions Centre, Centre for Health Research, Toowoomba, Queensland, Australia
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16
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Sumransub N, Cao Q, Juckett M, Betts B, Holtan S, Jurdi NE, Hu M, Allred J, Assi R, Maakaron JE. Sarcopenia Predicts Inferior Progression-Free Survival in Lymphoma Patients Treated with Autologous Hematopoietic Stem Cell Transplantation. Transplant Cell Ther 2023; 29:263.e1-263.e7. [PMID: 36682471 DOI: 10.1016/j.jtct.2023.01.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 01/12/2023] [Accepted: 01/15/2023] [Indexed: 01/21/2023]
Abstract
Autologous hematopoietic stem cell transplantation (ASCT) improves survival for patients with chemotherapy-sensitive lymphoma. Validated scoring systems are used in the clinical setting to predict treatment toxicity and survival; however, complications related to disease and treatment still occur, highlighting challenges in optimal patient selection and the need for novel predictors. Analysis of body composition and muscle mass can provide an objective assessment to identify vulnerable populations, as sarcopenia and frailty have been reported to predict outcomes in other tumor types. In this retrospective cohort study of patients undergoing ASCT for lymphoma, we investigated associations of sarcopenia with clinically significant outcomes, including overall survival (OS) and progression-free survival (PFS). Computed tomography (CT) images of 78 patients obtained routinely pretransplantation were used to assess skeletal muscle mass and are reported as skeletal muscle index (SMI). OS, PFS, and clinical outcomes of interest were compared between groups. Twenty-seven patients (34.6%) in the cohort met the criteria for sarcopenia. Patients with sarcopenia had a significantly shorter 3-year PFS (59% [95% confidence interval (CI), 38% to 75%] versus 84% [95% CI, 71% to 92%]; P = .02) after 3 years of follow up, whereas there was no difference in OS between patients with and those without sarcopenia (78% [95% CI, 57% to 89%] versus 88% [95% CI, 76% to 95%]; P = .25). Interestingly, no difference in survival was found with stratification based on the Karnofsky Performance Scale or Hematopoietic Cell Transplantation-Specific Comorbidity Index. There also were no significant between-group differences in length of hospital stay and the incidences of other clinical outcomes of interest, including febrile neutropenia, mucositis, total parenteral nutrition requirement, acute kidney injury, rate of readmission, or intensive care unit admission. This is the first study to our knowledge to correlate sarcopenia with disease control and PFS after ASCT in lymphoma. Possible explanations include a higher rate of chemotherapy-related toxicity, leading to disruptions of treatment as well as dysfunction of antitumor immunity secondary to impaired regulations from myokines from the loss of muscle mass or an unknown cause that is yet to be elucidated. Physical therapy programs and personalized regimens for treatment based on the analysis of body composition indices can be further studied and implemented to mitigate treatment-related toxicity and to optimize survival in patients with sarcopenia.
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Affiliation(s)
| | - Qing Cao
- Biostatistics and Informatics, Clinical and Translational Science Institute, University of Minnesota, Minneapolis, Minnesota
| | - Mark Juckett
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Brian Betts
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Shernan Holtan
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Najla El Jurdi
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Marie Hu
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Jeremy Allred
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Rita Assi
- Division of Hematology and Oncology, Department of Medicine, Stony Brook University Hospital, Stony Brook, New York
| | - Joseph E Maakaron
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
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17
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Sun S, Ma S, Cai Y, Wang S, Ren J, Yang Y, Ping J, Wang X, Zhang Y, Yan H, Li W, Esteban CR, Yu Y, Liu F, Izpisua Belmonte JC, Zhang W, Qu J, Liu GH. A single-cell transcriptomic atlas of exercise-induced anti-inflammatory and geroprotective effects across the body. Innovation (N Y) 2023; 4:100380. [PMID: 36747595 PMCID: PMC9898793 DOI: 10.1016/j.xinn.2023.100380] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Accepted: 01/02/2023] [Indexed: 01/07/2023] Open
Abstract
Exercise benefits the whole organism, yet, how tissues across the body orchestrally respond to exercise remains enigmatic. Here, in young and old mice, with or without exercise, and exposed to infectious injury, we characterized the phenotypic and molecular adaptations to a 12-month exercise across 14 tissues/organs at single-cell resolution. Overall, exercise protects tissues from infectious injury, although more effectively in young animals, and benefits aged individuals in terms of inflammaging suppression and tissue rejuvenation, with structural improvement in the central nervous system and systemic vasculature being the most prominent. In vascular endothelial cells, we found that readjusting the rhythmic machinery via the core circadian clock protein BMAL1 delayed senescence and facilitated recovery from infectious damage, recapitulating the beneficial effects of exercise. Our study underscores the effect of exercise in reconstituting the youthful circadian clock network and provides a foundation for further investigating the interplay between exercise, aging, and immune challenges across the whole organism.
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Affiliation(s)
- Shuhui Sun
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Shuai Ma
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Yusheng Cai
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Si Wang
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Jie Ren
- Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- China National Center for Bioinformation, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuanhan Yang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jiale Ping
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- China National Center for Bioinformation, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xuebao Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yiyuan Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Haoteng Yan
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | - Wei Li
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Beijing Municipal Geriatric Medical Research Center, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
| | | | - Yan Yu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Feifei Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | | | - Weiqi Zhang
- Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- China National Center for Bioinformation, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
- Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
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18
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van Diemen MPJ, Ziagkos D, Kruizinga MD, Bénard MR, Lambrechtse P, Jansen JAJ, Snoeker BAM, Gademan MGJ, Cohen AF, Nelissen RGHH, Groeneveld GJ. Mitochondrial function, grip strength, and activity are related to recovery of mobility after a total knee arthroplasty. Clin Transl Sci 2022; 16:224-235. [PMID: 36401590 PMCID: PMC9926084 DOI: 10.1111/cts.13441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/09/2022] [Accepted: 10/14/2022] [Indexed: 11/21/2022] Open
Abstract
Low muscle quality and a sedentary lifestyle are indicators for a slow recovery after a total knee arthroplasty (TKA). Mitochondrial function is an important part of muscle quality and a key driver of sarcopenia. However, it is not known whether it relates to recovery. In this pilot study, we monitored activity after TKA using a wrist mounted activity tracker and assessed the relation of mitochondrial function on the rate of recovery after TKA. Additionally, we compared the increase in activity as a way to measure recovery to traditional outcome measures. Patients were studied 2 weeks before TKA and up to 6 months after. Activity was monitored continuously. Baseline mitochondrial function (citrate synthase and complex [CP] 1-5 abundance of the electron transport chain) was determined on muscle tissue taken during TKA. Traditional outcome measures (Knee Injury and Osteoarthritis Outcome Score [KOOS], timed up-and-go [TUG] completion time, grip, and quadriceps strength) were performed 2 weeks before, 6 weeks after, and 6 months after TKA. Using a multivariate regression model with various clinical baseline parameters, the following were significantly related to recovery: CP5 abundance, grip strength, and activity (regression weights 0.13, 0.02, and 2.89, respectively). During recovery, activity correlated to the KOOS-activities of daily living (ADL) score (r = 0.55, p = 0.009) and TUG completion time (r = -0.61, p = 0.001). Mitochondrial function seems to be related to recovery, but so are activity and grip strength, all indicators of sarcopenia. Using activity trackers before and after TKA might give the surgeon valuable information on the expected recovery and the opportunity to intervene if recovery is low.
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Affiliation(s)
- Marcus P. J. van Diemen
- Centre for Human Drug ResearchLeidenThe Netherlands,Department of OrthopedicsLeiden University Medical CenterLeidenThe Netherlands
| | | | | | - Menno R. Bénard
- Department of OrthopedicsAlrijne HospitalLeidenThe Netherlands
| | | | | | | | - Maaike G. J. Gademan
- Department of OrthopedicsLeiden University Medical CenterLeidenThe Netherlands,Department of Clinical EpidemiologyLeiden University Medical CenterLeidenThe Netherlands
| | - Adam F. Cohen
- Centre for Human Drug ResearchLeidenThe Netherlands,Department of NephrologyLeiden University Medical CenterLeidenThe Netherlands
| | | | - Geert Jan Groeneveld
- Centre for Human Drug ResearchLeidenThe Netherlands,Department of AnesthesiologyLeiden University Medical CenterLeidenThe Netherlands
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19
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Salmón P, Millet C, Selman C, Monaghan P, Dawson NJ. Tissue-specific reductions in mitochondrial efficiency and increased ROS release rates during ageing in zebra finches, Taeniopygia guttata. GeroScience 2022; 45:265-276. [PMID: 35986126 PMCID: PMC9886749 DOI: 10.1007/s11357-022-00624-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 07/11/2022] [Indexed: 02/03/2023] Open
Abstract
Mitochondrial dysfunction and oxidative damage have long been suggested as critically important mechanisms underlying the ageing process in animals. However, conflicting data exist on whether this involves increased production of mitochondrial reactive oxygen species (ROS) during ageing. We employed high-resolution respirometry and fluorometry on flight muscle (pectoralis major) and liver mitochondria to simultaneously examine mitochondrial function and ROS (H2O2) release rates in young (3 months) and old (4 years) zebra finches (Taeniopygia guttata). Respiratory capacities for oxidative phosphorylation did not differ between the two age groups in either tissue. Respiratory control ratios (RCR) of liver mitochondria also did not differ between the age classes. However, RCR in muscle mitochondria was 55% lower in old relative to young birds, suggesting that muscle mitochondria in older individuals are less efficient. Interestingly, this observed reduction in muscle RCR was driven almost entirely by higher mitochondrial LEAK-state respiration. Maximum mitochondrial ROS release rates were found to be greater in both flight muscle (1.3-fold) and the liver (1.9-fold) of old birds. However, while maximum ROS (H2O2) release rates from mitochondria increased with age across both liver and muscle tissues, the liver demonstrated a proportionally greater age-related increase in ROS release than muscle. This difference in age-related increases in ROS release rates between muscle and liver tissues may be due to increased mitochondrial leakiness in the muscle, but not the liver, of older birds. This suggests that age-related changes in cellular function seem to occur in a tissue-specific manner in zebra finches, with flight muscle exhibiting signs of minimising age-related increase in ROS release, potentially to reduce damage to this crucial tissue in older individuals.
