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Takahashi K, Mukai K, Takahashi Y, Ebisuda Y, Hatta H, Kitaoka Y. Comparison of long- and short-rest periods during high-intensity interval exercise on transcriptomic responses in equine skeletal muscle. Physiol Genomics 2025; 57:28-39. [PMID: 39661768 DOI: 10.1152/physiolgenomics.00066.2024] [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: 05/31/2024] [Revised: 09/17/2024] [Accepted: 11/23/2024] [Indexed: 12/13/2024] Open
Abstract
The purpose of this study was to elucidate the skeletal muscle transcriptomic response unique to rest duration during high-intensity interval exercise. Thoroughbred horses performed three 1-min bouts of exercise at their maximal oxygen uptake (10.7-12.5 m/s), separated by 15 min (long) or 2 min (short) walking at 1.7 m/s. Gluteus medius muscle was collected before and at 4 h after the exercise and used for RNA sequencing. We identified 1,756 and 1,421 differentially expressed genes in response to the long and short protocols, respectively, using DEseq2 analysis [false discovery rate (FDR) cutoff = 0.05, minimal fold change = 1.5]. The overall transcriptional response was partially aligned, with 43% (n = 949) of genes altered in both protocols, whereas no discordant directional changes were observed. K-means clustering and gene set enrichment analyses based on Gene Ontology biological process terms showed that genes associated with muscle adaptation and development were upregulated regardless of exercise conditions; genes related to immune and cytokine responses were more upregulated following the long protocol, and protein folding and temperature response were highly expressed after the short protocol. We found that 11 genes were upregulated to a greater extent by the short protocol and one was by the long protocol, with GNA13, SPART, PHAF1, and PTX3 identified as potential candidates for skeletal muscle remodeling. Our results suggest that altered metabolic fluctuations dependent on the intermittent pattern of interval exercise modulate skeletal muscle gene expression, and therefore, rest interval length could be an important consideration in optimizing skeletal muscle adaptation.NEW & NOTEWORTHY This is the first study to address the comparison of transcriptional responses to high-intensity interval exercise with two different rest periods in skeletal muscle. The expression of genes related to metabolic adaptations altered in both conditions, while genes associated with immune and cytokine responses and protein folding and temperature response were varied with the length of the rest period. These results provide evidence for rest duration-specific transcriptional response to high-intensity interval training.
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Affiliation(s)
- Kenya Takahashi
- Department of Sports Sciences, The University of Tokyo, Tokyo, Japan
| | - Kazutaka Mukai
- Sports Science Division, Equine Research Institute, Japan Racing Association, Tochigi, Japan
| | - Yuji Takahashi
- Sports Science Division, Equine Research Institute, Japan Racing Association, Tochigi, Japan
| | - Yusaku Ebisuda
- Sports Science Division, Equine Research Institute, Japan Racing Association, Tochigi, Japan
| | - Hideo Hatta
- Department of Sports Sciences, The University of Tokyo, Tokyo, Japan
| | - Yu Kitaoka
- Department of Human Sciences, Kanagawa University, Yokohama, Kanagawa, Japan
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Takahashi K, Kitaoka Y, Hatta H. Better maintenance of enzymatic capacity and higher levels of substrate transporter proteins in skeletal muscle of aging female mice. Appl Physiol Nutr Metab 2024; 49:1100-1114. [PMID: 38710106 DOI: 10.1139/apnm-2024-0016] [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] [Indexed: 05/08/2024]
Abstract
This study investigated sex-specific differences in high-energy phosphate, glycolytic, and mitochondrial enzyme activities and also metabolite transporter protein levels in the skeletal muscles of adult (5 months old), middle-aged (12 months old), and advanced-aged (24 months old) mice. While gastrocnemius glycogen content increased with age regardless of sex, gastrocnemius triglyceride levels increased only in advanced-aged female mice. Aging decreased creatine kinase and adenylate kinase activities in the plantaris muscle of both sexes and in the soleus muscle of male mice but not in female mice. Irrespective of sex, phosphofructokinase and lactate dehydrogenase (LDH) activities decreased in the plantaris and soleus muscles. Additionally, hexokinase activity in the plantaris muscle and LDH activity in the soleus muscle decreased to a greater extent in aged male mice compared with those in aged female mice. Mitochondrial enzyme activities increased in the plantaris muscle of aged female mice but did not change in male mice. The protein content of the glucose transporter 4 in the aged plantaris muscle and fatty acid translocase/cluster of differentiation 36 increased in the aged plantaris and soleus muscles of both sexes, with a significantly higher content in female mice. These findings suggest that females possess a better ability to maintain metabolic enzyme activity and higher levels of metabolite transport proteins in skeletal muscle during aging, despite alterations in lipid metabolism. Our data provide a basis for studying muscle metabolism in the context of age-dependent metabolic perturbations and diseases that affect females and males differently.
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Affiliation(s)
- Kenya Takahashi
- Department of Sports Sciences, The University of Tokyo, 3-8-1, Komaba, Meguro-ku, Tokyo 153-8902, Japan
| | - Yu Kitaoka
- Department of Human Sciences, Kanagawa University, 3-27-1, Rokkakubashi, Kanagawa-ku, Yokohama, Kanagawa 221-8686, Japan
| | - Hideo Hatta
- Department of Sports Sciences, The University of Tokyo, 3-8-1, Komaba, Meguro-ku, Tokyo 153-8902, Japan
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Taghizadeh-Hesary F, Houshyari M, Farhadi M. Mitochondrial metabolism: a predictive biomarker of radiotherapy efficacy and toxicity. J Cancer Res Clin Oncol 2023; 149:6719-6741. [PMID: 36719474 DOI: 10.1007/s00432-023-04592-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 01/18/2023] [Indexed: 02/01/2023]
Abstract
INTRODUCTION Radiotherapy is a mainstay of cancer treatment. Clinical studies revealed a heterogenous response to radiotherapy, from a complete response to even disease progression. To that end, finding the relative prognostic factors of disease outcomes and predictive factors of treatment efficacy and toxicity is essential. It has been demonstrated that radiation response depends on DNA damage response, cell cycle phase, oxygen concentration, and growth rate. Emerging evidence suggests that altered mitochondrial metabolism is associated with radioresistance. METHODS This article provides a comprehensive evaluation of the role of mitochondria in radiotherapy efficacy and toxicity. In addition, it demonstrates how mitochondria might be involved in the famous 6Rs of radiobiology. RESULTS In terms of this idea, decreasing the mitochondrial metabolism of cancer cells may increase radiation response, and enhancing the mitochondrial metabolism of normal cells may reduce radiation toxicity. Enhancing the normal cells (including immune cells) mitochondrial metabolism can potentially improve the tumor response by enhancing immune reactivation. Future studies are invited to examine the impacts of mitochondrial metabolism on radiation efficacy and toxicity. Improving radiotherapy response with diminishing cancer cells' mitochondrial metabolism, and reducing radiotherapy toxicity with enhancing normal cells' mitochondrial metabolism.
