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Yoo A, Kim JI, Lee H, Nirmala FS, Hahm JH, Seo HD, Jung CH, Ha TY, Ahn J. Gromwell ameliorates glucocorticoid-induced muscle atrophy through the regulation of Akt/mTOR pathway. Chin Med 2024; 19:20. [PMID: 38287373 PMCID: PMC10826094 DOI: 10.1186/s13020-024-00890-5] [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: 11/19/2023] [Accepted: 01/18/2024] [Indexed: 01/31/2024] Open
Abstract
BACKGROUND Muscle atrophy is characterized by decreased muscle mass, function, and strength. Synthetic glucocorticoids, including dexamethasone (Dexa), are commonly used to treat autoimmune diseases. However, prolonged exposure of Dexa with high dose exerts severe side effects, including muscle atrophy. The purpose of this study was to investigate whether Gromwell root extract (GW) can prevent Dexa-induced muscle atrophy in C2C12 cells and mice and to characterize the composition of GW to identify bioactive compounds. METHODS For in vitro experiments, GW (0.5 and 1 µg/mL) or lithospermic acid (LA, 5 and 10 µM) was added to C2C12 myotubes on day 4 of differentiation and incubated for 24 h, along with 50 µM Dexa. For in vivo experiment, four-week-old male C57BL/6 mice were randomly divided into the four following groups (n = 7/group): Con group, Dexa group, GW0.1 group, and GW0.2 group. Mice were fed experimental diets of AIN-93 M with or without 0.1 or 0.2% GW for 4 weeks. Subsequently, muscle atrophy was induced by administering an intraperitoneal injection of Dexa at a dose of 15 mg/kg/day for 38 days, in conjunction with dietary intake. RESULTS In Dexa-induced myotube atrophy, treatment with GW increased myotube diameter, reduced the expression of muscle atrophy markers, and enhanced the expression of myosin heavy chain (MHC) isoforms in C2C12 cells. Supplementation with the GW improved muscle function and performance in mice with Dexa-induced muscle atrophy, evidenced in the grip strength and running tests. The GW group showed increased lean body mass, skeletal muscle mass, size, and myosin heavy chain isoform expression, along with reduced skeletal muscle atrophy markers in Dexa-injected mice. Supplementation with GW increased protein synthesis and decreased protein degradation through the Akt/mammalian target of rapamycin and glucocorticoid receptor/forkhead box O3 signaling pathways, respectively. We identified LA as a potential bioactive component of the GW. LA treatment increased myotube diameter and decreased the expression of muscle atrophy markers in Dexa-induced C2C12 cells. CONCLUSIONS These findings underscore the potential of the GW in preventing Dexa-induced skeletal muscle atrophy and highlight the contribution of LA to its effects.
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Affiliation(s)
- Ahyoung Yoo
- Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, 55365, Korea
| | - Jung-In Kim
- Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, 55365, Korea
- Division of Food Biotechnology, University of Science and Technology, Daejeon, 34113, Korea
| | - Hyunjung Lee
- Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, 55365, Korea
| | - Farida S Nirmala
- Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, 55365, Korea
- Division of Food Biotechnology, University of Science and Technology, Daejeon, 34113, Korea
| | - Jeong-Hoon Hahm
- Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, 55365, Korea
| | - Hyo Deok Seo
- Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, 55365, Korea
| | - Chang Hwa Jung
- Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, 55365, Korea
- Division of Food Biotechnology, University of Science and Technology, Daejeon, 34113, Korea
| | - Tae Youl Ha
- Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, 55365, Korea
- Division of Food Biotechnology, University of Science and Technology, Daejeon, 34113, Korea
| | - Jiyun Ahn
- Aging and Metabolism Research Group, Korea Food Research Institute, Wanju-gun, 55365, Korea.
- Division of Food Biotechnology, University of Science and Technology, Daejeon, 34113, Korea.
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Lin GT, Huang JB, Lin JL, Lin JX, Xie JW, Wang JB, Lu J, Zheng CH, Huang CM, Li P. Body composition parameters for predicting the efficacy of neoadjuvant chemotherapy with immunotherapy for gastric cancer. Front Immunol 2022; 13:1061044. [PMID: 36569876 PMCID: PMC9772614 DOI: 10.3389/fimmu.2022.1061044] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 11/24/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Immune checkpoint inhibitors are increasingly used in neoadjuvant therapy for locally advanced gastric cancer. However, the effect of body composition on the efficacy of neoadjuvant therapy has not been reported. METHODS The computed tomography (CT) images and clinicopathological data of 101 patients with locally advanced gastric cancer who received neoadjuvant chemotherapy combined with immunotherapy (NCI) from 2019 to 2021 were collected. The CT image of L3 vertebral body section was selected, and the body composition before and after the neoadjuvant treatment was calculated using the SliceOmatic software, mainly including skeletal muscle index (SMI), subcutaneous adipose index (SAI), and visceral adipose index (VAI). The relationship between body composition and the efficacy and adverse events of NCI was analyzed. RESULTS Of the 101 patients, 81 with evaluable data were included in the analysis. Of the included patients, 77.8% were male; the median age of all the patients was 62 years, and the median neoadjuvant therapy cycle was three. After the neoadjuvant therapy, 62.9% of the tumors were in remission (residual tumor cells ≤ 50%), and 37.1% of the tumors had no remission (residual tumor cells>50%). Moreover, 61.7% of the patients had treatment-related adverse events (TRAEs), and 18.5% had immune-related adverse events (irAEs). After neoadjuvant therapy, the body mass index (from 23 to 22.6 cm2/m2, p=0.042), SAI (from 34.7 to 32.9 cm2/m2, p=0.01) and VAI (from 32.4 to 26.8 cm2/m2, p=0.005) were significantly lower than those before treatment, while the SMI had no significant change (44.7 vs 42.5 cm2/m2, p=0.278). The multivariate logistics regression analysis revealed that low SMI (odds ratio [OR]: 3.23,95% confidence interval [CI]: 1.06-9.81, p=0.047), SMI attenuation (△SMI) ≥ 1.8(OR: 1.45,95%CI: 1.20-3.48, p=0.048), and clinical node positivity (OR: 6.99,95%CI: 2.35-20.82, p=0.001) were independent risk factors for non-remission. Additionally, high SAI is an independent risk factor for irAEs (OR: 14, 95%CI: 1.73-112.7, p=0.013). CONCLUSION Low SMI and △SMI≥1.8 are independent risk factors for poor tumor regression in patients with advanced gastric cancer receiving NCI. Patients with a high SAI are more likely to develop irAEs.
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Affiliation(s)
- Guang-Tan Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Jiao-Bao Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Ju-Li Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Jian-Xian Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Jian-Wei Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Jia-Bin Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Jun Lu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Chao-Hui Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Chang-Ming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou, China
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Murphy BT, Mackrill JJ, O'Halloran KD. Impact of cancer cachexia on respiratory muscle function and the therapeutic potential of exercise. J Physiol 2022; 600:4979-5004. [PMID: 36251564 PMCID: PMC10091733 DOI: 10.1113/jp283569] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 09/09/2022] [Indexed: 01/05/2023] Open
Abstract
Cancer cachexia is defined as a multi-factorial syndrome characterised by an ongoing loss of skeletal muscle mass and progressive functional impairment, estimated to affect 50-80% of patients and responsible for 20% of cancer deaths. Elevations in the morbidity and mortality rates of cachectic cancer patients has been linked to respiratory failure due to atrophy and dysfunction of the ventilatory muscles. Despite this, there is a distinct scarcity of research investigating the structural and functional condition of the respiratory musculature in cancer, with the majority of studies exclusively focusing on limb muscle. Treatment strategies are largely ineffective in mitigating the cachectic state. It is now widely accepted that an efficacious intervention will likely combine elements of pharmacology, nutrition and exercise. However, of these approaches, exercise has received comparatively little attention. Therefore, it is unlikely to be implemented optimally, whether in isolation or combination. In consideration of these limitations, the current review describes the mechanistic basis of cancer cachexia and subsequently explores the available respiratory- and exercise-focused literature within this context. The molecular basis of cachexia is thoroughly reviewed. The pivotal role of inflammatory mediators is described. Unravelling the mechanisms of exercise-induced support of muscle via antioxidant and anti-inflammatory effects in addition to promoting efficient energy metabolism via increased mitochondrial biogenesis, mitochondrial function and muscle glucose uptake provide avenues for interventional studies. Currently available pre-clinical mouse models including novel transgenic animals provide a platform for the development of multi-modal therapeutic strategies to protect respiratory muscles in people with cancer.