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Affiliation(s)
- Pablo Salmón
- School of Biodiversity, One Health and Veterinary Medicine, University of Glasgow, Graham Kerr Building, Glasgow, G12 8QQ, UK.
| | - Caroline Millet
- School of Biodiversity, One Health and Veterinary Medicine, University of Glasgow, Graham Kerr Building, Glasgow, G12 8QQ UK
| | - Colin Selman
- School of Biodiversity, One Health and Veterinary Medicine, University of Glasgow, Graham Kerr Building, Glasgow, G12 8QQ UK
| | - Pat Monaghan
- School of Biodiversity, One Health and Veterinary Medicine, University of Glasgow, Graham Kerr Building, Glasgow, G12 8QQ UK
| | - Neal J. Dawson
- School of Biodiversity, One Health and Veterinary Medicine, University of Glasgow, Graham Kerr Building, Glasgow, G12 8QQ UK
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20
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Palmer AK, Jensen MD. Metabolic changes in aging humans: current evidence and therapeutic strategies. J Clin Invest 2022; 132:158451. [PMID: 35968789 PMCID: PMC9374375 DOI: 10.1172/jci158451] [Citation(s) in RCA: 109] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Aging and metabolism are inextricably linked, and many age-related changes in body composition, including increased central adiposity and sarcopenia, have underpinnings in fundamental aging processes. These age-related changes are further exacerbated by a sedentary lifestyle and can be in part prevented by maintenance of activity with aging. Here we explore the age-related changes seen in individual metabolic tissues - adipose, muscle, and liver - as well as globally in older adults. We also discuss the available evidence for therapeutic interventions such as caloric restriction, resistance training, and senolytic and senomorphic drugs to maintain healthy metabolism with aging, focusing on data from human studies.
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Affiliation(s)
| | - Michael D. Jensen
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA
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21
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Kim YJ, Moon S, Yu JM, Chung HS. Implication of diet and exercise on the management of age‐related sarcopenic obesity in Asians. Geriatr Gerontol Int 2022; 22:695-704. [PMID: 35871525 PMCID: PMC9544230 DOI: 10.1111/ggi.14442] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 05/25/2022] [Accepted: 06/28/2022] [Indexed: 11/30/2022]
Abstract
The incidence of sarcopenic obesity among adults aged ≥65 years is rising worldwide. Sarcopenic obesity is a high‐risk geriatric syndrome defined as a gain in the amount of adipose tissue along with the age‐related loss of muscle mass and strength or physical performance. Sarcopenic obesity is associated with increased risks of falls, physical limitations, cardiovascular diseases, metabolic diseases, and/or mortality. Thus, the identification of preventive and treatment strategies against sarcopenic obesity is important for healthy aging. Diet and exercise are the reasons for the development of sarcopenic obesity and are key targets in its prevention and treatment. Regarding weight reduction alone, it is most effective to maintain a negative energy balance with dietary calorie restriction and aerobic exercise. However, it is important to preserve skeletal muscle mass while reducing fat mass. Resistance exercise and appropriate protein supply are the main ways of preserving skeletal muscle mass, as well as muscle function. Therefore, in order to improve sarcopenic obesity, a complex treatment strategy is needed to limit energy ingestion with proper nutrition and to increase multimodal exercises. In this review, we focus on recently updated interventions for diet and exercise and potential future management strategies for Asian individuals with aging‐related sarcopenic obesity. Geriatr Gerontol Int 2022; 22: 695–704.
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Affiliation(s)
- Yoon Jung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangnam Sacred Heart Hospital College of Medicine, Hallym University Seoul South Korea
| | - Shinje Moon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangnam Sacred Heart Hospital College of Medicine, Hallym University Seoul South Korea
| | - Jae Myung Yu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangnam Sacred Heart Hospital College of Medicine, Hallym University Seoul South Korea
| | - Hye Soo Chung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangnam Sacred Heart Hospital College of Medicine, Hallym University Seoul South Korea
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22
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Huang H, Zhao Y. Effect of clove on improving running ability in aging mice. J Food Biochem 2022; 46:e14339. [DOI: 10.1111/jfbc.14339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 06/16/2022] [Accepted: 06/28/2022] [Indexed: 11/29/2022]
Affiliation(s)
- Haifeng Huang
- Department of Physical Education South China Agricultural University Guangzhou China
| | - Yan Zhao
- Department of Physical Education South China Agricultural University Guangzhou China
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23
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Abstract
The Exercise Boom of the 1970's resulted in the adoption of habitual exercise in a significant portion of the population. Many of these individuals are defying the cultural norms by remaining physically active and competing at a high level in their later years. The juxtaposition between masters athletes and non-exercisers demonstrate the importance of remaining physically active throughout the lifespan on physiological systems related to healthspan (years of healthy living). This includes ~50% improved maximal aerobic capacity (VO2max) and enhanced skeletal muscle health (size, function, as well as metabolic and communicative properties) compared to non-exercisers at a similar age. By taking a reductionist approach to VO2max and skeletal muscle health, we can gain insight into how aging and habitual exercise affects the aging process. Collectively, this review provides a physiological basis for the elite performances seen in masters athletes, as well as the health implications of lifelong exercise with a focus on VO2max, skeletal muscle metabolic fitness, whole muscle size and function, single muscle fiber physiology, and communicative properties of skeletal muscle. This review has significant public health implications due to the potent health benefits of habitual exercise across the lifespan.
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Affiliation(s)
- Kevin J Gries
- Exercise and Sports Science, Marian University, Indianapolis, United States
| | - S W Trappe
- Human Performance Laboratory, Ball State University, Muncie, United States
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24
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WU J, CHEN H, WANG D, ZHAO X. Effect of Clerodendranthus spicatus (Thunb.) C. Y. Wu on the exercise ability of D-galactose-induced oxidative aging mice. FOOD SCIENCE AND TECHNOLOGY 2022. [DOI: 10.1590/fst.09822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
| | | | - Dan WANG
- China University of Geosciences, China
| | - Xin ZHAO
- Chongqing University of Education, China
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25
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The Effect of a Single Bout of Exercise on Vitamin B2 Status Is Not Different between High- and Low-Fit Females. Nutrients 2021; 13:nu13114097. [PMID: 34836352 PMCID: PMC8618623 DOI: 10.3390/nu13114097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/11/2021] [Accepted: 11/12/2021] [Indexed: 12/05/2022] Open
Abstract
High-fitness individuals have been suggested to be at risk of a poor vitamin B2 (riboflavin) status due to a potentially higher vitamin B2 demand, as measured by the erythrocyte glutathione reductase (EGR) activation coefficient (EGRAC). Longer-term exercise interventions have been shown to result in a lower vitamin B2 status, but studies are contradictory. Short-term exercise effects potentially contribute to discrepancies between studies but have only been tested in limited study populations. This study investigated if vitamin B2 status, measured by EGRAC, is affected by a single exercise bout in females who differ in fitness levels, and that represents long-term physical activity. At baseline and overnight after a 60-min cycling bout at 70% V·O2peak, EGR activity and EGRAC were measured in 31 young female adults, divided into a high-fit (V·O2peak ≥ 47 mL/kg/min, N = 15) and low-fit (V·O2peak ≤ 37 mL/kg/min, N = 16) group. A single exercise bout significantly increased EGR activity in high-fit and low-fit females (Ptime = 0.006). This response was not affected by fitness level (Ptime*group = 0.256). The effect of exercise on EGRAC was not significant (Ptime = 0.079) and not influenced by EGR activity. The exercise response of EGRAC was not significantly different between high-fit and low-fit females (Ptime*group = 0.141). Thus, a single exercise bout increased EGR activity, but did not affect EGRAC, indicating that vitamin B2 status was not affected. The exercise response on EGRAC and EGR did not differ between high-fit and low-fit females.