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Affiliation(s)
- Farzad Taghizadeh-Hesary
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Clinical Oncology Department, Iran University of Medical Sciences, Tehran, Iran.
| | - Mohammad Houshyari
- Clinical Oncology Department, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Farhadi
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Smith SJ, Lopresti AL, Fairchild TJ. The effects of alcohol on testosterone synthesis in men: a review. Expert Rev Endocrinol Metab 2023; 18:155-166. [PMID: 36880700 DOI: 10.1080/17446651.2023.2184797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 02/22/2023] [Indexed: 03/02/2023]
Abstract
INTRODUCTION Testosterone concentrations in men decline with advancing age, with low testosterone concentrations being associated with multiple morbidities, an increased risk of early mortality, and a reduced quality of life. The purpose of this study was to examine the effects of alcohol on testosterone synthesis in men by investigating its effects on each level of the hypothalamic-pituitary-gonadal axis. AREAS COVERED Acute consumption of a low-to-moderate amount of alcohol increases testosterone concentrations in men, while consumption of a large volume of alcohol is associated with a reduction in serum testosterone concentrations. Elevated testosterone concentrations result from the increased activity of detoxification enzymes in the liver. Conversely, the primary mechanisms of action involved in the reduction of testosterone are increased hypothalamic-pituitary-adrenal axis activity, inflammation, and oxidative stress. When alcohol is consumed in excess, particularly chronically, it negatively affects testosterone production in men. EXPERT OPINION Since testosterone is an important component of men's health and wellbeing, current levels of alcohol consumption in many countries of the world require urgent attention. Elucidating the relationship between alcohol consumption and testosterone may be useful in identifying strategies to attenuate the testosterone-reducing effects of excessive or chronic alcohol consumption.
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Affiliation(s)
- Stephen James Smith
- Clinical Research Australia, Perth, Australia
- The Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, Australia
| | - Adrian Leo Lopresti
- Clinical Research Australia, Perth, Australia
- The Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, Australia
| | - Timothy John Fairchild
- The Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, Australia
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Takahashi K, Kitaoka Y, Hatta H. Effects of endurance training on metabolic enzyme activity and transporter protein levels in the skeletal muscles of orchiectomized mice. J Physiol Sci 2022; 72:14. [PMID: 35768774 PMCID: PMC10717707 DOI: 10.1186/s12576-022-00839-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 06/18/2022] [Indexed: 12/20/2022]
Abstract
This study investigated whether endurance training attenuates orchiectomy (ORX)-induced metabolic alterations. At 7 days of recovery after sham operation or ORX surgery, the mice were randomized to remain sedentary or undergo 5 weeks of treadmill running training (15-20 m/min, 60 min, 5 days/week). ORX decreased glycogen concentration in the gastrocnemius muscle, enhanced phosphofructokinase activity in the plantaris muscle, and decreased lactate dehydrogenase activity in the plantaris and soleus muscles. Mitochondrial enzyme activities and protein content in the plantaris and soleus muscles were also decreased after ORX, but preserved, in part, by endurance training. In the treadmill running test (15 m/min, 60 min) after 4 weeks of training, orchiectomized sedentary mice showed impaired exercise performance, which was restored by endurance training. Thus, endurance training could be a potential therapeutic strategy to prevent the hypoandrogenism-induced decline in muscle mitochondrial content and physical performance.
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Affiliation(s)
- Kenya Takahashi
- Department of Sports Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1, Komaba, Meguro-ku, Tokyo, 153-8902, Japan.
| | - Yu Kitaoka
- Department of Human Sciences, Kanagawa University, 3-27-1, Rokkakubashi, Kanagawa-ku, Yokohama, Kanagawa, 221-8686, Japan
| | - Hideo Hatta
- Department of Sports Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1, Komaba, Meguro-ku, Tokyo, 153-8902, Japan
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Li Q, Wang L, Fang X, Zhao L. Highly Efficient Biotransformation of Notoginsenoside R1 into Ginsenoside Rg1 by Dictyoglomus thermophilum β-xylosidase Xln-DT. J Microbiol Biotechnol 2022; 32:447-457. [PMID: 35131955 PMCID: PMC9628812 DOI: 10.4014/jmb.2111.11020] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 02/03/2022] [Accepted: 02/08/2022] [Indexed: 12/15/2022]
Abstract
Notoginsenoside R1 and ginsenoside Rg1 are the main active ingredients of Panax notoginseng, exhibiting anti-fatigue, anti-tumor, anti-inflammatory, and other activities. In a previous study, a GH39 β-xylosidase Xln-DT was responsible for the bioconversion of saponin, a natural active substance with a xylose group, with high selectivity for cleaving the outer xylose moiety of notoginsenoside R1 at the C-6 position, producing ginsenoside Rg1 with potent anti-fatigue activity. The optimal bioconversion temperature, pH, and enzyme dosage were obtained by optimizing the transformation conditions. Under optimal conditions (pH 6.0, 75°C, enzyme dosage 1.0 U/ml), 1.0 g/l of notoginsenoside R1 was converted into 0.86 g/l of ginsenoside Rg1 within 30 min, with a molar conversion rate of approximately 100%. Furthermore, the in vivo anti-fatigue activity of notoginsenoside R1 and ginsenoside Rg1 were compared using a suitable rat model. Compared with the control group, the forced swimming time to exhaustion was prolonged in mice by 17.3% in the Rg1 high group (20 mg/kg·d). Additionally, the levels of hepatic glycogen (69.9-83.3% increase) and muscle glycogen (36.9-93.6% increase) were increased. In the Rg1 group, hemoglobin levels were also distinctly increased by treatment concentrations. Our findings indicate that treatment with ginsenoside Rg1 enhances the anti-fatigue effects. In this study, we reveal a GH39 β-xylosidase displaying excellent hydrolytic activity to produce ginsenoside Rg1 in the pharmaceutical and food industries.