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Affiliation(s)
- Ben T. Murphy
- Department of PhysiologySchool of MedicineCollege of Medicine and HealthUniversity College CorkCorkIreland
| | - John J. Mackrill
- Department of PhysiologySchool of MedicineCollege of Medicine and HealthUniversity College CorkCorkIreland
| | - Ken D. O'Halloran
- Department of PhysiologySchool of MedicineCollege of Medicine and HealthUniversity College CorkCorkIreland
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Amelioration of muscle wasting by gintonin in cancer cachexia. Neoplasia 2021; 23:1307-1317. [PMID: 34798386 PMCID: PMC8605064 DOI: 10.1016/j.neo.2021.11.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 10/11/2021] [Accepted: 11/08/2021] [Indexed: 11/20/2022] Open
Abstract
Cancer cachexia is characterized by systemic inflammation, protein degradation, and loss of skeletal muscle. Despite extensive efforts to develop therapeutics, only few effective treatments are available to protect against cancer cachexia. Here, we found that gintonin (GT), a ginseng-derived lysophosphatidic acid receptor (LPAR) ligand, protected C2C12 myotubes from tumor necrosis factor α (TNFα)/interferon γ (IFNγ)- induced muscle wasting condition. The activity of GT was found to be dependent on LPAR/Gαi2, as the LPAR antagonist Ki16425 and Gαi2 siRNA abolished the anti-atrophic effects of GT on myotubes. GT suppressed TNFα-induced oxidative stress by reducing reactive oxygen species and suppressing inflammation-related genes, such as interleukin 6 (IL-6) and NADPH oxidase 2 (NOX-2). In addition, GT exhibited anti-atrophy effects in primary normal human skeletal myoblasts. Further, GT protected against Lewis lung carcinoma cell line (LLC1)-induced cancer cachexia in a mouse model. Specifically, GT rescued the lower levels of grip strength, hanging, and cross-sectional area caused by LLC1. Collectively, our findings suggest that GT may be a good therapeutic candidate for protecting against cancer cachexia.
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A Blueprint for Cancer-Related Inflammation and Host Innate Immunity. Cells 2021; 10:cells10113211. [PMID: 34831432 PMCID: PMC8623541 DOI: 10.3390/cells10113211] [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: 09/17/2021] [Revised: 10/27/2021] [Accepted: 11/10/2021] [Indexed: 12/30/2022] Open
Abstract
Both in situ and allograft models of cancer in juvenile and adult Drosophila melanogaster fruit flies offer a powerful means for unravelling cancer gene networks and cancer-host interactions. They can also be used as tools for cost-effective drug discovery and repurposing. Moreover, in situ modeling of emerging tumors makes it possible to address cancer initiating events-a black box in cancer research, tackle the innate antitumor immune responses to incipient preneoplastic cells and recurrent growing tumors, and decipher the initiation and evolution of inflammation. These studies in Drosophila melanogaster can serve as a blueprint for studies in more complex organisms and help in the design of mechanism-based therapies for the individualized treatment of cancer diseases in humans. This review focuses on new discoveries in Drosophila related to the diverse innate immune responses to cancer-related inflammation and the systemic effects that are so detrimental to the host.
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Screening of phytochemicals effective on relieving cancer cachexia in cisplatin-induced in vitro sarcopenia model. Mol Cell Toxicol 2021. [DOI: 10.1007/s13273-021-00181-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Baba MR, Buch SA. Revisiting Cancer Cachexia: Pathogenesis, Diagnosis, and Current Treatment Approaches. Asia Pac J Oncol Nurs 2021; 8:508-518. [PMID: 34527780 PMCID: PMC8420916 DOI: 10.4103/apjon.apjon-2126] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 04/15/2021] [Indexed: 01/06/2023] Open
Abstract
The objective of this article is to group together various management strategies and to highlight the recent treatment modifications that attempt to target the multimodal etiological factors involved in cancer cachexia. The contemporary role of nursing fraternity in psychosocial and nutritional assessment of cancer patients is briefly discussed. Cachexia is a syndrome of metabolic disturbance, characterized by the inflammation and loss of muscle with or without loss of adipose tissue. In cancer cachexia, a multifaceted condition, patients suffer from loss of body weight that leads to a negative impact on the quality of life and survival of the patients. The main cancers associated with cachexia are that of pancreas, stomach, lung, esophagus, liver, and that of bowel. The changes include increased proteolysis, lipolysis, insulin resistance, high energy expenditure, and reduced intake of food, all leading to impaired response to different treatments. There is no standardized treatment for cancer cachexia that can stabilize or reverse this complex metabolic disorder at present. The mainstay of cancer cachexia therapy remains to be sufficient nutritional supplements with on-going efforts to explore the drugs that target heightened catabolic processes and complex inflammation. There is a need to develop a multimodal treatment approach combining pharmacology, exercise program, and nutritional support to target anorexia and the severe metabolic changes encountered in cancer cachexia.
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Affiliation(s)
- Mudasir Rashid Baba
- Department of Paediatric Rehabilitation, Yenepoya Physiotherapy College, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
| | - Sajad Ahmad Buch
- Department of Oral Medicine and Radiology, Yenepoya Dental College, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
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Muthanna FMS, Karuppannan M, Hassan BAR, Mohammed AH. Impact of fatigue on quality of life among breast cancer patients receiving chemotherapy. Osong Public Health Res Perspect 2021; 12:115-125. [PMID: 33980002 PMCID: PMC8102880 DOI: 10.24171/j.phrp.2021.12.2.09] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/27/2021] [Indexed: 02/07/2023] Open
Abstract
Objectives Fatigue is the most frequently reported symptom experienced by cancer patients and has a profound effect on their quality of life (QOL). The study aimed to determine the impact of fatigue on QOL among breast cancer patients receiving chemotherapy and to identify the risk factors associated with severe fatigue incidence. Methods This was an observational prospective study carried out at multiple centers. In total, 172 breast cancer patients were included. The Functional Assessment of Chronic Illness Therapy-Fatigue Questionnaire was used to measure QOL, while the Brief Fatigue Inventory (BFI) was used to assess the severity of fatigue. Results The total average mean and standard deviation of QOL were 84.58±18.07 and 4.65±1.14 for BFI scores, respectively. A significant association between fatigue and QOL was found in linear and multiple regression analyses. The relationships between fatigue severity and cancer stage, chemotherapy dose delay, dose reduction, chemotherapy regimen, and ethnicity were determined using binary logistic regression analysis. Conclusion The findings of this study are believed to be useful for helping oncologists effectively evaluate, monitor, and treat fatigue related to QOL changes.
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Affiliation(s)
- Fares Mohammed Saeed Muthanna
- Department of Pharmacy Practice, Faculty of Pharmacy, Universiti Teknologi MARA, Cawangan Selangor, Kampus Puncak Alam, Selangor, Malaysia
| | - Mahmathi Karuppannan
- Department of Pharmacy Practice, Faculty of Pharmacy, Universiti Teknologi MARA, Cawangan Selangor, Kampus Puncak Alam, Selangor, Malaysia
| | | | - Ali Haider Mohammed
- School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Selangor, Malaysia
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Ezzatvar Y, Ramírez-Vélez R, Sáez de Asteasu ML, Martínez-Velilla N, Zambom-Ferraresi F, Izquierdo M, García-Hermoso A. Physical Function and All-Cause Mortality in Older Adults Diagnosed With Cancer: A Systematic Review and Meta-Analysis. J Gerontol A Biol Sci Med Sci 2020; 76:1447-1453. [PMID: 33421059 DOI: 10.1093/gerona/glaa305] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Physical function is an independent predictor of numerous chronic diseases, but its association with all-cause mortality in older adults diagnosed with cancer has received little attention. The aim of this study was to conduct a systematic review and meta-analysis on the prospective association between physical function and all-cause mortality in older adults diagnosed with cancer. METHODS Two authors systematically searched MEDLINE, EMBASE, and SPORTDiscus databases. Prospective studies reporting associations of baseline physical function with all-cause mortality in patients aged 60 years or older diagnosed with any type of cancer were included. Hazard ratios (HR) with associated 95% confidence intervals (CI) were extracted from studies for all-cause mortality, and pooled HRs were then calculated using the random-effects inverse-variance model with the Hartung-Knapp-Sidik-Jonkman adjustment. RESULTS Data from 25 studies with 8109 adults diagnosed with cancer aged 60 and older were included in the study. Higher levels of physical function (short physical performance battery, HR = 0.44, 95% CI 0.29-0.67; I2 = 16.0%; timed up and go, HR = 0.40, 95% CI 0.31-0.53; I2 = 61.9%; gait speed, HR = 0.41, 95% CI 0.17-0.96; I2 = 73.3%; handgrip strength: HR = 0.61 95% CI 0.43-0.85, I2 = 85.6%; and overall, HR = 0.45 95% CI 0.35-0.57; I2 = 88.6%) were associated with a lower risk of all-cause mortality compared to lower levels of functionality. Neither age at baseline nor length of follow-up had a significant effect on the HR estimates for lower all-cause mortality risk. CONCLUSION Physical function may exert an independent protective effect on all-cause mortality in older adults diagnosed with cancer.