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26
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Latham CM, Owen RN, Dickson EC, Guy CP, White-Springer SH. Skeletal Muscle Adaptations to Exercise Training in Young and Aged Horses. FRONTIERS IN AGING 2021; 2:708918. [PMID: 35822026 PMCID: PMC9261331 DOI: 10.3389/fragi.2021.708918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 09/17/2021] [Indexed: 11/17/2022]
Abstract
In aged humans, low-intensity exercise increases mitochondrial density, function and oxidative capacity, decreases the prevalence of hybrid fibers, and increases lean muscle mass, but these adaptations have not been studied in aged horses. Effects of age and exercise training on muscle fiber type and size, satellite cell abundance, and mitochondrial volume density (citrate synthase activity; CS), function (cytochrome c oxidase activity; CCO), and integrative (per mg tissue) and intrinsic (per unit CS) oxidative capacities were evaluated in skeletal muscle from aged (n = 9; 22 ± 5 yr) and yearling (n = 8; 9.7 ± 0.7 mo) horses. Muscle was collected from the gluteus medius (GM) and triceps brachii at wk 0, 8, and 12 of exercise training. Data were analyzed using linear models with age, training, muscle, and all interactions as fixed effects. At wk 0, aged horses exhibited a lower percentage of type IIx (p = 0.0006) and greater percentage of hybrid IIa/x fibers (p = 0.002) in the GM, less satellite cells per type II fiber (p = 0.03), lesser integrative and intrinsic (p ≤ 0.04) CCO activities, lesser integrative oxidative phosphorylation capacity with complex I (PCI; p = 0.02) and maximal electron transfer system capacity (ECI+II; p = 0.06), and greater intrinsic PCI, ECI+II, and electron transfer system capacity with complex II (ECII; p ≤ 0.05) than young horses. The percentage of type IIx fibers increased (p < 0.0001) and of type IIa/x fibers decreased (p = 0.001) in the GM, and the number of satellite cells per type II fiber increased (p = 0.0006) in aged horses following exercise training. Conversely, the percentage of type IIa/x fibers increased (p ≤ 0.01) and of type IIx fibers decreased (p ≤ 0.002) in young horses. Integrative maximal oxidative capacity (p ≤ 0.02), ECI+II (p ≤ 0.07), and ECII (p = 0.0003) increased for both age groups from wk 0 to 12. Following exercise training, aged horses had a greater percentage of IIx (p ≤ 0.002) and lesser percentage of IIa/x fibers (p ≤ 0.07), and more satellite cells per type II fiber (p = 0.08) than young horses, but sustained lesser integrative and intrinsic CCO activities (p ≤ 0.04) and greater intrinsic PCI, ECI+II, and ECII (p ≤ 0.05). Exercise improved mitochondrial measures in young and aged horses; however, aged horses showed impaired mitochondrial function and differences in adaptation to exercise training.
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Affiliation(s)
| | | | | | | | - Sarah H. White-Springer
- Texas A&M AgriLife Research and Department of Animal Science, Texas A&M University, College Station, TX, United States
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27
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Lagerwaard B, Janssen JJE, Cuijpers I, Keijer J, de Boer VCJ, Nieuwenhuizen AG. Muscle mitochondrial capacity in high- and low-fitness females using near-infrared spectroscopy. Physiol Rep 2021; 9:e14838. [PMID: 33991439 PMCID: PMC8123566 DOI: 10.14814/phy2.14838] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 03/09/2021] [Accepted: 03/12/2021] [Indexed: 11/24/2022] Open
Abstract
The recovery of muscle oxygen consumption (m V ˙ O2 ) after exercise measured using near-infrared spectroscopy (NIRS) provides a measure of skeletal muscle mitochondrial capacity. Nevertheless, due to sex differences in factors that can influence scattering and thus penetration depth of the NIRS signal in the tissue, e.g., subcutaneous adipose tissue thickness and intramuscular myoglobin and hemoglobin, it is unknown whether results in males can be extrapolated to a female population. Therefore, the aim of this study was to measure skeletal muscle mitochondrial capacity in females at different levels of aerobic fitness to test whether NIRS can measure relevant differences in mitochondrial capacity. Mitochondrial capacity was analyzed in the gastrocnemius muscle and the wrist flexors of 32 young female adults, equally divided in relatively high ( V ˙ O2 peak ≥ 47 ml/kg/min) and relatively low aerobic fitness group ( V ˙ O2 peak ≤ 37 ml/kg/min). m V ˙ O2 recovery was significantly faster in the high- compared to the low-fitness group in the gastrocnemius, but not in the wrist flexors (p = 0.009 and p = 0.0528, respectively). Furthermore, V ˙ O2 peak was significantly correlated to m V ˙ O2 recovery in both gastrocnemius (R2 = 0.27, p = 0.0051) and wrist flexors (R2 = 0.13, p = 0.0393). In conclusion, NIRS measurements can be used to assess differences in mitochondrial capacity within a female population and is correlated to V ˙ O2 peak. This further supports NIRS assessment of muscle mitochondrial capacity providing additional evidence for NIRS as a promising approach to monitor mitochondrial capacity, also in an exclusively female population.
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Affiliation(s)
- Bart Lagerwaard
- Human and Animal Physiology, Wageningen University and Research, Wageningen, The Netherlands.,TI Food and Nutrition, Wageningen, The Netherlands
| | - Joëlle J E Janssen
- Human and Animal Physiology, Wageningen University and Research, Wageningen, The Netherlands
| | - Iris Cuijpers
- Human and Animal Physiology, Wageningen University and Research, Wageningen, The Netherlands
| | - Jaap Keijer
- Human and Animal Physiology, Wageningen University and Research, Wageningen, The Netherlands
| | - Vincent C J de Boer
- Human and Animal Physiology, Wageningen University and Research, Wageningen, The Netherlands
| | - Arie G Nieuwenhuizen
- Human and Animal Physiology, Wageningen University and Research, Wageningen, The Netherlands
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Rackova L, Mach M, Brnoliakova Z. An update in toxicology of ageing. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2021; 84:103611. [PMID: 33581363 DOI: 10.1016/j.etap.2021.103611] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 01/17/2021] [Accepted: 02/03/2021] [Indexed: 06/12/2023]
Abstract
The field of ageing research has been rapidly advancing in recent decades and it had provided insight into the complexity of ageing phenomenon. However, as the organism-environment interaction appears to significantly affect the organismal pace of ageing, the systematic approach for gerontogenic risk assessment of environmental factors has yet to be established. This puts demand on development of effective biomarker of ageing, as a relevant tool to quantify effects of gerontogenic exposures, contingent on multidisciplinary research approach. Here we review the current knowledge regarding the main endogenous gerontogenic pathways involved in acceleration of ageing through environmental exposures. These include inflammatory and oxidative stress-triggered processes, dysregulation of maintenance of cellular anabolism and catabolism and loss of protein homeostasis. The most effective biomarkers showing specificity and relevancy to ageing phenotypes are summarized, as well. The crucial part of this review was dedicated to the comprehensive overview of environmental gerontogens including various types of radiation, certain types of pesticides, heavy metals, drugs and addictive substances, unhealthy dietary patterns, and sedentary life as well as psychosocial stress. The reported effects in vitro and in vivo of both recognized and potential gerontogens are described with respect to the up-to-date knowledge in geroscience. Finally, hormetic and ageing decelerating effects of environmental factors are briefly discussed, as well.
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Affiliation(s)
- Lucia Rackova
- Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine, Slovak Academy of Sciences, Dubravska cesta 9, 841 04 Bratislava, Slovakia.
| | - Mojmir Mach
- Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine, Slovak Academy of Sciences, Dubravska cesta 9, 841 04 Bratislava, Slovakia
| | - Zuzana Brnoliakova
- Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine, Slovak Academy of Sciences, Dubravska cesta 9, 841 04 Bratislava, Slovakia
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Braun N, Hunsdieck B, Theek C, Ickstadt K, Heinrich U. Exercises and Skin Physiology During International Space Station Expeditions. Aerosp Med Hum Perform 2021; 92:160-166. [PMID: 33754973 DOI: 10.3357/amhp.5717.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
BACKGROUND: The first skin physiological pilot experiment (SkinA) on a single astronaut showed a deterioration of the skin. In a follow-up experiment (SkinB) we showed that skin physiological parameters improved on average. However, it is well known that sports have positive effects on the skin, that astronauts prefer special sports devices, and do sports with different intensity. The aim of this study was to analyze the different sports activities of SkinB astronauts and to find out whether they have an influence on the skin physiological parameters.METHODS: The cumulative distance covered on the treadmill and on the cycle ergometer as well as the repetition of arm-related exercises have been calculated and possible correlation between sports activities and skin physiological parameters have been analyzed.RESULTS: The average distance covered for all six astronauts per day is 1364 AU on the treadmill T2, and 11,077 AU on the cycle ergometer CEVIS. In addition, the astronauts performed an average of about 73 repetitions of all arm-related exercises daily. Here, we were able to show very well how differently the astronauts on the ISS train. In addition, a decreasing trend in skin volume can be observed in astronauts with increasing activity on the bicycle and more repetitions on arm-related exercises.CONCLUSION: Increased activity on the cycle ergometer and increased arm-related exercises have a medium negative impact on the parameter skin volume and thus reflects more fluid content in the skin. No correlations between sports activities and skin moisture/skin barrier function could be found.Braun N, Hunsdieck B, Theek C, Ickstadt K, Heinrich U. Exercises and skin physiology during International Space Station expeditions. Aerosp Med Hum Perform. 2021; 92(3):160166.