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Affiliation(s)
- Qi Li
- Co-innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, 159 Long Pan Road, Nanjing 210037, P.R. China,College of Chemical Engineering, Nanjing Forestry University, 159 Long Pan Road, Nanjing 210037, P.R. China
| | - Lei Wang
- College of Chemical Engineering, Nanjing Forestry University, 159 Long Pan Road, Nanjing 210037, P.R. China
| | - Xianying Fang
- College of Chemical Engineering, Nanjing Forestry University, 159 Long Pan Road, Nanjing 210037, P.R. China,Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, Nanjing Forestry University, Nanjing 210037, P.R. China,Corresponding authors X. Fang Phone : +86-025-85427962 Fax : +86-025-85418873 E-mail :
| | - Linguo Zhao
- Co-innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, 159 Long Pan Road, Nanjing 210037, P.R. China,College of Chemical Engineering, Nanjing Forestry University, 159 Long Pan Road, Nanjing 210037, P.R. China,
L. Zhao Phone : +86-025-85427962 Fax : +86-025-85418873 E-mail :
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Gharahdaghi N, Rudrappa S, Brook MS, Farrash W, Idris I, Aziz MHA, Kadi F, Papaioannou K, Phillips BE, Sian T, Herrod PJ, Wilkinson DJ, Szewczyk NJ, Smith K, Atherton PJ. Pharmacological hypogonadism impairs molecular transducers of exercise-induced muscle growth in humans. J Cachexia Sarcopenia Muscle 2022; 13:1134-1150. [PMID: 35233984 PMCID: PMC8977972 DOI: 10.1002/jcsm.12843] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 08/25/2021] [Accepted: 09/30/2021] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND The relative role of skeletal muscle mechano-transduction in comparison with systemic hormones, such as testosterone (T), in regulating hypertrophic responses to exercise is contentious. We investigated the mechanistic effects of chemical endogenous T depletion adjuvant to 6 weeks of resistance exercise training (RET) on muscle mass, function, myogenic regulatory factors, and muscle anabolic signalling in younger men. METHODS Non-hypogonadal men (n = 16; 18-30 years) were randomized in a double-blinded fashion to receive placebo (P, saline n = 8) or the GnRH analogue, Goserelin [Zoladex (Z), 3.6 mg, n = 8], injections, before 6 weeks of supervised whole-body RET. Participants underwent dual-energy X-ray absorptiometry (DXA), ultrasound of m. vastus lateralis (VL), and VL biopsies for assessment of cumulative muscle protein synthesis (MPS), myogenic gene expression, and anabolic signalling pathway responses. RESULTS Zoladex suppressed endogenous T to within the hypogonadal range and was well tolerated; suppression was associated with blunted fat free mass [Z: 55.4 ± 2.8 to 55.8 ± 3.1 kg, P = 0.61 vs. P: 55.9 ± 1.7 to 57.4 ± 1.7 kg, P = 0.006, effect size (ES) = 0.31], composite strength (Z: 40 ± 2.3% vs. P: 49.8 ± 3.3%, P = 0.03, ES = 1.4), and muscle thickness (Z: 2.7 ± 0.4 to 2.69 ± 0.36 cm, P > 0.99 vs. P: 2.74 ± 0.32 to 2.91 ± 0.32 cm, P < 0.0001, ES = 0.48) gains. Hypogonadism attenuated molecular transducers of muscle growth related to T metabolism (e.g. androgen receptor: Z: 1.2 fold, P > 0.99 vs. P: 1.9 fold, P < 0.0001, ES = 0.85), anabolism/myogenesis (e.g. IGF-1Ea: Z: 1.9 fold, P = 0.5 vs. P: 3.3 fold, P = 0.0005, ES = 0.72; IGF-1Ec: Z: 2 fold, P > 0.99 vs. P: 4.7 fold, P = 0.0005, ES = 0.68; myogenin: Z: 1.3 fold, P > 0.99 vs. P: 2.7 fold, P = 0.002, ES = 0.72), RNA/DNA (Z: 0.47 ± 0.03 to 0.53 ± 0.03, P = 0.31 vs. P: 0.50 ± 0.01 to 0.64 ± 0.04, P = 0.003, ES = 0.72), and RNA/ASP (Z: 5.8 ± 0.4 to 6.8 ± 0.5, P > 0.99 vs. P: 6.5 ± 0.2 to 8.9 ± 1.1, P = 0.008, ES = 0.63) ratios, as well as acute RET-induced phosphorylation of growth signalling proteins (e.g. AKTser473 : Z: 2.74 ± 0.6, P = 0.2 vs. P: 5.5 ± 1.1 fold change, P < 0.001, ES = 0.54 and mTORC1ser2448 : Z: 1.9 ± 0.8, P > 0.99 vs. P: 3.6 ± 1 fold change, P = 0.002, ES = 0.53). Both MPS (Z: 1.45 ± 0.11 to 1.50 ± 0.06%·day-1 , P = 0.99 vs. P: 1.5 ± 0.12 to 2.0 ± 0.15%·day-1 , P = 0.01, ES = 0.97) and (extrapolated) muscle protein breakdown (Z: 93.16 ± 7.8 vs. P: 129.1 ± 13.8 g·day-1 , P = 0.04, ES = 0.92) were reduced with hypogonadism result in lower net protein turnover (3.9 ± 1.1 vs. 1.2 ± 1.1 g·day-1 , P = 0.04, ES = 0.95). CONCLUSIONS We conclude that endogenous T sufficiency has a central role in the up-regulation of molecular transducers of RET-induced muscle hypertrophy in humans that cannot be overcome by muscle mechano-transduction alone.