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Affiliation(s)
- Yasmin Ezzatvar
- Exercise Intervention for Health Research Group (EXINH-RG), Department of Physiotherapy, Universitat de València, Spain
| | - Robinson Ramírez-Vélez
- Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.,CIBER of Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | - Mikel L Sáez de Asteasu
- Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.,CIBER of Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | - Nicolás Martínez-Velilla
- Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.,CIBER of Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | - Fabricio Zambom-Ferraresi
- Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.,CIBER of Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | - Mikel Izquierdo
- Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.,CIBER of Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | - Antonio García-Hermoso
- Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), IdiSNA, Pamplona, Spain.,Laboratorio de Ciencias de la Actividad Física, el Deporte y la Salud, Facultad de Ciencias Médicas, Universidad de Santiago de Chile, USACH, Chile
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10
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Dave DT, Patel BM. Mitochondrial Metabolism in Cancer Cachexia: Novel Drug Target. Curr Drug Metab 2020; 20:1141-1153. [PMID: 31418657 DOI: 10.2174/1389200220666190816162658] [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] [Received: 03/29/2019] [Revised: 07/23/2019] [Accepted: 07/25/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Cancer cachexia is a metabolic syndrome prevalent in the majority of the advanced cancers and is associated with complications such as anorexia, early satiety, weakness, anaemia, and edema, thereby reducing performance and impairing quality of life. Skeletal muscle wasting is a characteristic feature of cancer-cachexia and mitochondria is responsible for regulating total protein turnover in skeletal muscle tissue. METHODS We carried out exhaustive search for cancer cachexia and role of mitochondria in the same in various databases. All the relevant articles were gathered and the pertinent information was extracted out and compiled which was further structured into different sub-sections. RESULTS Various findings on the mitochondrial alterations in connection to its disturbed normal physiology in various models of cancer-cachexia have been recently reported, suggesting a significant role of the organelle in the pathogenesis of the complications involved in the disorder. It has also been reported that reduced mitochondrial oxidative capacity is due to reduced mitochondrial biogenesis as well as altered balance between fusion and fission protein activities. Moreover, autophagy in mitochondria (termed as mitophagy) is reported to play an important role in cancer cachexia. CONCLUSION The present review aims to put forth the changes occurring in mitochondria and hence explore possible targets which can be exploited in cancer-induced cachexia for treatment of such a debilitating condition.
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Affiliation(s)
- Dhwani T Dave
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad 382481, Gujarat, India
| | - Bhoomika M Patel
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad 382481, Gujarat, India
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11
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Gray A, Dang BN, Moore TB, Clemens R, Pressman P. A review of nutrition and dietary interventions in oncology. SAGE Open Med 2020; 8:2050312120926877. [PMID: 32537159 PMCID: PMC7268120 DOI: 10.1177/2050312120926877] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 04/22/2020] [Indexed: 12/11/2022] Open
Abstract
The complex cellular mechanisms and inter-related pathways of cancer proliferation, evasion, and metastasis remain an emerging field of research. Over the last several decades, nutritional research has prominent role in identifying emerging adjuvant therapies in our fight against cancer. Nutritional and dietary interventions are being explored to improve the morbidity and mortality for cancer patients worldwide. In this review, we examine several dietary interventions and their proposed mechanisms against cancer as well as identifying limitations in the currently available literature. This review provides a comprehensive review of the cancer metabolism, dietary interventions used during cancer treatment, anti metabolic drugs, and their impact on nutritional deficiencies along with a critical review of the following diets: caloric restriction, intermittent fasting, ketogenic diet, Mediterranean diet, Japanese diet, and vegan diet.
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Affiliation(s)
- Ashley Gray
- Division of Pediatric Hematology/Oncology, Mattel Children's Hospital, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Brian N Dang
- David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Theodore B Moore
- Division of Pediatric Hematology/Oncology, Mattel Children's Hospital, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Roger Clemens
- Pharmacology & Pharmaceutical Sciences, USC School of Pharmacy, International Center for Regulatory Science, Los Angeles, CA, USA
| | - Peter Pressman
- Polyscience Consulting & Director of Nutrition and Public Health, The Daedalus Foundation, San Clemente, CA, USA
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12
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Peixoto da Silva S, Santos JMO, Costa E Silva MP, Gil da Costa RM, Medeiros R. Cancer cachexia and its pathophysiology: links with sarcopenia, anorexia and asthenia. J Cachexia Sarcopenia Muscle 2020; 11:619-635. [PMID: 32142217 PMCID: PMC7296264 DOI: 10.1002/jcsm.12528] [Citation(s) in RCA: 204] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 11/07/2019] [Accepted: 11/21/2019] [Indexed: 12/16/2022] Open
Abstract
Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass, along with adipose tissue wasting, systemic inflammation and other metabolic abnormalities leading to functional impairment. Cancer cachexia has long been recognized as a direct cause of complications in cancer patients, reducing quality of life and worsening disease outcomes. Some related conditions, like sarcopenia (age-related muscle wasting), anorexia (appetite loss) and asthenia (reduced muscular strength and fatigue), share some key features with cancer cachexia, such as weakness and systemic inflammation. Understanding the interplay and the differences between these conditions is critical to advance basic and translational research in this field, improving the accuracy of diagnosis and contributing to finally achieve effective therapies for affected patients.
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Affiliation(s)
- Sara Peixoto da Silva
- Molecular Oncology and Viral Pathology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
| | - Joana M O Santos
- Molecular Oncology and Viral Pathology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
| | - Maria Paula Costa E Silva
- Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal.,Palliative Care Service, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Rui M Gil da Costa
- Molecular Oncology and Viral Pathology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Center for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal.,Postgraduate Programme in Adult Health (PPGSAD) and Tumour Biobank, Federal University of Maranhão (UFMA), São Luís, Brazil
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal.,Virology Service, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Biomedical Research Center (CEBIMED), Faculty of Health Sciences of the Fernando Pessoa University, Porto, Portugal.,Research Department, Portuguese League Against Cancer - Regional Nucleus of the North (Liga Portuguesa Contra o Cancro - Núcleo Regional do Norte), Porto, Portugal
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13
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Gorjao R, Dos Santos CMM, Serdan TDA, Diniz VLS, Alba-Loureiro TC, Cury-Boaventura MF, Hatanaka E, Levada-Pires AC, Sato FT, Pithon-Curi TC, Fernandes LC, Curi R, Hirabara SM. New insights on the regulation of cancer cachexia by N-3 polyunsaturated fatty acids. Pharmacol Ther 2018; 196:117-134. [PMID: 30521881 DOI: 10.1016/j.pharmthera.2018.12.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cancer cachexia is a multifactorial syndrome that develops during malignant tumor growth. Changes in plasma levels of several hormones and inflammatory factors result in an intense catabolic state, decreased activity of anabolic pathways, anorexia, and marked weight loss, leading to cachexia development and/or accentuation. Inflammatory mediators appear to be related to the control of a highly regulated process of muscle protein degradation that accelerates the process of cachexia. Several mediators have been postulated to participate in this process, including TNF-α, myostatin, and activated protein degradation pathways. Some interventional therapies have been proposed, including nutritional (dietary, omega-3 fatty acid supplementation), hormonal (insulin), pharmacological (clenbuterol), and nonpharmacological (physical exercise) therapies. Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid, are recognized for their anti-inflammatory properties and have been used in therapeutic approaches to treat or attenuate cancer cachexia. In this review, we discuss recent findings on cellular and molecular mechanisms involved in inflammation in the cancer cachexia syndrome and the effectiveness of n-3 PUFAs to attenuate or prevent cancer cachexia.
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Affiliation(s)
- Renata Gorjao
- Institute of Physical Activity Sciences and Sports, Cruzeiro do Sul University, Sao Paulo, Brazil
| | | | | | | | | | | | - Elaine Hatanaka
- Institute of Physical Activity Sciences and Sports, Cruzeiro do Sul University, Sao Paulo, Brazil
| | | | - Fábio Takeo Sato
- Institute of Biology, State University of Campinas, Campinas, Brazil; School of Biomedical Sciences, Monash University, Melbourne, Australia
| | | | | | - Rui Curi
- Institute of Physical Activity Sciences and Sports, Cruzeiro do Sul University, Sao Paulo, Brazil; Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil
| | - Sandro Massao Hirabara
- Institute of Physical Activity Sciences and Sports, Cruzeiro do Sul University, Sao Paulo, Brazil; Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
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14
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Zhu R, Liu Z, Jiao R, Zhang C, Yu Q, Han S, Duan Z. Updates on the pathogenesis of advanced lung cancer-induced cachexia. Thorac Cancer 2018; 10:8-16. [PMID: 30461213 PMCID: PMC6312840 DOI: 10.1111/1759-7714.12910] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 10/10/2018] [Accepted: 10/10/2018] [Indexed: 12/15/2022] Open
Abstract
Advanced lung cancer is becoming a chronic disease threatening human life and health. Cachexia has been recognized as the most common problem associated with advanced lung cancer. Lung cancer‐induced cachexia seriously affects patients’ quality of life. The present article summarizes the pathogenesis of advanced lung cancer‐induced cachexia from three aspects: anorexia, cytokines, and energy and metabolic abnormalities. In addition, the present article proposes corresponding nursing measures based on cachexia pathogenesis to improve the quality of life and survival rate of cachectic patients with advanced lung cancer by combining continuously advancing treatment regimens and effective nursing. The present article also provides references for healthcare professionals when administering related treatments and nursing care.