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Physical performance level in sarcomeric mitochondria creatine kinase knockout mouse model throughout ageing. Exp Gerontol 2021; 146:111246. [PMID: 33515657 DOI: 10.1016/j.exger.2021.111246] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 01/10/2021] [Accepted: 01/16/2021] [Indexed: 11/20/2022]
Abstract
PURPOSE The objective of the present study was to establish the role of sarcomeric mitochondrial creatine kinase (Mt-CK) in muscle energy output during exercise in a murine model of ageing (the Mt-CK knock-out mouse, Mt-CK-/-). METHODS Three age groups of Mt-CK-/- mice and control male mice (6, 9, and 18 months of age) underwent incremental treadmill running tests. The maximum speed (Vpeak) and maximal oxygen consumption (VO2peak) values were recorded. Urine samples were analyzed using metabolomic techniques. The skeletal muscle (quadriceps) expression of proteins involved in mitochondria biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and dynamin-related GTPase mitofusin 2 (Mnf2) were quantified. RESULTS The VO2 peak (normalized to heart weight: HW) of 18-month-old (mo) Mt-CK-/- mice was 27% (p < 0.001) lower than in 18-mo control mice. The VO2peak/HW ratio was 29% (p < 0.001) lower in 18-mo Mt-CK-/- mice than in 6-mo (p < 0.001) and 32% (p < 0.001) than 9-mo Mt-CK-/- mice. With a 0° slope, Vpeak was 10% (p < 0.05) lower in 18-mo Mt-CK-/- mice than in 6-mo Mt-CK-/- mice but did not differ when comparing the 18-mo and 6-mo control groups. The skeletal muscles weight normalized on body weight in 6-mo Mt-CK-/- were 13 to 14% (p < 0.001, p < 0.05) lower versus the 6-mo control, in addition, the presence of branched-chain amino acids in the urine of 6-mo Mt-CK-/- mice suggests an imbalance in protein turnover (catabolism rather than anabolism) but we did not observe any age-related differences. The expression of PGC-1α and Mnf2 proteins in the quadriceps showed that age-related effects were more prominent than genotype effects. CONCLUSION The present study showed ageing is potentialized by Mt-CK deficiency with regard to VO2peak, Vpeak and mitochondrial protein expression. Our results support that Mt-CK-/- mice undergo physiological adaptations, enabling them to survive and to perform as well as wild-type mice. Furthermore, it is possible that these adaptations in Mt-CK-/- mice have a high energy cost and might trigger premature ageing.
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31
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Deshmukh AS, Steenberg DE, Hostrup M, Birk JB, Larsen JK, Santos A, Kjøbsted R, Hingst JR, Schéele CC, Murgia M, Kiens B, Richter EA, Mann M, Wojtaszewski JFP. Deep muscle-proteomic analysis of freeze-dried human muscle biopsies reveals fiber type-specific adaptations to exercise training. Nat Commun 2021; 12:304. [PMID: 33436631 PMCID: PMC7803955 DOI: 10.1038/s41467-020-20556-8] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 12/01/2020] [Indexed: 01/29/2023] Open
Abstract
Skeletal muscle conveys several of the health-promoting effects of exercise; yet the underlying mechanisms are not fully elucidated. Studying skeletal muscle is challenging due to its different fiber types and the presence of non-muscle cells. This can be circumvented by isolation of single muscle fibers. Here, we develop a workflow enabling proteomics analysis of pools of isolated muscle fibers from freeze-dried human muscle biopsies. We identify more than 4000 proteins in slow- and fast-twitch muscle fibers. Exercise training alters expression of 237 and 172 proteins in slow- and fast-twitch muscle fibers, respectively. Interestingly, expression levels of secreted proteins and proteins involved in transcription, mitochondrial metabolism, Ca2+ signaling, and fat and glucose metabolism adapts to training in a fiber type-specific manner. Our data provide a resource to elucidate molecular mechanisms underlying muscle function and health, and our workflow allows fiber type-specific proteomic analyses of snap-frozen non-embedded human muscle biopsies.
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Affiliation(s)
- A S Deshmukh
- The Novo Nordisk Foundation Center for Protein Research, Clinical Proteomics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
- The Novo Nordisk Foundation Center for Basic Metablic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - D E Steenberg
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - M Hostrup
- Section of Integrative Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - J B Birk
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - J K Larsen
- The Novo Nordisk Foundation Center for Basic Metablic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - A Santos
- The Novo Nordisk Foundation Center for Protein Research, Clinical Proteomics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - R Kjøbsted
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - J R Hingst
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - C C Schéele
- The Novo Nordisk Foundation Center for Basic Metablic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- The Centre of Inflammation and Metabolism and Centre for Physical Activity Research Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
| | - M Murgia
- Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Martinsried, Germany
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - B Kiens
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - E A Richter
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - M Mann
- The Novo Nordisk Foundation Center for Protein Research, Clinical Proteomics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Martinsried, Germany
| | - J F P Wojtaszewski
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.
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32
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Mohamed AA. Can Proprioceptive Training Enhance Fatigability and Decrease Progression Rate of Sarcopenia in Seniors? A Novel Approach. Curr Rheumatol Rev 2021; 17:58-67. [PMID: 32348231 DOI: 10.2174/1573397116666200429113226] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 04/08/2020] [Accepted: 04/13/2020] [Indexed: 01/03/2023]
Abstract
Sarcopenia is a common condition in older adults, which causes the frequent occurrence of muscle fatigue. Muscle fatigue commonly develops among seniors. Muscle fatigue is a type of physical fatigue that occurs due to either motor or sensory dysfunctions. Current interventions developed to decrease the occurrence of muscle fatigue, which include either increasing rest periods or subdividing large tasks into small ones. The effectiveness of these interventions is highly contradicted. Recently, researchers discovered that mechanoreceptors are the main receptors of muscle fatigue, however, no clinical study investigated the effect of performing proprioceptive training to enhance the mechanoreceptors and decrease the occurrence of muscle fatigue. Performing proprioceptive training could improve muscle fatigue by improving its sensory part. The function of mechanoreceptors might consequently enhance fatigue and decrease the progression rate of sarcopenia. Thus, this review was conducted to suggest a novel approach of treatment to enhance fatigue and decrease Sarcopenia in seniors. This might be accomplished through increasing the firing rate of α- motor neurons, increasing the amount of Ca2+ ions in the neuromuscular junction, slowing the progression rate of Sarcopenia, and correcting movement deviations, which commonly occur with muscle fatigue in seniors. In conclusion, proprioceptive training could play an effective role in decreasing the progression rate of sarcopenia and enhancing the fatigability among seniors.
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Affiliation(s)
- Ayman A Mohamed
- Department of Physiotherapy and Rehabilitation, School of Health Sciences, Istanbul Gelisim University, Istanbul, Turkey
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33
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van Diemen MPJ, Hart EP, Hameeteman PW, Coppen EM, Winder JY, den Heijer J, Moerland M, Kan H, van der Grond J, Webb A, Roos RAC, Groeneveld GJ. Brain Bio-Energetic State Does Not Correlate to Muscle Mitochondrial Function in Huntington's Disease. J Huntingtons Dis 2020; 9:335-344. [PMID: 33325391 DOI: 10.3233/jhd-200413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Huntington's disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. A toxic accumulation of misfolded mutant huntingtin protein (Htt) induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. Improving mitochondrial function has been proposed as an opportunity to treat HD, but it is not known how mitochondrial function in different tissues relates. OBJECTIVE We explored associations between central and peripheral mitochondrial function in a group of mild to moderate staged HD patients. METHODS We used phosphorous magnetic resonance spectroscopy (31P-MRS) to measure mitochondrial function in vivo in the calf muscle (peripheral) and the bio-energetic state in the visual cortex (central). Mitochondrial function was also assessed ex vivo in circulating peripheral blood mononuclear cells (PBMCs). Clinical function was determined by the Unified Huntington's Disease Rating Scale (UHDRS) total motor score. Pearson correlation coefficients were computed to assess the correlation between the different variables. RESULTS We included 23 manifest HD patients for analysis. There was no significant correlation between central bio-energetics and peripheral mitochondrial function. Central mitochondrial function at rest correlated significantly to the UHDRS total motor score (R = -0.45 and -0.48), which increased in a subgroup with the largest number of CAG repeats. DISCUSSION We did not observe a correlation between peripheral and central mitochondrial function. Central, but not peripheral, mitochondrial function correlated to clinical function. Muscle mitochondrial function is a promising biomarker to evaluate disease-modifying compounds that improve mitochondrial function, but Huntington researchers should use central mitochondrial function to demonstrate proof-of-pharmacology of disease-modifying compounds.