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Affiliation(s)
- Nima Gharahdaghi
- MRC-Verus Arthritis Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Supreeth Rudrappa
- MRC-Verus Arthritis Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Matthew S Brook
- MRC-Verus Arthritis Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Wesam Farrash
- MRC-Verus Arthritis Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK.,Laboratory Medicine Department, College of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Iskandar Idris
- MRC-Verus Arthritis Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Muhammad Hariz Abdul Aziz
- MRC-Verus Arthritis Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Fawzi Kadi
- Division of Sports Sciences, School of Health and Medical Sciences, Örebro University, Örebro, Sweden
| | - Konstantinos Papaioannou
- Division of Sports Sciences, School of Health and Medical Sciences, Örebro University, Örebro, Sweden
| | - Bethan E Phillips
- MRC-Verus Arthritis Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Tanvir Sian
- MRC-Verus Arthritis Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Philip J Herrod
- MRC-Verus Arthritis Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Daniel J Wilkinson
- MRC-Verus Arthritis Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Nathaniel J Szewczyk
- MRC-Verus Arthritis Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Kenneth Smith
- MRC-Verus Arthritis Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Philip J Atherton
- MRC-Verus Arthritis Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
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Cung S, Pyle L, Nadeau K, Dabelea D, Cree-Green M, Davis SM. In-vivo skeletal muscle mitochondrial function in Klinefelter syndrome. J Investig Med 2022; 70:104-107. [PMID: 34493629 PMCID: PMC8712372 DOI: 10.1136/jim-2021-001966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2021] [Indexed: 01/03/2023]
Abstract
Klinefelter syndrome (XXY) occurs in 1 in 600 males, resulting in testosterone deficiency and a high prevalence of insulin resistance. Testosterone deficiency in men is a known cause of insulin resistance, and mitochondrial dysfunction is hypothesized to mediate this relationship. The aim of this cross-sectional study was to evaluate muscle mitochondrial function in XXY compared with male controls. Twenty-seven boys with XXY (age 14.7±1.8 years) were compared with 87 controls (age 16.9±0.9). In-vivo calf muscle mitochondrial function was assessed via phosphorus magnetic resonance spectroscopy (31P-MRS) following 90 s of isometric 70% maximal exercise. Multiple linear regression was used to compare 31P-MRS outcomes (ADP and phosphocreatine (PCr) time constants, rate of oxidative phosphorylation (Oxphos), and Qmax or the maximal mitochondrial function relative to mitochondrial density) between groups after adjusting for age differences. There were no statistically significant differences in the mitochondrial outcomes of ADP, Oxphos, PCr, and Qmax between the groups. There were also no differences in a sensitivity analysis within the XXY group by testosterone treatment status. In this study, in-vivo postexercise skeletal muscle mitochondrial function does not appear to be impaired in adolescents with XXY compared with controls and is not significantly different by testosterone treatment status in XXY.
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Affiliation(s)
- Stephanie Cung
- University of Colorado School of Medicine; Aurora, CO USA
| | - Laura Pyle
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO USA.,Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO USA
| | - Kristin Nadeau
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO USA
| | - Dana Dabelea
- Department of Epidemiology, Colorado School of Public Health, Aurora, CO USA.,Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, Aurora, CO USA
| | - Melanie Cree-Green
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO USA
| | - Shanlee M. Davis
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO USA.,eXtraordinarY Kids Clinic and Research Program, Children’s Hospital Colorado, Aurora, CO USA
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Maseroli E, Comeglio P, Corno C, Cellai I, Filippi S, Mello T, Galli A, Rapizzi E, Presenti L, Truglia MC, Lotti F, Facchiano E, Beltrame B, Lucchese M, Saad F, Rastrelli G, Maggi M, Vignozzi L. Testosterone treatment is associated with reduced adipose tissue dysfunction and nonalcoholic fatty liver disease in obese hypogonadal men. J Endocrinol Invest 2021; 44:819-842. [PMID: 32772323 PMCID: PMC7946690 DOI: 10.1007/s40618-020-01381-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 07/31/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE In both preclinical and clinical settings, testosterone treatment (TTh) of hypogonadism has shown beneficial effects on insulin sensitivity and visceral and liver fat accumulation. This prospective, observational study was aimed at assessing the change in markers of fat and liver functioning in obese men scheduled for bariatric surgery. METHODS Hypogonadal patients with consistent symptoms (n = 15) undergoing 27.63 ± 3.64 weeks of TTh were compared to untreated eugonadal (n = 17) or asymptomatic hypogonadal (n = 46) men. A cross-sectional analysis among the different groups was also performed, especially for data derived from liver and fat biopsies. Preadipocytes isolated from adipose tissue biopsies were used to evaluate insulin sensitivity, adipogenic potential and mitochondrial function. NAFLD was evaluated by triglyceride assay and by calculating NAFLD activity score in liver biopsies. RESULTS In TTh-hypogonadal men, histopathological NAFLD activity and steatosis scores, as well as liver triglyceride content were lower than in untreated-hypogonadal men and comparable to eugonadal ones. TTh was also associated with a favorable hepatic expression of lipid handling-related genes. In visceral adipose tissue and preadipocytes, TTh was associated with an increased expression of lipid catabolism and mitochondrial bio-functionality markers. Preadipocytes from TTh men also exhibited a healthier morpho-functional phenotype of mitochondria and higher insulin-sensitivity compared to untreated-hypogonadal ones. CONCLUSIONS The present data suggest that TTh in severely obese, hypogonadal individuals induces metabolically healthier preadipocytes, improving insulin sensitivity, mitochondrial functioning and lipid handling. A potentially protective role for testosterone on the progression of NAFLD, improving hepatic steatosis and reducing intrahepatic triglyceride content, was also envisaged. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02248467, September 25th 2014.
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Affiliation(s)
- E Maseroli
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - P Comeglio
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - C Corno
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - I Cellai
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - S Filippi
- Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - T Mello
- Gastroenterology Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - A Galli
- Gastroenterology Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - E Rapizzi
- Endocrinology Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - L Presenti
- General, Bariatric and Metabolic Surgery Unit, Santa Maria Nuova Hospital, , Piazza Santa Maria Nuova, 1, 50122, Florence, Italy
| | - M C Truglia
- General, Bariatric and Metabolic Surgery Unit, Santa Maria Nuova Hospital, , Piazza Santa Maria Nuova, 1, 50122, Florence, Italy
| | - F Lotti
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - E Facchiano
- General, Bariatric and Metabolic Surgery Unit, Santa Maria Nuova Hospital, , Piazza Santa Maria Nuova, 1, 50122, Florence, Italy
| | - B Beltrame
- General, Bariatric and Metabolic Surgery Unit, Santa Maria Nuova Hospital, , Piazza Santa Maria Nuova, 1, 50122, Florence, Italy
| | - M Lucchese
- General, Bariatric and Metabolic Surgery Unit, Santa Maria Nuova Hospital, , Piazza Santa Maria Nuova, 1, 50122, Florence, Italy
| | - F Saad
- Medical Affairs, Bayer AG, Kaiser-Wilhelm-Allee 1, 51373, Leverkusen, Germany
| | - G Rastrelli
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
| | - M Maggi
- Endocrinology Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy
- I.N.B.B. (Istituto Nazionale Biostrutture E Biosistemi), Viale delle Medaglie d'Oro 305, 00136, Rome, Italy
| | - L Vignozzi
- Andrology, Women's Endocrinology and Gender Incongruence Unit, Department of Experimental Clinical and Biomedical Sciences "Mario Serio", University of Florence, Viale Pieraccini 6, 50134, Florence, Italy.