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Affiliation(s)
- Ruifang Zhu
- School of Nursing, Shanxi Medical University, Taiyuan, China
| | - Zhihong Liu
- Department of Respiratory and Critical Care Medicine, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Ran Jiao
- School of Nursing, Shanxi Medical University, Taiyuan, China
| | - Chichen Zhang
- School of Management, Shanxi Medical University, Taiyuan, China
| | - Qi Yu
- School of Management, Shanxi Medical University, Taiyuan, China
| | - Shifan Han
- School of Nursing, Shanxi Medical University, Taiyuan, China
| | - Zhiguang Duan
- School of Nursing, Shanxi Medical University, Taiyuan, China
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15
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Pring ET, Malietzis G, Kennedy RH, Athanasiou T, Jenkins JT. Cancer cachexia and myopenia – Update on management strategies and the direction of future research for optimizing body composition in cancer – A narrative review. Cancer Treat Rev 2018; 70:245-254. [DOI: 10.1016/j.ctrv.2018.10.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 10/04/2018] [Accepted: 10/05/2018] [Indexed: 12/13/2022]
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16
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Gangadharan A, Choi SE, Hassan A, Ayoub NM, Durante G, Balwani S, Kim YH, Pecora A, Goy A, Suh KS. Protein calorie malnutrition, nutritional intervention and personalized cancer care. Oncotarget 2017; 8:24009-24030. [PMID: 28177923 PMCID: PMC5410360 DOI: 10.18632/oncotarget.15103] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 01/23/2017] [Indexed: 12/27/2022] Open
Abstract
Cancer patients often experience weight loss caused by protein calorie malnutrition (PCM) during the course of the disease or treatment. PCM is expressed as severe if the patient has two or more of the following characteristics: obvious significant muscle wasting, loss of subcutaneous fat; nutritional intake of <50% of recommended intake for 2 weeks or more; bedridden or otherwise significantly reduced functional capacity; weight loss of >2% in 1 week, 5% in 1 month, or 7.5% in 3 months. Cancer anorexia-cachexia syndrome (CACS) is a multifactorial condition of advanced PCM associated with underlying illness (in this case cancer) and is characterized by loss of muscle with or without loss of fat mass. Cachexia is defined as weight loss of more than 5% of body weight in 12 months or less in the presence of chronic disease. Hence with a chronic illness on board even a small amount of weight loss can open the door to cachexia. These nutritional challenges can lead to severe morbidity and mortality in cancer patients. In the clinic, the application of personalized medicine and the ability to withstand the toxic effects of anti-cancer therapies can be optimized when the patient is in nutritional homeostasis and is free of anorexia and cachexia. Routine assessment of nutritional status and appropriate intervention are essential components of the effort to alleviate effects of malnutrition on quality of life and survival of patients.
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Affiliation(s)
- Anju Gangadharan
- The Genomics and Biomarkers Program, JT Cancer Center, Hackensack University Medical Center, Hackensack Meridian Health, Hackensack, NJ, USA
| | - Sung Eun Choi
- Department of Family, Nutrition, and Exercise Sciences, Queens College, The City University of New York, Flushing, NY, USA
| | - Ahmed Hassan
- The Genomics and Biomarkers Program, JT Cancer Center, Hackensack University Medical Center, Hackensack Meridian Health, Hackensack, NJ, USA
| | - Nehad M Ayoub
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Gina Durante
- Department of Clinical Nutrition, Baystate Medical Center, Springfield, MA, USA
| | - Sakshi Balwani
- The Genomics and Biomarkers Program, JT Cancer Center, Hackensack University Medical Center, Hackensack Meridian Health, Hackensack, NJ, USA
| | - Young Hee Kim
- Department of Clinical Nutrition, Baystate Medical Center, Springfield, MA, USA
| | - Andrew Pecora
- Clinical Divisions, JT Cancer Center, Hackensack University Medical Center, Hackensack Meridian Health, Hackensack, NJ, USA
| | - Andre Goy
- Clinical Divisions, JT Cancer Center, Hackensack University Medical Center, Hackensack Meridian Health, Hackensack, NJ, USA
| | - K Stephen Suh
- The Genomics and Biomarkers Program, JT Cancer Center, Hackensack University Medical Center, Hackensack Meridian Health, Hackensack, NJ, USA
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17
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Patel HJ, Patel BM. TNF-α and cancer cachexia: Molecular insights and clinical implications. Life Sci 2016; 170:56-63. [PMID: 27919820 DOI: 10.1016/j.lfs.2016.11.033] [Citation(s) in RCA: 230] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Revised: 11/27/2016] [Accepted: 11/30/2016] [Indexed: 12/20/2022]
Abstract
Cancer cachexia characterized by a chronic wasting syndrome, involves skeletal muscle loss and adipose tissue loss and resistance to conventional nutritional support. Cachexia is responsible for the reduction in quality and length of life of cancer patients. It also decreases the muscle strength of the patients. The pro-inflammatory and pro-cachectic factors produced by the tumor cells have important role in genesis of cachexia. A number of pro-inflammatory cytokines, like interleukin-1 (IL-1), IL-6, tumor necrosis factor- alpha (TNF-α) may have important role in the pathological mechanisms of cachexia in cancer. Particularly, TNF-α has a direct catabolic effect on skeletal muscle and causes wasting of muscle by the induction of the ubiquitin-proteasome system (UPS). In cancer cachexia condition, there is alteration in carbohydrate, protein and fat metabolism. TNF-α is responsible for the increase in gluconeogenesis, loss of adipose tissue and proteolysis, while causing decrease in protein, lipid and glycogen synthesis. It has been associated with the formation of IL-1 and increases the uncoupling protein-2 (UCP2) and UCP3 expression in skeletal muscle in cachectic state. The main aim of the present review is to evaluate and discuss the role of TNF-α in different metabolic alterations and muscle wasting in cancer cachexia.
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18
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Global Mapping of Traditional Chinese Medicine into Bioactivity Space and Pathways Annotation Improves Mechanistic Understanding and Discovers Relationships between Therapeutic Action (Sub)classes. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 2016:2106465. [PMID: 26989424 PMCID: PMC4775820 DOI: 10.1155/2016/2106465] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 12/03/2015] [Indexed: 02/08/2023]
Abstract
Traditional Chinese medicine (TCM) still needs more scientific rationale to be proven for it to be accepted further in the West. We are now in the position to propose computational hypotheses for the mode-of-actions (MOAs) of 45 TCM therapeutic action (sub)classes from in silico target prediction algorithms, whose target was later annotated with Kyoto Encyclopedia of Genes and Genomes pathway, and to discover the relationship between them by generating a hierarchical clustering. The results of 10,749 TCM compounds showed 183 enriched targets and 99 enriched pathways from Estimation Score ≤ 0 and ≥ 5% of compounds/targets in a (sub)class. The MOA of a (sub)class was established from supporting literature. Overall, the most frequent top three enriched targets/pathways were immune-related targets such as tyrosine-protein phosphatase nonreceptor type 2 (PTPN2) and digestive system such as mineral absorption. We found two major protein families, G-protein coupled receptor (GPCR), and protein kinase family contributed to the diversity of the bioactivity space, while digestive system was consistently annotated pathway motif, which agreed with the important treatment principle of TCM, “the foundation of acquired constitution” that includes spleen and stomach. In short, the TCM (sub)classes, in many cases share similar targets/pathways despite having different indications.
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19
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Cancer-associated muscle weakness: What's bone got to do with it? BONEKEY REPORTS 2015; 4:691. [PMID: 25992285 DOI: 10.1038/bonekey.2015.59] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 03/20/2015] [Indexed: 12/17/2022]
Abstract
Cancer-associated muscle weakness is an important paraneoplastic syndrome for which there is currently no treatment. Tumor cells commonly metastasize to bone in advanced cancer to disrupt normal bone remodeling and result in morbidity that includes muscle weakness. Tumor in bone stimulates excessive osteoclast activity, which causes the release of growth factors stored in the mineralized bone matrix. These factors fuel a feed-forward vicious cycle of tumor growth in bone and bone destruction. Recent evidence indicates that these bone-derived growth factors can act systemically to cause muscle weakness. Muscle weakness can be caused by reduced muscle mass or reduced muscle function; in advanced disease, it is likely due to a combination of both reduced quantity and quality of muscle. In this review, we discuss possible mechanisms that lead to skeletal muscle weakness due to bone metastases.
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20
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Aoyagi T, Terracina KP, Raza A, Matsubara H, Takabe K. Cancer cachexia, mechanism and treatment. World J Gastrointest Oncol 2015; 7:17-29. [PMID: 25897346 PMCID: PMC4398892 DOI: 10.4251/wjgo.v7.i4.17] [Citation(s) in RCA: 298] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Revised: 01/17/2015] [Accepted: 03/30/2015] [Indexed: 02/05/2023] Open
Abstract
It is estimated that half of all patients with cancer eventually develop a syndrome of cachexia, with anorexia and a progressive loss of adipose tissue and skeletal muscle mass. Cancer cachexia is characterized by systemic inflammation, negative protein and energy balance, and an involuntary loss of lean body mass. It is an insidious syndrome that not only has a dramatic impact on patient quality of life, but also is associated with poor responses to chemotherapy and decreased survival. Cachexia is still largely an underestimated and untreated condition, despite the fact that multiple mechanisms are reported to be involved in its development, with a number of cytokines postulated to play a role in the etiology of the persistent catabolic state. Existing therapies for cachexia, including orexigenic appetite stimulants, focus on palliation of symptoms and reduction of the distress of patients and families rather than prolongation of life. Recent therapies for the cachectic syndrome involve a multidisciplinary approach. Combination therapy with diet modification and/or exercise has been added to novel pharmaceutical agents, such as Megestrol acetate, medroxyprogesterone, ghrelin, omega-3-fatty acid among others. These agents are reported to have improved survival rates as well as quality of life. In this review, we will discuss the emerging understanding of the mechanisms of cancer cachexia, the current treatment options including multidisciplinary combination therapies, as well an update on new and ongoing clinical trials.