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Affiliation(s)
| | - Ellen P Hart
- Centre for Human Drug Research, Leiden, The Netherlands
| | | | - Emma M Coppen
- Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
| | - Jessica Y Winder
- Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
| | | | | | - Hermien Kan
- Gorter Centre for High-field MRI, Leiden University Medical Center, Leiden, The Netherlands
| | - Jeroen van der Grond
- Radiology Research Center, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Andrew Webb
- Gorter Centre for High-field MRI, Leiden University Medical Center, Leiden, The Netherlands
| | - Raymund A C Roos
- Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
| | - Geert Jan Groeneveld
- Centre for Human Drug Research, Leiden, The Netherlands.,Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
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Von Schulze AT, Deng F, Morris JK, Geiger PC. Heat therapy: possible benefits for cognitive function and the aging brain. J Appl Physiol (1985) 2020; 129:1468-1476. [PMID: 32969779 DOI: 10.1152/japplphysiol.00168.2020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease, yet there are no disease-modifying treatments available and there is no cure. It is becoming apparent that metabolic and vascular conditions such as type 2 diabetes (T2D) and hypertension promote the development and accumulation of Alzheimer's disease-related dementia pathologies. To this end, aerobic exercise, which is a common lifestyle intervention for both metabolic disease and hypertension, is shown to improve brain health during both healthy aging and dementia. However, noncompliance or other barriers to exercise response are common in exercise treatment paradigms. In addition, reduced intracellular proteostasis and mitochondrial function could contribute to the etiology of AD. Specifically, compromised chaperone systems [i.e., heat shock protein (HSP) systems] can contribute to protein aggregates (i.e., β-amyloid plaques and neurofibrillary tangles) and reduced mitochondrial quality control (i.e., mitophagy). Therefore, novel therapies that target whole body metabolism, the vasculature, and chaperone systems (like HSPs) are needed to effectively treat AD. This review focuses on the role of heat therapy in the treatment and prevention of AD. Heat therapy has been independently shown to reduce whole body insulin resistance, improve vascular function, activate interorgan cross talk via endocytic vesicles, and activate HSPs to improve mitochondrial function and proteostasis in a variety of tissues. Thus, heat therapy could offer immense clinical benefit to patients suffering from AD. Importantly, future studies in patients are needed to determine the safety and efficacy of heat therapy in preventing AD.
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Affiliation(s)
- Alex T Von Schulze
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, Kansas
| | - Fengyan Deng
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, Kansas
| | - Jill K Morris
- Department of Neurology, The University of Kansas Medical Center, Kansas City, Kansas
| | - Paige C Geiger
- Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, Kansas
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Genders AJ, Holloway GP, Bishop DJ. Are Alterations in Skeletal Muscle Mitochondria a Cause or Consequence of Insulin Resistance? Int J Mol Sci 2020; 21:ijms21186948. [PMID: 32971810 PMCID: PMC7554894 DOI: 10.3390/ijms21186948] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 09/18/2020] [Accepted: 09/18/2020] [Indexed: 12/14/2022] Open
Abstract
As a major site of glucose uptake following a meal, skeletal muscle has an important role in whole-body glucose metabolism. Evidence in humans and animal models of insulin resistance and type 2 diabetes suggests that alterations in mitochondrial characteristics accompany the development of skeletal muscle insulin resistance. However, it is unclear whether changes in mitochondrial content, respiratory function, or substrate oxidation are central to the development of insulin resistance or occur in response to insulin resistance. Thus, this review will aim to evaluate the apparent conflicting information placing mitochondria as a key organelle in the development of insulin resistance in skeletal muscle.
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Affiliation(s)
- Amanda J. Genders
- Institute for Health and Sport (iHeS), Victoria University, Melbourne 8001, Australia;
- Correspondence: ; Tel.: +61-3-9919-9556
| | - Graham P. Holloway
- Dept. Human Health and Nutritional Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada;
| | - David J. Bishop
- Institute for Health and Sport (iHeS), Victoria University, Melbourne 8001, Australia;
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Aas V, Thoresen GH, Rustan AC, Lund J. Substrate oxidation in primary human skeletal muscle cells is influenced by donor age. Cell Tissue Res 2020; 382:599-608. [PMID: 32897419 PMCID: PMC7683494 DOI: 10.1007/s00441-020-03275-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 08/07/2020] [Indexed: 12/21/2022]
Abstract
Primary human myotubes represent an alternative system to intact skeletal muscle for the study of human diseases related to changes in muscle energy metabolism. This work aimed to study if fatty acid and glucose metabolism in human myotubes in vitro were related to muscle of origin, donor gender, age, or body mass index (BMI). Myotubes from a total of 82 donors were established from three different skeletal muscles, i.e., musculus vastus lateralis, musculus obliquus internus abdominis, and musculi interspinales, and cellular energy metabolism was evaluated. Multiple linear regression analyses showed that donor age had a significant effect on glucose and oleic acid oxidation after correcting for gender, BMI, and muscle of origin. Donor BMI was the only significant contributor to cellular oleic acid uptake, whereas cellular glucose uptake did not rely on any of the variables examined. Despite the effect of age on substrate oxidation, cellular mRNA expression of pyruvate dehydrogenase kinase 4 (PDK4) and peroxisome proliferator–activated receptor gamma coactivator 1 alpha (PPARGC1A) did not correlate with donor age. In conclusion, donor age significantly impacts substrate oxidation in cultured human myotubes, whereas donor BMI affects cellular oleic acid uptake.
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Affiliation(s)
- Vigdis Aas
- Department of Life Sciences and Health, Faculty of Health Sciences, OsloMet - Oslo Metropolitan University, Oslo, Norway
| | - G Hege Thoresen
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Blindern, P.O. Box 1068, 0316, Oslo, Norway.,Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Arild C Rustan
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Blindern, P.O. Box 1068, 0316, Oslo, Norway
| | - Jenny Lund
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Blindern, P.O. Box 1068, 0316, Oslo, Norway.
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Paul JA, Whittington RA, Baldwin MR. Critical Illness and the Frailty Syndrome: Mechanisms and Potential Therapeutic Targets. Anesth Analg 2020; 130:1545-1555. [PMID: 32384344 DOI: 10.1213/ane.0000000000004792] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Frailty is a syndrome characterized by decreased reserves across multiple physiologic systems resulting in functional limitations and vulnerability to new stressors. Physical frailty develops over years in community-dwelling older adults but presents or worsens within days in the intensive care unit (ICU) because common mechanisms governing age-related physical frailty are often exacerbated by critical illness. The hallmark of physical frailty is a combined loss of muscle mass, force, and endurance. About one-third of ICU patients have frailty before hospitalization, which increases their risk for both short- and long-term disability and mortality. While there are several valid ways to measure clinical frailty in patients before or after an ICU admission, the mechanistic underpinnings of frailty in critically ill patients and ICU survivors have not been thoroughly investigated. Furthermore, therapeutic interventions to treat frailty during and after time in the ICU are lacking. In this narrative review, we examine studies that identify potential biological mechanisms underlying the development and propagation of physical frailty in both aging and critical illness (eg, inflammation, mitochondrial myopathy, and neuroendocrinopathy). We discuss specific aspects of these frailty mechanisms in older adults, critically ill patients, and ICU survivors that may represent therapeutic targets. Consistent with complexity underlying frailty, this syndrome is unlikely to result from an excess of a single harmful mediator or deficit of a single protective mediator. Rather, frailty occurs in the presence of an incompletely understood state of multisystem dysregulation. We further describe knowledge gaps that warrant clinical and translational research in frailty and critical care with an overall goal of developing effective frailty treatments in critically ill patients and ICU survivors.
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Affiliation(s)
- Jonathan A Paul
- From the Department of Anesthesiology, Columbia University Irving Medical Center, New York, New York
| | - Robert A Whittington
- From the Department of Anesthesiology, Columbia University Irving Medical Center, New York, New York
| | - Matthew R Baldwin
- Division of Pulmonary, Allergy, and Critical Care, Department of Internal Medicine, Columbia University Irving Medical Center, New York, New York
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38
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Association of Diabetes and Other Clinical and Sociodemographic Factors With Guideline-concordant Breast Cancer Treatment for Breast Cancer. Am J Clin Oncol 2020; 43:101-106. [PMID: 31850918 DOI: 10.1097/coc.0000000000000638] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Women with breast cancer have worse health outcomes with co-occurring type 2 diabetes, possibly due to suboptimal breast cancer treatment. METHODS We created a cohort of women ages 66 to 85 y with stage I to III breast cancer from 1993 to 2012 from an integrated health care delivery system (n=1612) and fee-for-service Medicare beneficiaries (n=98,915), linked to Surveillance, Epidemiology, and End Results (SEER) data (total n=100,527). We evaluated associations between type 2 diabetes and other factors with undergoing guideline-concordant cancer treatment. We estimated χ tests for univariate analysis and relative risks (RRs) using multivariable log-binomial models for outcomes of (1) overall guideline-concordant treatment, (2) definitive surgical therapy (mastectomy or lumpectomy with radiation), (3) chemotherapy if indicated, and (4) endocrine therapy. RESULTS Our cohort included 60% of subjects with stage 1 tumors, one quarter below 70 years old, 23% had diabetes, 35% underwent overall guideline-concordant treatment, 24% chemotherapy, and 83% endocrine therapy. Women with diabetes were less likely to undergo overall guideline-concordant treatment (RR: 0.96; 95% confidence interval: 0.94-0.98), and only slightly less likely to undergo guideline-concordant definitive surgical therapy (RR: 0.99; 95% confidence interval: 0.99-1.00). No differences were found for chemotherapy or endocrine therapy. Other factors significantly associated with a lower risk of guideline-concordant care were cancer stages II to III (vs. I; RR=0.47-0.69, P<0.0001), older age (vs. 66 to 69 y; RR=0.56-0.90, P<0.0001), higher comorbidity burden, and Medicaid dual-eligibility. CONCLUSIONS Diabetes was associated with lower adherence to overall guideline-concordant breast cancer treatment. However, higher stage, older age, higher comorbidity burden, and Medicaid insurance were more strongly associated with lower use of guideline-concordant treatment. Given the heavy burden of breast cancer and diabetes, long-term outcomes analysis should consider guideline-concordant treatment. IMPACT Other factors besides diabetes are more strongly associated with guideline-concordant breast cancer treatment.