- I.N.B.B. (Istituto Nazionale Biostrutture E Biosistemi), Viale delle Medaglie d'Oro 305, 00136, Rome, Italy.
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10
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Saxena N, Beraldi E, Fazli L, Somasekharan SP, Adomat H, Zhang F, Molokwu C, Gleave A, Nappi L, Nguyen K, Brar P, Nikesitch N, Wang Y, Collins C, Sorensen PH, Gleave M. Androgen receptor (AR) antagonism triggers acute succinate-mediated adaptive responses to reactivate AR signaling. EMBO Mol Med 2021; 13:e13427. [PMID: 33709547 PMCID: PMC8103094 DOI: 10.15252/emmm.202013427] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 02/05/2021] [Accepted: 02/09/2021] [Indexed: 11/09/2022] Open
Abstract
Treatment-induced adaptive pathways converge to support androgen receptor (AR) reactivation and emergence of castration-resistant prostate cancer (PCa) after AR pathway inhibition (ARPI). We set out to explore poorly defined acute adaptive responses that orchestrate shifts in energy metabolism after ARPI and identified rapid changes in succinate dehydrogenase (SDH), a TCA cycle enzyme with well-known tumor suppressor activity. We show that AR directly regulates transcription of its catalytic subunits (SDHA, SDHB) via androgen response elements (AREs). ARPI acutely suppresses SDH activity, leading to accumulation of the oncometabolite, succinate. Succinate triggers calcium ions release from intracellular stores, which in turn phospho-activates the AR-cochaperone, Hsp27 via p-CaMKK2/p-AMPK/p-p38 axis to enhance AR protein stabilization and activity. Activation of this pathway was seen in tissue microarray analysis on prostatectomy tissues and patient-derived xenografts. This adaptive response is blocked by co-targeting AR with Hsp27 under both in vitro and in vivo studies, sensitizing PCa cells to ARPI treatments.
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Affiliation(s)
- Neetu Saxena
- Vancouver Prostate Centre, Vancouver, BC, Canada
| | | | - Ladan Fazli
- Vancouver Prostate Centre, Vancouver, BC, Canada
| | | | - Hans Adomat
- Vancouver Prostate Centre, Vancouver, BC, Canada
| | - Fan Zhang
- Vancouver Prostate Centre, Vancouver, BC, Canada
| | | | - Anna Gleave
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Lucia Nappi
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | | | - Pavn Brar
- Vancouver Prostate Centre, Vancouver, BC, Canada
| | | | - Yuzhuo Wang
- Vancouver Prostate Centre, Vancouver, BC, Canada.,Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Colin Collins
- Vancouver Prostate Centre, Vancouver, BC, Canada.,Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Poul H Sorensen
- Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Martin Gleave
- Vancouver Prostate Centre, Vancouver, BC, Canada.,Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
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11
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Traish AM. Health Risks Associated with Long-Term Finasteride and Dutasteride Use: It's Time to Sound the Alarm. World J Mens Health 2020; 38:323-337. [PMID: 32202088 PMCID: PMC7308241 DOI: 10.5534/wjmh.200012] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 01/29/2020] [Accepted: 01/30/2020] [Indexed: 12/12/2022] Open
Abstract
5α-dihydrotestosterone (5α-DHT) is the most potent natural androgen. 5α-DHT elicits a multitude of physiological actions, in a host of tissues, including prostate, seminal vesicles, hair follicles, skin, kidney, and lacrimal and meibomian glands. However, the physiological role of 5α-DHT in human physiology, remains questionable and, at best, poorly appreciated. Recent emerging literature supports a role for 5α-DHT in the physiological function of liver, pancreatic β-cell function and survival, ocular function and prevention of dry eye disease and kidney physiological function. Thus, inhibition of 5α-reductases with finasteride or dutasteride to reduce 5α-DHT biosynthesis in the course of treatment of benign prostatic hyperplasia (BPH) or male pattern hair loss, known as androgenetic alopecia (AGA) my induces a novel form of tissue specific androgen deficiency and contributes to a host of pathophysiological conditions, that are yet to be fully recognized. Here, we advance the concept that blockade of 5α-reductases by finasteride or dutasteride in a mechanism-based, irreversible, inhabitation of 5α-DHT biosynthesis results in a novel state of androgen deficiency, independent of circulating testosterone levels. Finasteride and dutasteride are frequently prescribed for long-term treatment of lower urinary tract symptoms in men with BPH and in men with AGA. This treatment may result in development of non-alcoholic fatty liver diseases (NAFLD), insulin resistance (IR), type 2 diabetes (T2DM), dry eye disease, potential kidney dysfunction, among other metabolic dysfunctions. We suggest that long-term use of finasteride and dutasteride may be associated with health risks including NAFLD, IR, T2DM, dry eye disease and potential kidney disease.
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Affiliation(s)
- Abdulmaged M Traish
- Department of Urology, Boston University School of Medicine, Boston, MA, USA.
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12
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Kang W, Tong T, Park T. Corticotropin releasing factor-overexpressing mouse is a model of chronic stress-induced muscle atrophy. PLoS One 2020; 15:e0229048. [PMID: 32049987 PMCID: PMC7015416 DOI: 10.1371/journal.pone.0229048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 01/28/2020] [Indexed: 12/20/2022] Open
Abstract
Chronic stress and continually high glucocorticoid levels can induce muscle atrophy. Unfortunately, there is a lack of appropriate animal models for stress-induced muscle atrophy research. Corticotropin releasing factor-overexpressing (CRF-OE) mice are a transgenic model of chronic stress that exhibit increased plasma corticosterone levels and Cushing’s syndrome; however, the skeletal muscle pathology of the CRF-OE mouse has not been well studied. We observed that male, 19-week-old CRF-OE mice had significantly lower skeletal muscle mass, average cross-sectional myofiber area, and total muscle protein content than their wild type (WT) littermates. Muscle function determined by grip strength, wire-hang, and open field tests showed that 19-week-old male CRF-OE mice had impaired physical ability. Additionally, the skeletal muscles of CRF-mice exhibited decreased expression of factors involved in the IGF-1/AKT/mTOR protein synthesis pathway and increased ubiquitin proteasome pathway activity compared to the WT control mice. In conclusion, 19-week-old CRF-OE mice display numerous features of muscle atrophy and thus serve as a model for investigating stress-induced muscle atrophy and interventions to target the deleterious effects of stress on skeletal muscle.