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21
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Cancer-related fatigue in the elderly. Support Care Cancer 2013; 21:2899-911. [PMID: 23852408 DOI: 10.1007/s00520-013-1897-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Accepted: 06/26/2013] [Indexed: 12/29/2022]
Abstract
PURPOSE Cancer is a disease of the elderly: 60 % of tumours occur in patients aged 65 years or older. Cancer-related fatigue is a common symptom experienced by cancer patients and cancer survivors that profoundly affects all aspects of the quality of life. Although it has been estimated that up to 70 % of elderly with cancer experience fatigue, this symptom is still largely ignored in ageing population. METHODS We performed a systematic review of the literature identified by MEDLINE. RESULTS The relationship between ageing process and pathogenesis of cancer-related fatigue is still not fully understood. CONCLUSIONS Ageing is associated with an increased prevalence of chronic diseases, decreased functional reserve in multiple organ systems and enhanced susceptibility to stress. Ageing and the concomitant presence of a condition of frailty may predispose to the presence of fatigue. Nevertheless, only few studies have to date specifically assessed the impact of fatigue in the geriatric population. Since cancer-related fatigue is a peculiarly debilitating condition characteristic of elderly cancer patient population, we suggest the early recognition and thorough evaluation of the symptom fatigue, its co-existing causes (i.e. anaemia, mood disorders and sleep disturbances) and co-morbidities (i.e., endocrine disorders, metabolic, cardiovascular and liver diseases).
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22
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Tzika AA, Fontes-Oliveira CC, Shestov AA, Constantinou C, Psychogios N, Righi V, Mintzopoulos D, Busquets S, Lopez-Soriano FJ, Milot S, Lepine F, Mindrinos MN, Rahme LG, Argiles JM. Skeletal muscle mitochondrial uncoupling in a murine cancer cachexia model. Int J Oncol 2013; 43:886-94. [PMID: 23817738 PMCID: PMC6903904 DOI: 10.3892/ijo.2013.1998] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 01/14/2013] [Indexed: 12/20/2022] Open
Abstract
Approximately half of all cancer patients present with cachexia, a condition in which disease-associated metabolic changes lead to a severe loss of skeletal muscle mass. Working toward an integrated and mechanistic view of cancer cachexia, we investigated the hypothesis that cancer promotes mitochondrial uncoupling in skeletal muscle. We subjected mice to in vivo phosphorous-31 nuclear magnetic resonance (31P NMR) spectroscopy and subjected murine skeletal muscle samples to gas chromatography/mass spectrometry (GC/MS). The mice used in both experiments were Lewis lung carcinoma models of cancer cachexia. A novel ‘fragmented mass isotopomer’ approach was used in our dynamic analysis of 13C mass isotopomer data. Our 31P NMR and GC/MS results indicated that the adenosine triphosphate (ATP) synthesis rate and tricarboxylic acid (TCA) cycle flux were reduced by 49% and 22%, respectively, in the cancer-bearing mice (p<0.008; t-test vs. controls). The ratio of ATP synthesis rate to the TCA cycle flux (an index of mitochondrial coupling) was reduced by 32% in the cancer-bearing mice (p=0.036; t-test vs. controls). Genomic analysis revealed aberrant expression levels for key regulatory genes and transmission electron microscopy (TEM) revealed ultrastructural abnormalities in the muscle fiber, consistent with the presence of abnormal, giant mitochondria. Taken together, these data suggest that mitochondrial uncoupling occurs in cancer cachexia and thus point to the mitochondria as a potential pharmaceutical target for the treatment of cachexia. These findings may prove relevant to elucidating the mechanisms underlying skeletal muscle wasting observed in other chronic diseases, as well as in aging.
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Affiliation(s)
- A Aria Tzika
- NMR Surgical Laboratory, Department of Surgery, Massachusetts General Hospital and Shriners Burn Institute, Harvard Medical School, Boston, MA 02114, USA
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23
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Vaughan VC, Martin P, Lewandowski PA. Cancer cachexia: impact, mechanisms and emerging treatments. J Cachexia Sarcopenia Muscle 2013; 4:95-109. [PMID: 23097000 PMCID: PMC3684701 DOI: 10.1007/s13539-012-0087-1] [Citation(s) in RCA: 156] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Accepted: 09/03/2012] [Indexed: 12/18/2022] Open
Abstract
Many forms of cancer present with a complex metabolic profile characterised by loss of lean body mass known as cancer cachexia. The physical impact of cachexia contributes to decreased patient quality of life, treatment success and survival due to gross alterations in protein metabolism, increased oxidative stress and systemic inflammation. The psychological impact also contributes to decreased quality of life for both patients and their families. Combination therapies that target multiple pathways, such as eicosapentaenoic acid administered in combination with exercise, appetite stimulants, antioxidants or anti-inflammatories, have potential in the treatment of this complex syndrome and require further development.
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Affiliation(s)
- Vanessa C Vaughan
- School of Medicine, Deakin University, 75 Pigdons Road, Waurn Ponds, Victoria, 3216, Australia
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24
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Chen S, Hoene M, Li J, Li Y, Zhao X, Häring HU, Schleicher ED, Weigert C, Xu G, Lehmann R. Simultaneous extraction of metabolome and lipidome with methyl tert-butyl ether from a single small tissue sample for ultra-high performance liquid chromatography/mass spectrometry. J Chromatogr A 2013; 1298:9-16. [PMID: 23743007 DOI: 10.1016/j.chroma.2013.05.019] [Citation(s) in RCA: 163] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Revised: 03/30/2013] [Accepted: 05/05/2013] [Indexed: 12/20/2022]
Abstract
A common challenge for scientists working with animal tissue or human biopsy samples is the limitation of material and consequently, the difficulty to perform comprehensive metabolic profiling within one experiment. Here, we present a novel approach to simultaneously perform targeted and non-targeted metabolomics as well as lipidomics from one small piece of liver or muscle tissue by ultra-high performance liquid chromatography/mass spectrometry (UHPLC/MS) following a methyl tert-butyl ether (MTBE)-based extraction. Equal relative amounts of the resulting polar and non-polar fractions were pooled, evaporated and reconstituted in the appropriate solvent for UHPLC/MS analysis. This mix was comparable or superior in yield and reproducibility to a standard 80% methanol extraction for the profiling of polar and lipophilic metabolites (free carnitine, acylcarnitines and FFA). The mix was also suitable for non-targeted metabolomics, an easy measure to increase the metabolite coverage by 30% relative to using the polar fraction alone. Lipidomics was performed from an aliquot of the non-polar fraction. This novel strategy could successfully be applied to one mouse soleus muscle with a dry weight of merely 2.5 mg. By enabling a simultaneous profiling of lipids and metabolites with mixed polarity while saving material for molecular, biochemical or histological analyses, our approach may open up new perspectives toward a comprehensive investigation of small, valuable tissue samples.
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Affiliation(s)
- Shili Chen
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
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25
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Coleman EA, Goodwin JA, Kennedy R, Coon SK, Richards K, Enderlin C, Stewart CB, McNatt P, Lockhart K, Anaissie EJ. Effects of exercise on fatigue, sleep, and performance: a randomized trial. Oncol Nurs Forum 2013; 39:468-77. [PMID: 22940511 DOI: 10.1188/12.onf.468-477] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
PURPOSE/OBJECTIVES To compare usual care with a home-based individualized exercise program (HBIEP) in patients receiving intensive treatment for multiple myeloma (MM)and epoetin alfa therapy. DESIGN Randomized trial with repeated measures of two groups (one experimental and one control) and an approximate 15-week experimental period. SETTING Outpatient setting of the Myeloma Institute for Research and Therapy at the Rockfellow Cancer Center at the University of Arkansas for Medical Sciences. SAMPLE 187 patients with newly diagnosed MM enrolled in a separate study evaluating effectiveness of the Total Therapy regimen, with or without thalidomide. METHODS Measurements included the Profile of Mood States fatigue scale, Functional Assessment of Cancer Therapy-Fatigue, ActiGraph® recordings, 6-Minute Walk Test, and hemoglobin levels at baseline and before and after stem cell collection. Descriptive statistics were used to compare demographics and treatment effects, and repeated measures analysis of variance was used to determine effects of HBIEP. MAIN RESEARCH VARIABLES Fatigue, nighttime sleep, performance (aerobic capacity) as dependent or outcome measures, and HBIEP combining strength building and aerobic exercise as the independent variable. FINDINGS Both groups were equivalent for age, gender, race, receipt of thalidomide, hemoglobin levels, and type of treatment regimen for MM. No statistically significant differences existed among the experimental and control groups for fatigue, sleep, or performance (aerobic capacity). Statistically significant differences (p < 0.05) were found in each of the study outcomes for all patients as treatment progressed and patients experienced more fatigue and poorer nighttime sleep and performance (aerobic capacity). CONCLUSIONS The effect of exercise seemed to be minimal on decreasing fatigue, improving sleep, and improving performance (aerobic capacity). IMPLICATIONS FOR NURSING Exercise is safe and has physiologic benefits for patients undergoing MM treatment; exercise combined with epoetin alfa helped alleviate anemia.