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Lo JHT, U KP, Yiu T, Ong MTY, Lee WYW. Sarcopenia: Current treatments and new regenerative therapeutic approaches. J Orthop Translat 2020; 23:38-52. [PMID: 32489859 PMCID: PMC7256062 DOI: 10.1016/j.jot.2020.04.002] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 03/31/2020] [Accepted: 04/02/2020] [Indexed: 12/16/2022] Open
Abstract
Sarcopenia is characterized by loss of muscle and reduction in muscle strength that contributes to higher mortality rate and increased incidence of fall and hospitalization in the elderly. Mitochondria dysfunction and age-associated inflammation in muscle are two of the main attributors to sarcopenia progression. Recent clinical trials on sarcopenia therapies such as physical exercise, nutraceutical, and pharmaceutical interventions have revealed that exercise is the only effective strategy shown to alleviate sarcopenia. Unlike nutraceutical and pharmaceutical interventions that showed controversial results in sarcopenia alleviation, exercise was found to restore mitochondria homeostasis and dampen inflammatory responses via a complex exchange of myokines and osteokines signalling between muscle and bone. However, as exercise have limited benefit to immobile patients, the use of stem cells and their secretome are being suggested to be novel therapeutics that can be catered to a larger patient population owing to their mitochondria restoration effects and immune modulatory abilities. As such, we reviewed the potential pros and cons associated with various stem cell types/secretome in sarcopenia treatment and the regulatory and production barriers that need to be overcome to translate such novel therapeutic agents into bedside application. Translational potential: This review summarizes the causes underlying sarcopenia from the perspective of mitochondria dysfunction and age-associated inflammation, and the progress of clinical trials for the treatment of sarcopenia. We also propose therapeutic potential of stem cell therapy and bioactive secretome for sarcopenia.
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Affiliation(s)
- Jessica Hiu-Tung Lo
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China.,Stem Cells and Regenerative Medicine Laboratory, Lui Che Woo Institute of Innovative Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China
| | - Kin Pong U
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China.,Stem Cells and Regenerative Medicine Laboratory, Lui Che Woo Institute of Innovative Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China
| | - Tszlam Yiu
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China.,Stem Cells and Regenerative Medicine Laboratory, Lui Che Woo Institute of Innovative Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China
| | - Michael Tim-Yun Ong
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China
| | - Wayne Yuk-Wai Lee
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China.,Stem Cells and Regenerative Medicine Laboratory, Lui Che Woo Institute of Innovative Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, PR China
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Sun Y. Thrifty Hormone Ghrelin: The Secret of Aging Muscularly. JOURNAL OF AGING SCIENCE 2020; 8:005. [PMID: 34368393 PMCID: PMC8341557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Sarcopenia is a debilitating muscle-wasting disease that is the major cause of frailty and disability in aging. Ghrelin (aka acylated ghrelin, AG) is a circulating peptide hormone with an unique octanoylation on Ser3. AG induces growth hormone (GH) secretion, increases food intake, and promotes adiposity and insulin resistance via its receptor, Growth Hormone Secretagogue Receptor (GHS-R). Unlike AG, unacylated ghrelin (UAG) is a peptide generated from the same ghrelin gene with amino acid sequence identical to AG but without the octanoylation modification, so UAG does not activate GHS-R. Intriguingly, both AG and UAG have been shown to promote differentiation and fusion of muscle C2C12 cells, regulate metabolic and mitochondrial signaling pathways in myotubes, and attenuate fasting- or denervation-induced muscle atrophy. Furthermore, it has also been shown that ghrelin gene deficiency increases vulnerability to fasting-induced muscle loss in aging mice, and AG and UAG effectively protects against muscle atrophy of aging mice. Because UAG doesn't bind to GHS-R, it doesn't have the undesired side-effects of elevated GH-release and increased obesity as AG. In summary, UAG has an impressive anti-atrophic effect in muscle protecting against muscle atrophy in aging, it has potential to be a unique and superior therapeutic candidate for muscle-wasting diseases such as sarcopenia.
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Sarcolipin Signaling Promotes Mitochondrial Biogenesis and Oxidative Metabolism in Skeletal Muscle. Cell Rep 2019; 24:2919-2931. [PMID: 30208317 PMCID: PMC6481681 DOI: 10.1016/j.celrep.2018.08.036] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 04/30/2018] [Accepted: 08/13/2018] [Indexed: 12/19/2022] Open
Abstract
The major objective of this study was to understand the molecular basis of how sarcolipin uncoupling of SERCA regulates muscle oxidative metabolism. Using genetically engineered sarcolipin (SLN) mouse models and primary muscle cells, we demonstrate that SLN plays a crucial role in mitochondrial biogenesis and oxidative metabolism in muscle. Loss of SLN severely compromised muscle oxidative capacity without affecting fiber-type composition. Mice overexpressing SLN in fast-twitch glycolytic muscle reprogrammed mitochondrial phenotype, increasing fat utilization and protecting against high-fat dietinduced lipotoxicity. We show that SLN affects cytosolic Ca2+ transients and activates the Ca2+/ calmodulin-dependent protein kinase II (CamKII) and PGC1α axis to increase mitochondrial biogenesis and oxidative metabolism. These studies provide a fundamental framework for understanding the role of sarcoplasmic reticulum (SR)-Ca2+ cycling as an important factor in mitochondrial health and muscle metabolism. We propose that SLN can be targeted to enhance energy expenditure in muscle and prevent metabolic disease. Maurya et al. report that sarcolipin, a regulator of the SERCA pump, promotes mitochondrial biogenesis and oxidative phenotype in muscle. Loss of SLN decreases fat oxidation, whereas overexpression of SLN in muscle provides resistance against diet-induced lipotoxicity. By increasing cytosolic Ca2+ transients, SLN activates the CamKII-PGC1α signaling pathway to promote mitochondrial biogenesis.
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Lewis MT, Kasper JD, Bazil JN, Frisbee JC, Wiseman RW. Quantification of Mitochondrial Oxidative Phosphorylation in Metabolic Disease: Application to Type 2 Diabetes. Int J Mol Sci 2019; 20:E5271. [PMID: 31652915 PMCID: PMC6862501 DOI: 10.3390/ijms20215271] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 10/17/2019] [Accepted: 10/22/2019] [Indexed: 12/17/2022] Open
Abstract
Type 2 diabetes (T2D) is a growing health concern with nearly 400 million affected worldwide as of 2014. T2D presents with hyperglycemia and insulin resistance resulting in increased risk for blindness, renal failure, nerve damage, and premature death. Skeletal muscle is a major site for insulin resistance and is responsible for up to 80% of glucose uptake during euglycemic hyperglycemic clamps. Glucose uptake in skeletal muscle is driven by mitochondrial oxidative phosphorylation and for this reason mitochondrial dysfunction has been implicated in T2D. In this review we integrate mitochondrial function with physiologic function to present a broader understanding of mitochondrial functional status in T2D utilizing studies from both human and rodent models. Quantification of mitochondrial function is explained both in vitro and in vivo highlighting the use of proper controls and the complications imposed by obesity and sedentary lifestyle. This review suggests that skeletal muscle mitochondria are not necessarily dysfunctional but limited oxygen supply to working muscle creates this misperception. Finally, we propose changes in experimental design to address this question unequivocally. If mitochondrial function is not impaired it suggests that therapeutic interventions and drug development must move away from the organelle and toward the cardiovascular system.
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Affiliation(s)
- Matthew T Lewis
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
| | - Jonathan D Kasper
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
- Present address: Molecular Physiology Institute, Duke University, Durham, NC 27701, USA.
| | - Jason N Bazil
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
| | - Jefferson C Frisbee
- Department of Medical Biophysics, University of Western Ontario, London, ON N6A 3K7, Canada.
| | - Robert W Wiseman
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
- Department of Radiology, Michigan State University, East Lansing, MI 48824, USA.