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Affiliation(s)
- Wesuk Kang
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, Yonsei University, Seodaemun-gu, Seoul, Korea
| | - Tao Tong
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, Yonsei University, Seodaemun-gu, Seoul, Korea
| | - Taesun Park
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, Yonsei University, Seodaemun-gu, Seoul, Korea
- * E-mail:
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13
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Gharahdaghi N, Rudrappa S, Brook MS, Idris I, Crossland H, Hamrock C, Abdul Aziz MH, Kadi F, Tarum J, Greenhaff PL, Constantin-Teodosiu D, Cegielski J, Phillips BE, Wilkinson DJ, Szewczyk NJ, Smith K, Atherton PJ. Testosterone therapy induces molecular programming augmenting physiological adaptations to resistance exercise in older men. J Cachexia Sarcopenia Muscle 2019; 10:1276-1294. [PMID: 31568675 PMCID: PMC6903447 DOI: 10.1002/jcsm.12472] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 05/14/2019] [Accepted: 06/12/2019] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND The andropause is associated with declines in serum testosterone (T), loss of muscle mass (sarcopenia), and frailty. Two major interventions purported to offset sarcopenia are anabolic steroid therapies and resistance exercise training (RET). Nonetheless, the efficacy and physiological and molecular impacts of T therapy adjuvant to short-term RET remain poorly defined. METHODS Eighteen non-hypogonadal healthy older men, 65-75 years, were assigned in a random double-blinded fashion to receive, biweekly, either placebo (P, saline, n = 9) or T (Sustanon 250 mg, n = 9) injections over 6 week whole-body RET (three sets of 8-10 repetitions at 80% one-repetition maximum). Subjects underwent dual-energy X-ray absorptiometry, ultrasound of vastus lateralis (VL) muscle architecture, and knee extensor isometric muscle force tests; VL muscle biopsies were taken to quantify myogenic/anabolic gene expression, anabolic signalling, muscle protein synthesis (D2 O), and breakdown (extrapolated). RESULTS Testosterone adjuvant to RET augmented total fat-free mass (P=0.007), legs fat-free mass (P=0.02), and appendicular fat-free mass (P=0.001) gains while decreasing total fat mass (P=0.02). Augmentations in VL muscle thickness, fascicle length, and quadriceps cross-section area with RET occured to a greater extent in T (P < 0.05). Sum strength (P=0.0009) and maximal voluntary contract (e.g. knee extension at 70°) (P=0.002) increased significantly more in the T group. Mechanistically, both muscle protein synthesis rates (T: 2.13 ± 0.21%·day-1 vs. P: 1.34 ± 0.13%·day-1 , P=0.0009) and absolute breakdown rates (T: 140.2 ± 15.8 g·day-1 vs. P: 90.2 ± 11.7 g·day-1 , P=0.02) were elevated with T therapy, which led to higher net turnover and protein accretion in the T group (T: 8.3 ± 1.4 g·day-1 vs. P: 1.9 ± 1.2 g·day-1 , P=0.004). Increases in ribosomal biogenesis (RNA:DNA ratio); mRNA expression relating to T metabolism (androgen receptor: 1.4-fold; Srd5a1: 1.6-fold; AKR1C3: 2.1-fold; and HSD17β3: two-fold); insulin-like growth factor (IGF)-1 signalling [IGF-1Ea (3.5-fold) and IGF-1Ec (three-fold)] and myogenic regulatory factors; and the activity of anabolic signalling (e.g. mTOR, AKT, and RPS6; P < 0.05) were all up-regulated with T therapy. Only T up-regulated mitochondrial citrate synthase activity (P=0.03) and transcription factor A (1.41 ± 0.2-fold, P=0.0002), in addition to peroxisome proliferator-activated receptor-γ co-activator 1-α mRNA (1.19 ± 0.21-fold, P=0.037). CONCLUSIONS Administration of T adjuvant to RET enhanced skeletal muscle mass and performance, while up-regulating myogenic gene programming, myocellular translational efficiency and capacity, collectively resulting in higher protein turnover, and net protein accretion. T coupled with RET is an effective short-term intervention to improve muscle mass/function in older non-hypogonadal men.
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Affiliation(s)
- Nima Gharahdaghi
- MRC-ARUK Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Supreeth Rudrappa
- MRC-ARUK Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Matthew S Brook
- MRC-ARUK Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Iskandar Idris
- MRC-ARUK Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Hannah Crossland
- MRC-ARUK Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Claire Hamrock
- Institute of Food and Health, University College Dublin, Belfield, Dublin, Ireland
| | - Muhammad Hariz Abdul Aziz
- MRC-ARUK Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Fawzi Kadi
- Division of Sports Sciences, School of Health and Medical Sciences, Örebro University, Örebro, Sweden
| | - Janelle Tarum
- Division of Sports Sciences, School of Health and Medical Sciences, Örebro University, Örebro, Sweden
| | - Paul L Greenhaff
- MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Life Sciences, University of Nottingham, Nottingham, Nottingham, UK
| | - Dumitru Constantin-Teodosiu
- MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Life Sciences, University of Nottingham, Nottingham, Nottingham, UK
| | - Jessica Cegielski
- MRC-ARUK Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Bethan E Phillips
- MRC-ARUK Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Daniel J Wilkinson
- MRC-ARUK Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Nathaniel J Szewczyk
- MRC-ARUK Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Kenneth Smith
- MRC-ARUK Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
| | - Philip J Atherton
- MRC-ARUK Centre for Musculoskeletal Ageing Research and Nottingham NIHR BRC, School of Medicine, University of Nottingham, Derby, UK
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14
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Role of Gender in Regulation of Redox Homeostasis in Pulmonary Arterial Hypertension. Antioxidants (Basel) 2019; 8:antiox8050135. [PMID: 31100969 PMCID: PMC6562572 DOI: 10.3390/antiox8050135] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 04/18/2019] [Accepted: 05/09/2019] [Indexed: 12/21/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is one of the diseases with a well-established gender dimorphism. The prevalence of PAH is increased in females with a ratio of 4:1, while poor survival prognosis is associated with the male gender. Nevertheless, the specific contribution of gender in disease development and progression is unclear due to the complex nature of the PAH. Oxidative and nitrosative stresses are important contributors in PAH pathogenesis; however, the role of gender in redox homeostasis has been understudied. This review is aimed to overview the possible sex-specific mechanisms responsible for the regulation of the balance between oxidants and antioxidants in relation to PAH pathobiology.