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Affiliation(s)
- Elizabeth Ann Coleman
- College of Nursing, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
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26
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Bhatnagar S, Kumar A. The TWEAK-Fn14 system: breaking the silence of cytokine-induced skeletal muscle wasting. Curr Mol Med 2012; 12:3-13. [PMID: 22082477 PMCID: PMC3257753 DOI: 10.2174/156652412798376107] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2011] [Revised: 05/22/2011] [Accepted: 07/30/2011] [Indexed: 01/23/2023]
Abstract
The occurrence of skeletal muscle atrophy, a devastating complication of a large number of disease states and inactivity/disuse conditions, provides a never ending quest to identify novel targets for its therapy. Proinflammatory cytokines are considered the mediators of muscle wasting in chronic diseases; however, their role in disuse atrophy has just begun to be elucidated. An inflammatory cytokine, tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), has recently been identified as a potent inducer of skeletal muscle wasting. TWEAK activates various proteolytic pathways and stimulates the degradation of myofibril protein both in vitro and in vivo. Moreover, TWEAK mediates the loss of skeletal muscle mass and function in response to denervation, a model of disuse atrophy. Adult skeletal muscle express very low to minimal levels of TWEAK receptor, Fn14. Specific catabolic conditions such as denervation, immobilization, or unloading rapidly increase the expression of Fn14 in skeletal muscle which in turn stimulates the TWEAK activation of various catabolic pathways leading to muscle atrophy. In this article, we have discussed the emerging roles and the mechanisms of action of TWEAK-Fn14 system in skeletal muscle with particular reference to different models of muscle atrophy and injury and its potential to be used as a therapeutic target for prevention of muscle loss.
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Affiliation(s)
- S Bhatnagar
- Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202, USA
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27
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Sullivan-Gunn MJ, Campbell-O'Sullivan SP, Tisdale MJ, Lewandowski PA. Decreased NADPH oxidase expression and antioxidant activity in cachectic skeletal muscle. J Cachexia Sarcopenia Muscle 2011; 2:181-188. [PMID: 21966644 PMCID: PMC3177039 DOI: 10.1007/s13539-011-0037-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Accepted: 07/27/2011] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND: Cancer cachexia is the progressive loss of skeletal muscle protein that contributes significantly to cancer morbidity and mortality. Evidence of antioxidant attenuation and the presence of oxidised proteins in patients with cancer cachexia indicate a role for oxidative stress. The level of oxidative stress in tissues is determined by an imbalance between reactive oxygen species production and antioxidant activity. This study aimed to investigate the superoxide generating NADPH oxidase (NOX) enzyme and antioxidant enzyme systems in murine adenocarcinoma tumour-bearing cachectic mice. METHODS: Superoxide levels, mRNA levels of NOX enzyme subunits and the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidise (GPx) and catalase was measured in the skeletal muscle of mice with cancer and cancer cachexia. Protein expression levels of NOX enzyme subunits and antioxidant enzyme activity was also measured in the same muscle samples. RESULTS: Superoxide levels increased 1.4-fold in the muscle of mice with cancer cachexia, and this was associated with a decrease in mRNA of NOX enzyme subunits, NOX2, p40(phox) and p67(phox) along with the antioxidant enzymes SOD1, SOD2 and GPx. Cancer cachexia was also associated with a 1.3-fold decrease in SOD1 and 2.0-fold decrease in GPx enzyme activity. CONCLUSION: Despite increased superoxide levels in cachectic skeletal muscle, NOX enzyme subunits, NOX2, p40(phox) and p67(phox), were downregulated along with the expression and activity of the antioxidant enzymes. Therefore, the increased superoxide levels in cachectic skeletal muscle may be attributed to the reduction in the activity of endogenous antioxidant enzymes.
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Affiliation(s)
| | - Siun P. Campbell-O'Sullivan
- School of Biomedical Sciences Victoria University, Centre for Aging, Rehabilitation, Exercise and Sport PO Box 14428 8001 Melbourne
| | - Michael J. Tisdale
- School of Life Sciences Aston University Aston Triangle B4 7ET Birmingham
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Wang H, Lai YJ, Chan YL, Li TL, Wu CJ. Epigallocatechin-3-gallate effectively attenuates skeletal muscle atrophy caused by cancer cachexia. Cancer Lett 2011; 305:40-9. [PMID: 21397390 DOI: 10.1016/j.canlet.2011.02.023] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2010] [Revised: 02/15/2011] [Accepted: 02/16/2011] [Indexed: 10/18/2022]
Abstract
Cachexia, also known as wasting syndrome notably with skeletal muscle atrophy, costs nearly one-third of all cancer deaths in man. (-)-Epigallocatechin-3-gallate (EGCG), the principal polyphenolic component in green tea, is a potent preventive against cachexia as well as cancers. However, how EGCG counteracts cachexia-provoked muscle wasting is unclear. EGCG was demonstrated to be able to retard tumor progression as well as to prevent body weight from loss, because EGCG attenuates skeletal muscle leukocytic infiltration and down-regulates tumor-induced NF-κB and E3-ligases in muscle. In mice, the dosages optimized against cachexia were determined to be 0.2 mg/mouse/day for prevention and to be 0.6 mg/mouse/day for treatment. Anti-cachexia effects were assessed using the LLC tumor model. Mice with the same body weight were divided into groups, including control, tumor bearing, and tumor-bearing but receiving water or EGCG in both prevention and treatment experiments. RT-PCR was used to assess mRNA expressions of NF-κB, MuRF 1, and MAFbx. The intracellular NF-κB, MuRF 1 and MAFbx were determined and quantified by immunofluorescence and Western blotting, respectively. Our results conclude EGCG regulates the expressions of NF-κB as well as downstream mediators, MuRF 1 and MAFbx, so EGCG may be an appropriate agent to be included in ensemble therapeutics of the tumor-induced muscle atrophy.
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Affiliation(s)
- Hang Wang
- Department of Food Science, National Taiwan Ocean University, Keelung, Taiwan
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29
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Constantinou C, Fontes de Oliveira CC, Mintzopoulos D, Busquets S, He J, Kesarwani M, Mindrinos M, Rahme LG, Argilés JM, Tzika AA. Nuclear magnetic resonance in conjunction with functional genomics suggests mitochondrial dysfunction in a murine model of cancer cachexia. Int J Mol Med 2010; 27:15-24. [PMID: 21069263 PMCID: PMC3712618 DOI: 10.3892/ijmm.2010.557] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2010] [Accepted: 05/03/2010] [Indexed: 12/18/2022] Open
Abstract
Cancer patients commonly suffer from cachexia, a syndrome in which tumors induce metabolic changes in the host that lead to massive loss in skeletal muscle mass. Using a preclinical mouse model of cancer cachexia, we tested the hypothesis that tumor inoculation causes a reduction in ATP synthesis and genome-wide aberrant expression in skeletal muscle. Mice implanted with Lewis lung carcinomas were examined by in vivo31P nuclear magnetic resonance (NMR). We examined ATP synthesis rate and the expression of genes that play key-regulatory roles in skeletal muscle metabolism. Our in vivo NMR results showed reduced ATP synthesis rate in tumor-bearing (TB) mice relative to control (C) mice, and were cross-validated with whole genome transcriptome data showing atypical expression levels of skeletal muscle regulatory genes such as peroxisomal proliferator activator receptor γ coactivator 1 ß (PGC-1ß), a major regulator of mitochondrial biogenesis and, mitochondrial uncoupling protein 3 (UCP3). Aberrant pattern of gene expression was also associated with genes involved in inflammation and immune response, protein and lipid catabolism, mitochondrial biogenesis and uncoupling, and inadequate oxidative stress defenses, and these effects led to cachexia. Our findings suggest that reduced ATP synthesis is linked to mitochondrial dysfunction, ultimately leading to skeletal muscle wasting and thus advance our understanding of skeletal muscle dysfunction suffered by cancer patients. This study represents a new line of research that can support the development of novel therapeutics in the molecular medicine of skeletal muscle wasting. Such therapeutics would have wide-spread applications not only for cancer patients, but also for many individuals suffering from other chronic or endstage diseases that exhibit muscle wasting, a condition for which only marginally effective treatments are currently available.
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Affiliation(s)
- Caterina Constantinou
- NMR Surgical Laboratory, Massachusetts General and Shriners Hospitals, Harvard Medical School, Boston, MA 02114, USA
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30
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Baltgalvis KA, Berger FG, Peña MMO, Mark Davis J, White JP, Carson JA. Activity level, apoptosis, and development of cachexia in Apc(Min/+) mice. J Appl Physiol (1985) 2010; 109:1155-61. [PMID: 20651218 DOI: 10.1152/japplphysiol.00442.2010] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Criteria for diagnosing cachexia in adults include unintentional loss in body weight, decreased strength, fatigue, anorexia, and low muscle mass. Cachexia is also associated with systemic inflammation, altered metabolism, and anemia. The Apc(Min/+) mouse is a model of cachexia directly related to intestinal tumor burden and subsequent chronic inflammation. These mice also demonstrate muscle weakness, fatigue, decreased volitional activity, and elevated circulating IL-6 levels. The purpose of this study was to determine the time course of changes in physical activity and their relationship to anemia, muscle apoptosis, and muscle mass and body mass loss during cachexia. A subset of male Apc(Min/+) mice were given access to voluntary activity wheels from 5 to 26 wk of age, while sedentary male Apc(Min/+) mice were housed in cages lacking wheels. At the study's end mice were stratified by cachectic symptoms. Severely cachectic mice had decreased wheel running performance at 15 wk of age, while anemia and body weight loss were not present until 18 wk of age. Severely cachectic mice had lower hemoglobin levels compared with mildly cachectic mice at 13, 18, and 22 wk of age. Severely cachectic mice also demonstrated threefold more BCL2-associated X protein (BAX) protein in the gastrocnemius muscle at 26 wk of age compared with mildly cachectic mice. In sedentary Apc(Min/+) mice at 26 wk of age anemia was present, and markers of apoptosis were induced in severely cachectic muscle. Proapoptotic protein expression was induced in both red and white portions of gastrocnemius muscle as well as in soleus muscle of severely cachectic mice compared with mildly cachectic mice. These data demonstrate that decrements in wheel running performance precede loss of body mass and that inherent muscle oxidative capacity is not protective against muscle apoptosis.