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43
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Treadmill Training Effect on Kinematics: An Aging Study in Rats. J Med Biol Eng 2019. [DOI: 10.1007/s40846-019-00490-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Lewis MT, Kasper JD, Bazil JN, Frisbee JC, Wiseman RW. Skeletal muscle energetics are compromised only during high-intensity contractions in the Goto-Kakizaki rat model of type 2 diabetes. Am J Physiol Regul Integr Comp Physiol 2019; 317:R356-R368. [PMID: 31188651 PMCID: PMC6732426 DOI: 10.1152/ajpregu.00127.2019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 06/07/2019] [Accepted: 06/07/2019] [Indexed: 12/24/2022]
Abstract
Type 2 diabetes (T2D) presents with hyperglycemia and insulin resistance, affecting over 30 million people in the United States alone. Previous work has hypothesized that mitochondria are dysfunctional in T2D and results in both reduced ATP production and glucose disposal. However, a direct link between mitochondrial function and T2D has not been determined. In the current study, the Goto-Kakizaki (GK) rat model of T2D was used to quantify mitochondrial function in vitro and in vivo over a broad range of contraction-induced metabolic workloads. During high-frequency sciatic nerve stimulation, hindlimb muscle contractions at 2- and 4-Hz intensities, the GK rat failed to maintain similar bioenergetic steady states to Wistar control (WC) rats measured by phosphorus magnetic resonance spectroscopy, despite similar force production. Differences were not due to changes in mitochondrial content in red (RG) or white gastrocnemius (WG) muscles (cytochrome c oxidase, RG: 22.2 ± 1.6 vs. 23.3 ± 1.7 U/g wet wt; WG: 10.8 ± 1.1 vs. 12.1 ± 0.9 U/g wet wt; GK vs. WC, respectively). Mitochondria isolated from muscles of GK and WC rats also showed no difference in mitochondrial ATP production capacity in vitro, measured by high-resolution respirometry. At lower intensities (0.25-1 Hz) there were no detectable differences between GK and WC rats in sustained energy balance. There were similar phosphocreatine concentrations during steady-state contraction and postcontractile recovery (τ = 72 ± 6 s GK versus 71 ± 2 s WC). Taken together, these results suggest that deficiencies in skeletal muscle energetics seen at higher intensities are not due to mitochondrial dysfunction in the GK rat.
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Affiliation(s)
- Matthew T Lewis
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Jonathan D Kasper
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Jason N Bazil
- Department of Physiology, Michigan State University, East Lansing, Michigan
| | - Jefferson C Frisbee
- Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada
| | - Robert W Wiseman
- Department of Physiology, Michigan State University, East Lansing, Michigan
- Department of Radiology, Michigan State University, East Lansing, Michigan
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A novel mitochondrial micropeptide MPM enhances mitochondrial respiratory activity and promotes myogenic differentiation. Cell Death Dis 2019; 10:528. [PMID: 31296841 PMCID: PMC6624212 DOI: 10.1038/s41419-019-1767-y] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 05/25/2019] [Accepted: 06/26/2019] [Indexed: 12/14/2022]
Abstract
Micropeptides belong to a class of newly identified small molecules with <100 amino acids in length, and their functions remain largely unknown. Here, we identified a novel muscle-enriched micropeptide that was localized to mitochondria (named MPM, micropeptide in mitochondria) and upregulated during in vitro differentiation of C2C12 myoblasts and in vivo early postnatal skeletal muscle development, and muscle regeneration after cardiotoxin (CTX) damage. Downregulation of MPM was observed in the muscular tissues of tibial muscular dystrophy and Duchenne muscular dystrophy patients. Furthermore, MPM silencing inhibited the differentiation of C2C12 myoblasts into myotubes, whereas MPM overexpression stimulated it. MPM−/− mice exhibited smaller skeletal muscle fibers and worse muscle performance, such as decrease in the maximum grip force of limbs, the latency to fall off rotarod, and the exhausting swimming time. Muscle regeneration was also impaired in MPM−/− mice, as evidenced by lower expression of Pax7, MyoD, and MyoG after CTX injection and smaller regenerated myofibers, compared with wild-type mice. Mechanistical investigations based on both gain- and loss-of function studies revealed that MPM increased oxygen consumption and ATP production of mitochondria. Moreover, ectopic expression of PGC-1α, which can enhance mitochondrial respiration, attenuated the inhibitory effect of siMPM on myogenic differentiation. These results imply that MPM may promote myogenic differentiation and muscle fiber growth by enhancing mitochondrial respiratory activity, which highlights the importance of micropeptides in the elaborate regulatory network of both myogenesis and mitochondrial activity and implicates MPM as a potential target for muscular dystrophy therapy.
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In vivo assessment of muscle mitochondrial function in healthy, young males in relation to parameters of aerobic fitness. Eur J Appl Physiol 2019; 119:1799-1808. [PMID: 31177324 PMCID: PMC6647177 DOI: 10.1007/s00421-019-04169-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 05/28/2019] [Indexed: 11/17/2022]
Abstract
Purpose The recovery of muscle oxygen consumption (m\documentclass[12pt]{minimal}
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\begin{document}$$\dot{V}$$\end{document}V˙O2) after exercise provides a measure of skeletal muscle mitochondrial capacity, as more and better-functioning mitochondria will be able to restore m\documentclass[12pt]{minimal}
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\begin{document}$$\dot{V}$$\end{document}V˙O2 faster to the pre-exercise state. The aim was to measure muscle mitochondrial capacity using near-infrared spectroscopy (NIRS) within a healthy, normally active population and relate this to parameters of aerobic fitness, investigating the applicability and relevance of using NIRS to assess muscle mitochondrial capacity non-invasively. Methods Mitochondrial capacity was analysed in the gastrocnemius and flexor digitorum superficialis (FDS) muscles of eight relatively high-aerobic fitness (\documentclass[12pt]{minimal}
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\begin{document}$$\dot{V}$$\end{document}V˙O2peak ≥ 57 mL/kg/min) and eight relatively low-aerobic fitness male subjects (\documentclass[12pt]{minimal}
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\begin{document}$$\dot{V}$$\end{document}V˙O2peak ≤ 47 mL/kg/min). Recovery of whole body \documentclass[12pt]{minimal}
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\begin{document}$$\dot{V}$$\end{document}V˙O2, i.e. excess post-exercise oxygen consumption (EPOC) was analysed after a cycling protocol. Results Mitochondrial capacity, as analysed using NIRS, was significantly higher in high-fitness individuals compared to low-fitness individuals in the gastrocnemius, but not in the FDS (p = 0.0036 and p = 0.20, respectively). Mitochondrial capacity in the gastrocnemius was significantly correlated with \documentclass[12pt]{minimal}
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\begin{document}$$\dot{V}$$\end{document}V˙O2peak (R2 = 0.57, p = 0.0019). Whole body \documentclass[12pt]{minimal}
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\begin{document}$$\dot{V}$$\end{document}V˙O2 recovery was significantly faster in the high-fitness individuals (p = 0.0048), and correlated significantly with mitochondrial capacity in the gastrocnemius (R2 = 0.34, p = 0.028). Conclusion NIRS measurements can be used to assess differences in mitochondrial muscle oxygen consumption within a relatively normal, healthy population. Furthermore, mitochondrial capacity correlated with parameters of aerobic fitness (\documentclass[12pt]{minimal}
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\begin{document}$$\dot{V}$$\end{document}V˙O2peak and EPOC), emphasising the physiological relevance of the NIRS measurements.
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Proia P, Amato A, Contrò V, Monaco AL, Brusa J, Brighina F, Messina G. Relevance of lactate level detection in migrane and fibromyalgia. Eur J Transl Myol 2019; 29:8202. [PMID: 31354925 PMCID: PMC6615065 DOI: 10.4081/ejtm.2019.8202] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 04/17/2019] [Indexed: 02/08/2023] Open
Abstract
The aim of this study was to determine the blood lactate levels in healthy and pathological subjects, particularly with migraine and fibromyalgia. Moreover we investigated the possible correlation between lactate concentration, postural stability and balance disorders; the composition of the groups were: migraine (n = 25; age 49.7 ± 12.5), fibromyalgia (n = 10; age 43.7 ± 21.2), control group (n = 16 age 28.52 ± 2.4). The results showed that patients with fibromyalgia (FG) had higher lactate levels compared to migraine (MG) and control group (CG) (mean ± sd: FG = 1.78 ± 0.9 mmol/L; MG = 1.45±1 mmol/L; CG = 0,85 ± 0,07 mmol/L). The same situation was highlighted about the sway path length with eyes closed (FG = 518 ± 195 mm; MG = 465 ± 165 mm; CG = 405 ± 94,72 mm) and with eyes open (FG = 430 ± 220 mm; MG = 411 ± 143 mm; CG = 389 ± 107 mm). This can be explained by the fact that energy-intensive postural strategies must be used to optimize both static and dynamic coordination, in particular with repeated contractions of tonic oxidative muscle cells responsible for postural control.