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15
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Coen PM, Musci RV, Hinkley JM, Miller BF. Mitochondria as a Target for Mitigating Sarcopenia. Front Physiol 2019; 9:1883. [PMID: 30687111 PMCID: PMC6335344 DOI: 10.3389/fphys.2018.01883] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 12/12/2018] [Indexed: 12/14/2022] Open
Abstract
Sarcopenia is the loss of muscle mass, strength, and physical function that is characteristic of aging. The progression of sarcopenia is gradual but may be accelerated by periods of muscle loss during physical inactivity secondary to illness or injury. The loss of mobility and independence and increased comorbidities associated with sarcopenia represent a major healthcare challenge for older adults. Mitochondrial dysfunction and impaired proteostatic mechanisms are important contributors to the complex etiology of sarcopenia. As such, interventions that target improving mitochondrial function and proteostatic maintenance could mitigate or treat sarcopenia. Exercise is currently the only effective option to treat sarcopenia and does so, in part, by improving mitochondrial energetics and protein turnover. Exercise interventions also serve as a discovery tool to identify molecular targets for development of alternative therapies to treat sarcopenia. In summary, we review the evidence linking mitochondria and proteostatic maintenance to sarcopenia and discuss the therapeutic potential of interventions addressing these two factors to mitigate sarcopenia.
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Affiliation(s)
- Paul M Coen
- Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL, United States
| | - Robert V Musci
- Department of Health and Exercise Science, Colorado State University, Fort Collins, CO, United States
| | - J Matthew Hinkley
- Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL, United States
| | - Benjamin F Miller
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
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16
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Rossetti ML, Gordon BS. The role of androgens in the regulation of muscle oxidative capacity following aerobic exercise training. Appl Physiol Nutr Metab 2017; 42:1001-1007. [PMID: 28570828 DOI: 10.1139/apnm-2017-0230] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Reduced production or bioavailability of androgens, termed hypogonadism, occurs in a variety of pathological conditions. While androgens target numerous tissues throughout the body, hypogonadism specifically reduces the ability of skeletal muscle to produce adenosine triphosphate aerobically, i.e., muscle oxidative capacity. This has important implications for overall health as muscle oxidative capacity impacts a number of metabolic processes. Although androgen replacement therapy is effective at restoring muscle oxidative capacity in hypogonadal individuals, this is not a viable therapeutic option for all who are experiencing hypogonadism. While aerobic exercise may be a viable alternative to increase muscle oxidative capacity, it is unknown whether androgen depletion affects this adaptation. To determine this, sham and castrated mice were randomized to remain sedentary or undergo 8 weeks of aerobic treadmill exercise training. All mice were fasted overnight prior to sacrifice. Though exercise increased markers of muscle oxidative capacity independent of castration (cytochrome c oxidase subunit IV and cytochrome c), these measures were lower in castrated mice. This reduction was not due to a difference in peroxisome proliferator activated receptor gamma coactivator 1 alpha protein content, as expression was increased to a similar absolute value in sham and castrated animals following exercise training. However, markers of BCL2/Adenovirus E1B 19 kDa Interacting Protein 3 (BNIP3)-mediated mitophagy were increased by castration independent of exercise. Together, these data show that exercise training can increase markers of muscle oxidative capacity following androgen depletion. However, these values are reduced by androgen depletion likely due in part to elevated BNIP3-mediated mitophagy.
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Affiliation(s)
- Michael L Rossetti
- Institute of Exercise Physiology and Wellness, The University of Central Florida, PO Box 161250, Orlando, FL 32816, USA.,Institute of Exercise Physiology and Wellness, The University of Central Florida, PO Box 161250, Orlando, FL 32816, USA
| | - Bradley S Gordon
- Institute of Exercise Physiology and Wellness, The University of Central Florida, PO Box 161250, Orlando, FL 32816, USA.,Institute of Exercise Physiology and Wellness, The University of Central Florida, PO Box 161250, Orlando, FL 32816, USA
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17
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Negative Impact of Testosterone Deficiency and 5α-Reductase Inhibitors Therapy on Metabolic and Sexual Function in Men. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1043:473-526. [DOI: 10.1007/978-3-319-70178-3_22] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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18
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Davis S, Lahlou N, Bardsley M, Temple MC, Kowal K, Pyle L, Zeitler P, Ross J. Gonadal function is associated with cardiometabolic health in pre-pubertal boys with Klinefelter syndrome. Andrology 2016; 4:1169-1177. [PMID: 27637014 DOI: 10.1111/andr.12275] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 07/21/2016] [Accepted: 07/24/2016] [Indexed: 01/19/2023]
Abstract
The most common sex chromosome aneuploidy, Klinefelter syndrome (KS), is associated with primary gonadal failure and increased morbidity and mortality from cardiometabolic disorders in adulthood. Children with KS also have a high prevalence of metabolic syndrome (MetS) features. To assess the relationship of gonadal and cardiometabolic function in children with KS, we evaluated serum hormones [gonadotropins, inhibin B (INHB), anti-mullerian hormone (AMH), total testosterone (TT)], and features of MetS (waist circumference, fasting lipid panel, fasting blood glucose (FBG), and blood pressure) in 93 pre-pubertal boys with KS age 4-12 years (mean 7.7 ± 2.5 years). The cohort was grouped by age and tanner stage, and biomarkers were compared to normal ranges. A total of 80% of this pre-pubertal cohort had ≥1 feature of metabolic syndrome (MetS) and 11% had ≥3 features of MetS. Risk of MetS was independent of age and body mass index. Sertoli cell dysfunction was common with 18% having an INHB below the normal range. A low INHB was associated with higher FBG, triglycerides, LDL, and lower HDL (p < 0.05). An INHB <50 ng/dL yielded a sensitivity of 83% and a specificity of 79% for having ≥3 features of MetS. INHB and AMH positively correlated with each other (p < 0.001), and high AMH was protective of MetS. TT was below the lower limit of normal in 49% of subjects, with mean values significantly lower than expected (3.3 ng/dL vs. 4.9 ng/dL, p < 0.0001), however, no convincing relationship between TT and MetS was seen. In conclusion, gonadal and cardiometabolic dysfunction are prevalent in pre-pubertal boys with KS. Although the relationship of testosterone deficiency and MetS is well-known, this study is the first to report an association between impaired Sertoli cell function and cardiometabolic risk.