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Affiliation(s)
- Kristen A Baltgalvis
- Integrative Muscle Biology Laboratory, Exercise Science Department, University of South Carolina, Columbia, South Carolina 29208, USA
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31
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El Rammouz R, Létisse F, Durand S, Portais JC, Moussa ZW, Fernandez X. Analysis of skeletal muscle metabolome: evaluation of extraction methods for targeted metabolite quantification using liquid chromatography tandem mass spectrometry. Anal Biochem 2009; 398:169-77. [PMID: 20026296 DOI: 10.1016/j.ab.2009.12.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2009] [Revised: 12/04/2009] [Accepted: 12/04/2009] [Indexed: 10/20/2022]
Abstract
Functional metabolomics of skeletal muscle involves the simultaneous identification and quantification of a large number of metabolites. For this purpose, the extraction of metabolites from animal tissues is a crucial technical step that needs to be optimized. In this work, five extraction methods for skeletal muscle metabolome analysis using liquid chromatography tandem mass spectrometry (LC-MS/MS) were tested. Bird skeletal muscles sampled postmortem and quenched in liquid nitrogen were used. Three replicates of the same sample were extracted using the following solvent systems of varying polarity: boiling water (BW, +100 degrees C), cold pure methanol (CPM, -80 degrees C), methanol/chloroform/water (MCW, -20 degrees C), boiling ethanol (BE, +80 degrees C), and perchloric acid (PCA, -20 degrees C). Three injections by extraction were performed. The BW extraction showed the highest recovery of metabolites with the lowest variability (<10%) except for creatine-phosphate (creatine-P). Considering yield (area of the peaks), reproducibility, and ease, the current experiment drew a scale for the muscle metabolome extraction starting from the best to the least convenient: BW>MCW>CPM>PCABE. In addition, the semiquantification of metabolites in two muscles showing different metabolic and contractile properties was carried out after BW extraction and showed expected differences in metabolite contents, thereby validating the technique for biological investigations. In conclusion, the BW extraction is recommended for analysis of skeletal muscle metabolome except for creatine-P, which was poorly recovered with this technique.
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Affiliation(s)
- Rabih El Rammouz
- Institut National de la Recherche Agronomique, UMR 1289 Tissus Animaux Nutrition Digestion Ecosystème et Métabolisme, Castanet-Tolosan, France
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32
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Weber MA, Krakowski-Roosen H, Schröder L, Kinscherf R, Krix M, Kopp-Schneider A, Essig M, Bachert P, Kauczor HU, Hildebrandt W. Morphology, metabolism, microcirculation, and strength of skeletal muscles in cancer-related cachexia. Acta Oncol 2009; 48:116-24. [PMID: 18607877 DOI: 10.1080/02841860802130001] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE Cancer-related cachexia is an obscure syndrome leading to muscle wasting, reduced physical fitness and quality of life. The aim of this study was to assess morphology, metabolism, and microcirculation in skeletal muscles of patients with cancer-related cachexia and to compare these data with matched healthy volunteers. METHODS In 19 patients with cancer-induced cachexia and 19 age-, gender-, and body-height-matched healthy volunteers body composition and aerobic capacity (VO(2max)) were analyzed. Skeletal muscle fiber size and capillarization were evaluated in biopsies of the vastus lateralis muscle. The cross-sectional area (CSA) of the quadriceps femoris muscle was measured by magnetic resonance imaging as well as its isokinetic and isometric force. The energy and lipid metabolism of the vastus lateralis muscle was quantified by (31)P and (1)H spectroscopy and parameters of its microcirculation by contrast-enhanced ultrasonography (CEUS). RESULTS Morphologic parameters were about 30% lower in cachexia than in volunteers (body mass index: 20 +/- 3 vs. 27 +/- 4 kg m(-2), CSA: 45 +/- 13 vs. 67 +/- 14 cm(2), total fiber size: 2854 +/- 1112 vs. 4181 +/- 1461 microm(2)). VO(2max) was reduced in cachexia (23 +/- 9 vs. 32 +/- 7 ml min(-1) kg(-1), p=0.03), whereas histologically determined capillary density and microcirculation in vivo were not different. Both concentrations of muscular energy metabolites, pH, and trimethyl-ammonium-containing compounds were comparable in both groups. Absolute strength of quadriceps muscle was reduced in cachexia (isometric: 107 +/- 40 vs. 160 +/- 40 Nm, isokinetic: 101 +/- 46 vs. 167 +/- 50 Nm; p=0.03), but identical when normalized on CSA (isometric: 2.4 +/- 0.5 vs. 2.4 +/- 0.4 Nm cm(-2), isokinetic: 2.2 +/- 0.4 vs. 2.5 +/- 0.5 Nm cm(-2)). CONCLUSIONS Cancer-related cachexia is associated with a loss of muscle volume but not of functionality, which can be a rationale for muscle training.
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Muscle wasting and interleukin-6-induced atrogin-I expression in the cachectic Apc ( Min/+ ) mouse. Pflugers Arch 2008; 457:989-1001. [PMID: 18712412 DOI: 10.1007/s00424-008-0574-6] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2008] [Accepted: 08/01/2008] [Indexed: 02/06/2023]
Abstract
Interleukin-6 (IL-6) is necessary for cachexia in Apc ( Min/+ ) mice, but the mechanisms inducing this myofiber wasting have not been established. The purpose of this study was to examine gastrocnemius muscle wasting in the Apc ( Min/+ ) mouse and to determine IL-6 regulated mechanisms contributing to muscle loss. Gastrocnemius type IIB mean fiber cross-sectional area (CSA) from Apc ( Min/+ ) mice decreased 32% between 13 and 22 weeks of age. Apc ( Min/+ ) mice lacking IL-6 did not have type IIB fiber atrophy, while overexpression of circulating IL-6 exacerbated the loss of type IIB fiber CSA in Apc ( Min/+ ) mice. Muscle Atrogin-I mRNA expression was induced at least ninefold at 18 and 22 weeks of age compared to 13-week-old mice. Atrogin-I gene expression was also induced by overexpression of circulating IL-6. These data suggest that high circulating IL-6 levels induce type IIB fiber CSA loss in Apc ( Min/+ ) mice, and circulating IL-6 is sufficient to regulate Atrogin-I gene expression in cachectic mice.
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34
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Voss JG, Raju R, Logun C, Danner RL, Munson PJ, Rangel Z, Dalakas MC. A focused microarray to study human mitochondrial and nuclear gene expression. Biol Res Nurs 2008; 9:272-9. [PMID: 18398222 DOI: 10.1177/1099800408315160] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
A focused microarray (huMITOchip) was developed to study alterations of human mitochondrial and nuclear gene expression in health and disease. The huMITOchip contains 4,774 probe sets identical to the Affymetrix U 133 plus 2.0 chip covering genes affecting mitochondrial, lipid, cytokine, apoptosis, and muscle function transcripts. Unlike other gene chips, the huMITOchip has 51 probe sets that interrogate 37 genes of the mitochondrial genome. The human mitochondrial gene chip was validated against the Affymetrix U133 plus 2.0 array using an in vitro system of CCL136 muscle cell line stimulated with or without interferon gamma (IFN-gamma). The 37 genes from the mtDNA demonstrated absolute gene expression levels ranging from 0.1 to 3,182. The comparison of the two gene chips yielded an excellent Pearson's correlation coefficient (r = 0.98). At least 17 probe sets were differentially expressed in response to IFN-gamma on both chips, with a high degree of concordance. This is the first report on the development of a focused oligonucleotide microarray containing genes of the mitochondrial genome.
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Affiliation(s)
- Joachim G Voss
- Neuromuscular Diseases Section, National Institute of Neurological Diseases and Stroke, NIH, Bethesda, MD, USA.