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Affiliation(s)
- Patrizia Proia
- Department of Psychology, Educational Science and Human Movement, University of Palermo
| | - Alessandra Amato
- Department of Psychology, Educational Science and Human Movement, University of Palermo
| | - Valentina Contrò
- Department of Psychology, Educational Science and Human Movement, University of Palermo
| | - Alessandra Lo Monaco
- Department of Psychology, Educational Science and Human Movement, University of Palermo
| | - Jessica Brusa
- Department of Psychology, Educational Science and Human Movement, University of Palermo
| | - Filippo Brighina
- Department of Experimental Biomedicine and Clinical Neurosciences (BIONEC), University of Palermo, Italy
| | - Giuseppe Messina
- Department of Psychology, Educational Science and Human Movement, University of Palermo
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48
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Faitg J, Leduc-Gaudet JP, Reynaud O, Ferland G, Gaudreau P, Gouspillou G. Effects of Aging and Caloric Restriction on Fiber Type Composition, Mitochondrial Morphology and Dynamics in Rat Oxidative and Glycolytic Muscles. Front Physiol 2019; 10:420. [PMID: 31114501 PMCID: PMC6503296 DOI: 10.3389/fphys.2019.00420] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 03/27/2019] [Indexed: 12/22/2022] Open
Abstract
Aging is associated with a progressive decline in muscle mass and strength, a process known as sarcopenia. Evidence indicates that mitochondrial dysfunction plays a causal role in sarcopenia and suggests that alterations in mitochondrial dynamics/morphology may represent an underlying mechanism. Caloric restriction (CR) is among the most efficient nonpharmacological interventions to attenuate sarcopenia in rodents and is thought to exert its beneficial effects by improving mitochondrial function. However, CR effects on mitochondrial morphology and dynamics, especially in aging muscle, remain unknown. To address this issue, we investigated mitochondrial morphology and dynamics in the oxidative soleus (SOL) and glycolytic white gastrocnemius (WG) muscles of adult (9-month-old) ad libitum-fed (AL; A-AL), old (22-month-old) AL-fed (O-AL), and old CR (O-CR) rats. We show that CR attenuates the aging-related decline in the muscle-to-body-weight ratio, a sarcopenic index. CR also prevented the effects of aging on muscle fiber type composition in both muscles. With aging, the SOL displayed fragmented SubSarcolemmal (SS) and InterMyoFibrillar (IMF) mitochondria, an effect attenuated by CR. Aged WG displayed enlarged SS and more complex/branched IMF mitochondria. CR had marginal anti-aging effects on WG mitochondrial morphology. In the SOL, DRP1 (pro-fission protein) content was higher in O-AL vs YA-AL, and Mfn2 (pro-fusion) content was higher in O-CR vs A-AL. In the gastrocnemius, Mfn2, Drp1, and Fis1 (pro-fission) contents were higher in O-AL vs A-AL. CR reduced this aging-related increase in Mfn2 and Fis1 content. Overall, these results reveal for the first time that aging differentially impacts mitochondrial morphology and dynamics in different muscle fiber types, by increasing fission/fragmentation in oxidative fibers while enhancing mitochondrial size and branching in glycolytic fibers. Our results also indicate that although CR partially attenuates aging-related changes in mitochondrial dynamics in glycolytic fibers, its anti-aging effect on mitochondrial morphology is restricted to oxidative fibers.
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Affiliation(s)
- Julie Faitg
- Département de Biologie, Faculté des Sciences, UQAM, Montreal, QC, Canada.,Groupe de recherche en Activité Physique Adaptée, Montreal, QC, Canada
| | - Jean-Philippe Leduc-Gaudet
- Groupe de recherche en Activité Physique Adaptée, Montreal, QC, Canada.,Meakins-Christie Laboratories, Department of Medicine and Division of Experimental Medicine, McGill University, Montreal, QC, Canada.,Département des sciences de l'activité physique, Faculté des Sciences, UQAM, Montreal, QC, Canada
| | - Olivier Reynaud
- Groupe de recherche en Activité Physique Adaptée, Montreal, QC, Canada.,Département des sciences de l'activité physique, Faculté des Sciences, UQAM, Montreal, QC, Canada
| | - Guylaine Ferland
- Institut de cardiologie de Montréal Research Center, Montreal, QC, Canada.,Department of Nutrition, University of Montreal, Montreal, QC, Canada
| | - Pierrette Gaudreau
- Laboratory of Neuroendocrinology of Aging, Centre Hospitalier de l'Université de Montréal Research Center (CRCHUM), Montreal, QC, Canada.,Department of Medicine,University of Montreal, Montreal, QC, Canada
| | - Gilles Gouspillou
- Groupe de recherche en Activité Physique Adaptée, Montreal, QC, Canada.,Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal, Montreal, QC, Canada
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49
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Lazarus NR, Lord JM, Harridge SDR. The relationships and interactions between age, exercise and physiological function. J Physiol 2019; 597:1299-1309. [PMID: 30422311 PMCID: PMC6395415 DOI: 10.1113/jp277071] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 10/29/2018] [Indexed: 01/01/2023] Open
Abstract
This brief review focuses on the relationships and interactions between human ageing, exercise and physiological function. It explores the importance of the selection of participants for ageing research, the strengths and deficiencies of both cross-sectional and longitudinal studies, and the complexities involved in understanding time-dependent, lifelong physiological processes. As being physically active is crucial to fostering healthy ageing, it is essential that participants in health and ageing research are defined in terms of their physical activity/exercise status as well as other lifestyle factors. Comparisons of exercisers with non-exercisers has suggested that there is a mosaic of regulation of ageing both within and across physiological systems. We suggest that four broad categories exist which encompass this regulation. These are (i) systems and indices that are age dependent, but activity independent; (ii) systems that are age dependent, but also malleable by exercise; (iii) systems that are not age affected but are altered by exercise; and (iv) systems that are neither age nor activity dependent. We briefly explore the concept of a mosaic of regulation in a selection of physiological systems. These include skeletal muscle, the immune and endocrine systems, gastrointestinal as well as cognitive function. We go onto examine how these categories might fit within the broad framework of understanding the physiology of human ageing.
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Affiliation(s)
- Norman R. Lazarus
- Centre for Human & Applied Physiological SciencesSchool of Basic & Medical BiosciencesFaculty of Life Sciences & MedicineKing's College LondonLondonUK
| | - Janet M. Lord
- Institute of Inflammation and AgeingMRC‐ARUK Centre for Musculoskeletal Ageing ResearchUniversity of BirminghamBirminghamUK
- NIHR Birmingham Biomedical Research CentreUniversity Hospital BirminghamBirminghamUK
| | - Stephen D. R. Harridge
- Centre for Human & Applied Physiological SciencesSchool of Basic & Medical BiosciencesFaculty of Life Sciences & MedicineKing's College LondonLondonUK
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50
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Polli A, Van Oosterwijck J, Nijs J, Marusic U, De Wandele I, Paul L, Meeus M, Moorkens G, Lambrecht L, Ickmans K. Relationship Between Exercise-induced Oxidative Stress Changes and Parasympathetic Activity in Chronic Fatigue Syndrome: An Observational Study in Patients and Healthy Subjects. Clin Ther 2019; 41:641-655. [PMID: 30665828 DOI: 10.1016/j.clinthera.2018.12.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 12/10/2018] [Accepted: 12/14/2018] [Indexed: 02/07/2023]
Abstract
PURPOSE Oxidative stress has been proposed as a contributor to pain in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). During incremental exercise in patients with ME/CFS, oxidative stress enhances sooner and antioxidant response is delayed. We explored whether oxidative stress is associated with pain symptoms or pain changes following exercise, and the possible relationships between oxidative stress and parasympathetic vagal nerve activity in patients with ME/CFS versus healthy, inactive controls. METHODS The present study reports secondary outcomes from a previous work. Data from 36 participants were studied (women with ME/CFS and healthy controls). Subjects performed a submaximal exercise test with continuous cardiorespiratory monitoring. Levels of thiobarbituric acid-reactive substances (TBARSs) were used as a measure of oxidative stress, and heart rate variability was used to assess vagal activity. Before and after the exercise, subjects were asked to rate their pain using a visual analogic scale. FINDINGS Significant between-group differences in pain at both baseline and following exercise were found (both, P < 0.007). In healthy controls, pain was significantly improved following exercise (P = 0.002). No change in oxidative stress level after exercise was found. Significant correlation between TBARS levels and pain was found at baseline (r = 0.540; P = 0.021) and after exercise (r = 0.524; P = 0.024) in patients only. No significant correlation between TBARS and heart rate variability at baseline or following exercise was found in either group. However, a significant correlation was found between exercise-induced changes in HRV and TBARS in healthy controls (r = -0.720; P = 0.001). IMPLICATIONS Oxidative stress showed an association with pain symptoms in people with ME/CFS, but no exercise-induced changes in oxidative stress were found. In addition, the change in parasympathetic activity following exercise partially accounted for the change in oxidative stress in healthy controls. More research is required to further explore this link.
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Affiliation(s)
- Andrea Polli
- Pain in Motion International Research Group, Belgium(12); Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium; Research Foundation-Flanders (FWO), Brussels, Belgium.
| | - Jessica Van Oosterwijck
- Pain in Motion International Research Group, Belgium(12); Research Foundation-Flanders (FWO), Brussels, Belgium; Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Jo Nijs
- Pain in Motion International Research Group, Belgium(12); Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium; Department of Physical Medicine and Physiotherapy, University Hospital Brussels, Brussels, Belgium
| | - Uros Marusic
- Institute for Kinesiology Research, Science and Research Centre Koper, Koper, Slovenia; Department of Health Sciences, Alma Mater Europaea-ECM, Maribor, Slovenia
| | - Inge De Wandele
- Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Lorna Paul
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, United Kingdom
| | - Mira Meeus
- Pain in Motion International Research Group, Belgium(12); Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Greta Moorkens
- Department of Internal Medicine, University Hospital Antwerp (UZA), Antwerp, Belgium
| | - Luc Lambrecht
- Private Practice for Internal Medicine, Ghent, Belgium
| | - Kelly Ickmans
- Pain in Motion International Research Group, Belgium(12); Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium; Department of Physical Medicine and Physiotherapy, University Hospital Brussels, Brussels, Belgium
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