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Affiliation(s)
- S Davis
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.,Section of Pediatric Endocrinology, Children's Hospital Colorado, Aurora, CO, USA
| | - N Lahlou
- Hormone Biology and Metabolism, Hospital Cochin, Paris, France
| | - M Bardsley
- Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA.,A.I. DuPont Hospital for Children, Wilmington, DE, USA
| | - M-C Temple
- Hormone Biology and Metabolism, Hospital Cochin, Paris, France
| | - K Kowal
- Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA.,A.I. DuPont Hospital for Children, Wilmington, DE, USA
| | - L Pyle
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.,Section of Pediatric Endocrinology, Children's Hospital Colorado, Aurora, CO, USA
| | - P Zeitler
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.,Section of Pediatric Endocrinology, Children's Hospital Colorado, Aurora, CO, USA
| | - J Ross
- Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA.,A.I. DuPont Hospital for Children, Wilmington, DE, USA
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19
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Wang J, Yang J, Mao S, Chai X, Hu Y, Hou X, Tang Y, Bi C, Li X. MitProNet: A knowledgebase and analysis platform of proteome, interactome and diseases for mammalian mitochondria. PLoS One 2014; 9:e111187. [PMID: 25347823 PMCID: PMC4210245 DOI: 10.1371/journal.pone.0111187] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Accepted: 09/26/2014] [Indexed: 12/18/2022] Open
Abstract
Mitochondrion plays a central role in diverse biological processes in most eukaryotes, and its dysfunctions are critically involved in a large number of diseases and the aging process. A systematic identification of mitochondrial proteomes and characterization of functional linkages among mitochondrial proteins are fundamental in understanding the mechanisms underlying biological functions and human diseases associated with mitochondria. Here we present a database MitProNet which provides a comprehensive knowledgebase for mitochondrial proteome, interactome and human diseases. First an inventory of mammalian mitochondrial proteins was compiled by widely collecting proteomic datasets, and the proteins were classified by machine learning to achieve a high-confidence list of mitochondrial proteins. The current version of MitProNet covers 1124 high-confidence proteins, and the remainders were further classified as middle- or low-confidence. An organelle-specific network of functional linkages among mitochondrial proteins was then generated by integrating genomic features encoded by a wide range of datasets including genomic context, gene expression profiles, protein-protein interactions, functional similarity and metabolic pathways. The functional-linkage network should be a valuable resource for the study of biological functions of mitochondrial proteins and human mitochondrial diseases. Furthermore, we utilized the network to predict candidate genes for mitochondrial diseases using prioritization algorithms. All proteins, functional linkages and disease candidate genes in MitProNet were annotated according to the information collected from their original sources including GO, GEO, OMIM, KEGG, MIPS, HPRD and so on. MitProNet features a user-friendly graphic visualization interface to present functional analysis of linkage networks. As an up-to-date database and analysis platform, MitProNet should be particularly helpful in comprehensive studies of complicated biological mechanisms underlying mitochondrial functions and human mitochondrial diseases. MitProNet is freely accessible at http://bio.scu.edu.cn:8085/MitProNet.
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Affiliation(s)
- Jiabin Wang
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, Chengdu, People’s Republic of China
| | - Jian Yang
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, Chengdu, People’s Republic of China
| | - Song Mao
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, Chengdu, People’s Republic of China
| | - Xiaoqiang Chai
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, Chengdu, People’s Republic of China
| | - Yuling Hu
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, Chengdu, People’s Republic of China
| | - Xugang Hou
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, Chengdu, People’s Republic of China
| | - Yiheng Tang
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, Chengdu, People’s Republic of China
| | - Cheng Bi
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, Chengdu, People’s Republic of China
| | - Xiao Li
- College of Life Sciences, Sichuan University, Ministry of Education Key Laboratory for Bio-resource and Eco-environment, Sichuan Key Laboratory of Molecular Biology and Biotechnology, Chengdu, People’s Republic of China
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20
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Abstract
PURPOSE OF REVIEW The purpose of this article is to examine the contemporary data linking testosterone therapy in overweight and obese men with testosterone deficiency to increased lean body mass, decreased fat mass, improvement in overall body composition and sustained weight loss. This is of paramount importance because testosterone therapy in obese men with testosterone deficiency represents a novel and a timely therapeutic strategy for managing obesity in men with testosterone deficiency. RECENT FINDINGS Long-term testosterone therapy in men with testosterone deficiency produces significant and sustained weight loss, marked reduction in waist circumference and BMI and improvement in body composition. Further, testosterone therapy ameliorates components of the metabolic syndrome. The aforementioned improvements are attributed to improved mitochondrial function, increased energy utilization, increased motivation and vigor resulting in improved cardio-metabolic function and enhanced physical activity. SUMMARY The implication of testosterone therapy in management of obesity in men with testosterone deficiency is of paramount clinical significance, as it produces sustained weight loss without recidivism. On the contrary, alternative therapeutic approaches other than bariatric surgery failed to produce significant and sustained outcome and exhibit a high rate of recidivism. These findings represent strong foundations for testosterone therapy in obese men with testosterone deficiency and should spur clinical research for better understanding of usefulness of testosterone therapy in treatment of underlying pathophysiological conditions of obesity.
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Affiliation(s)
- Abdulmaged M Traish
- Departments of Biochemistry and Urology, Boston University School of Medicine, Boston, Massachusetts, USA
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Abstract
Obesity, type 2 diabetes mellitus and the metabolic syndrome are major risk factors for cardiovascular disease. Studies have demonstrated an association between low levels of testosterone and the above insulin-resistant states, with a prevalence of hypogonadism of up to 50% in men with type 2 diabetes mellitus. Low levels of testosterone are also associated with an increased risk of all-cause and cardiovascular mortality. Hypogonadism and obesity share a bidirectional relationship as a result of the complex interplay between adipocytokines, proinflammatory cytokines and hypothalamic hormones that control the pituitary-testicular axis. Interventional studies have shown beneficial effects of testosterone on components of the metabolic syndrome, type 2 diabetes mellitus and other cardiovascular risk factors, including insulin resistance and high levels of cholesterol. Biochemical evidence indicates that testosterone is involved in promoting glucose utilization by stimulating glucose uptake, glycolysis and mitochondrial oxidative phosphorylation. Testosterone is also involved in lipid homeostasis in major insulin-responsive target tissues, such as liver, adipose tissue and skeletal muscle.
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Affiliation(s)
- Preethi M Rao
- Academic Unit of Diabetes, Endocrinology and Metabolism, School of Medicine and Biomedical Sciences, University of Sheffield, UK
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