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35
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Baltgalvis KA, Berger FG, Pena MMO, Davis JM, Muga SJ, Carson JA. Interleukin-6 and cachexia in ApcMin/+ mice. Am J Physiol Regul Integr Comp Physiol 2007; 294:R393-401. [PMID: 18056981 DOI: 10.1152/ajpregu.00716.2007] [Citation(s) in RCA: 224] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The Apc(Min/+) mouse has a mutation in the Apc tumor suppressor gene and develops intestinal polyps, beginning at 4 wk of age. This mouse develops cachexia by 6 mo, characterized by significant loss of muscle and fat tissue. The purpose of the present study was to determine the role of circulating interleukin-6 (IL-6) and the polyp burden for the development of cachexia in Apc(Min/+) mice. At 26 wk of age, mice exhibiting severe cachectic symptoms had a 61% decrease in gastrocnemius muscle weight, complete loss of epididymal fat, a 10-fold increase in circulating IL-6 levels, and an 89% increase in intestinal polyps compared with mildly cachectic animals. Apc(Min/+)/IL-6(-/-) mice did not lose gastrocnemius muscle mass or epididymal fat pad mass while overall polyp number decreased by 32% compared with Apc(Min/+) mice. Plasmid-based IL-6 overexpression in Apc(Min/+)/IL-6(-/-) mice led to a decrease in gastrocnemius muscle mass and epididymal fat pad mass and increased intestinal polyp burden. IL-6 overexpression did not induce cachexia in non-tumor-bearing mice. These data demonstrate that IL-6 is necessary for the onset of adipose and skeletal muscle wasting in the Apc(Min/+) mouse and that circulating IL-6 can regulate Apc(Min/+) mouse tumor burden.
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Affiliation(s)
- Kristen A Baltgalvis
- Department of Exercise Science, University of South Carolina, Public Health Research Center, 921 Assembly Street, Columbia, SC 29208, USA
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36
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Ryan JL, Carroll JK, Ryan EP, Mustian KM, Fiscella K, Morrow GR. Mechanisms of cancer-related fatigue. Oncologist 2007; 12 Suppl 1:22-34. [PMID: 17573453 DOI: 10.1634/theoncologist.12-s1-22] [Citation(s) in RCA: 354] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Cancer-related fatigue (CRF) is one of the most prevalent symptoms patients with cancer experience, both during and after treatment. CRF is pervasive and affects patients' quality of life considerably. It is important, therefore, to understand the underlying pathophysiology of CRF in order to develop useful strategies for prevention and treatment. At present, the etiology of CRF is poorly understood and the relative contributions of the neoplastic disease, various forms of cancer therapy, and comorbid conditions (e.g., anemia, cachexia, sleep disorders, depression) remain unclear. In any individual, the etiology of CRF probably involves the dysregulation of several physiological and biochemical systems. Mechanisms proposed as underlying CRF include 5-HT neurotransmitter dysregulation, vagal afferent activation, alterations in muscle and ATP metabolism, hypothalamic-pituitary-adrenal axis dysfunction, circadian rhythm disruption, and cytokine dysregulation. Currently, these hypotheses are largely based on evidence from other conditions in which fatigue is a characteristic, in particular chronic fatigue syndrome and exercise-induced fatigue. The mechanisms that lead to fatigue in these conditions provide a theoretical basis for future research into the complex etiology of this distressing and debilitating symptom. An understanding of relevant mechanisms may offer potential routes for its prevention and treatment in patients with cancer.Disclosure of potential conflicts of interest is found at the end of this article.
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Affiliation(s)
- Julie L Ryan
- Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, James P Wilmot Cancer Center, Rochester, NY 14642, USA.
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Ni B, Zhou J, Dong Y, Peng J, Wu X, Li R, Chen M, Zhou C, Tan Y, Wu Y. Interleukin-1 up-regulates the expression and activity of 26S proteasome in burned rat. Burns 2007; 33:621-7. [PMID: 17374458 DOI: 10.1016/j.burns.2006.08.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2006] [Accepted: 08/15/2006] [Indexed: 01/17/2023]
Abstract
Expression of IL-1 and proteasome are elevated in burned animals and patients. However, whether the increased level of IL-1 correlates with the increased activity and expression of 26S proteasome after burn has not been studied. In the present study, we investigated the role of single IL-1 factor on activation of the 26S proteasome first by injection of recombinant IL-1 into the normal rats. Results indicated that proteolytic activity and the expression of the 26S proteasome increased remarkably 24 and 48 h after-IL-1 injection, respectively. We then studied the potential role of IL-1 on activity and expression of the proteasome in the burned rat by using neutralizing monoclonal antibody against IL-1. Results demonstrated that activity and the expression of 26S proteasome were decreased partially but significantly 48 h after-burn when circulating IL-1 in injured animals was neutralized. These results indicate that IL-1 may play a key role on the activity and expression of 26S proteasome following burn. The proteasome has been verified as being deeply involved in the mechanism of accelerated muscle protein breakdown after burn, these results imply that IL-1 might be involved in the protein metabolism after-burn by activating the proteasome pathway, though protein metabolism directly affected by IL-1 had not been assessed in this study.
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Affiliation(s)
- Bing Ni
- Institute of Immunology PLA, Department of Immunology, Third Military Medical University, Chongqing 400038, China.
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38
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Weber MA, Kinscherf R, Krakowski-Roosen H, Aulmann M, Renk H, Künkele A, Edler L, Kauczor HU, Hildebrandt W. Myoglobin plasma level related to muscle mass and fiber composition: a clinical marker of muscle wasting? J Mol Med (Berl) 2007; 85:887-96. [PMID: 17605115 DOI: 10.1007/s00109-007-0220-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2006] [Revised: 04/19/2007] [Accepted: 05/08/2007] [Indexed: 01/15/2023]
Abstract
Progressive muscle wasting is a central feature of cancer-related cachexia and has been recognized as a determinant of poor prognosis and quality of life. However, until now, no easily assessable clinical marker exists that allows to predict or to track muscle wasting. The present study evaluated the potential of myoglobin (MG) plasma levels to indicate wasting of large locomotor muscles and, moreover, to reflect the loss of MG-rich fiber types, which are most relevant for daily performance. In 17 cancer-cachectic patients (weight loss 22%) and 27 age- and gender-matched healthy controls, we determined plasma levels of MG and creatine kinase (CK), maximal quadriceps muscle cross-sectional area (CSA) by magnetic resonance imaging, muscle morphology and fiber composition in biopsies from the vastus lateralis muscle, body cell mass (BCM) by impedance technique as well as maximal oxygen uptake (VO(2)max). In cachectic patients, plasma MG, muscle CSA, BCM, and VO(2)max were 30-35% below control levels. MG showed a significant positive correlation to total muscle CSA (r = 0.65, p < 0.001) and to the CSA fraction formed by type 1 and 2a fibers (r = 0.80, p < 0.001). However, when adjusted for body height and age by multiple regression, MG yielded a largely improved prediction of total CSA (multiple r = 0.83, p < 0.001) and of fiber type 1 and 2a CSA (multiple r = 0.89, p < 0.001). The correlations between CK and these muscle parameters were weaker, and elevated CK values were observed in 20% of control subjects despite a prior abstinence from exercise for 5 days. In conclusion, plasma MG, when adjusted for anthropometric parameters unaffected by weight, may be considered as a novel marker of muscle mass (CSA) indicating best the mass of MG-rich type 1 and 2a fibers as well as VO(2)max as an important functional readout. CK plasma levels appear to be less reliable because prolonged increases are observed in even subclinical myopathies or after exercise. Notably, cancer-related muscle wasting was not associated with increases in plasma MG or CK in this study.
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Affiliation(s)
- Marc-André Weber
- Department E010 (Radiology), Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
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Minnaard R, Schrauwen P, Schaart G, Hesselink MKC. UCP3 in muscle wasting, a role in modulating lipotoxicity? FEBS Lett 2006; 580:5172-6. [PMID: 16962595 DOI: 10.1016/j.febslet.2006.08.066] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2006] [Revised: 07/17/2006] [Accepted: 08/18/2006] [Indexed: 11/30/2022]
Abstract
UCP3 has been postulated to function in the defense against lipid-induced oxidative muscle damage (lipotoxicity). We explored this hypothesis during cachexia in rats (zymosan-induced sepsis), a condition characterized by increased oxidative stress and supply of fatty acids to the muscle. Muscle UCP3 protein content was increased 2, 6 and 11 days after zymosan injection. Plasma FFA levels were increased at day 2, but dropped below control levels on days 6 and 11. Muscular levels of the lipid peroxidation byproduct 4-hydroxy-2-nonenal (4-HNE) were increased at days 6 and 11 in zymosan-treated rats, supporting a role for UCP3 in modulating lipotoxicity during cachexia.
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Affiliation(s)
- Ronnie Minnaard
- Department of Movement Sciences, Nutrition and Toxicology Research Institute Maastricht, NUTRIM, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
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40
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Mehl KA, Davis JM, Berger FG, Carson JA. Myofiber degeneration/regeneration is induced in the cachecticApcMin/+mouse. J Appl Physiol (1985) 2005; 99:2379-87. [PMID: 16288100 DOI: 10.1152/japplphysiol.00778.2005] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Cachexia is characterized as an inflammatory state induced by the cancer environment, which is accompanied by the loss of muscle and fat mass. Well-investigated mechanisms of cachexia include the suppression of myofiber protein synthesis and the induction of the protein degradation. However, it is not well characterized whether chronic inflammation during cachexia induces myofiber degeneration, which contributes to muscle mass loss and decreased functional capacity. The purpose of this study was to determine whether Apc(Min/+) mice, which demonstrate a chronic systemic inflammatory state due to an intestinal tumor burden, undergo cachexia and whether the myofibers exhibit signs of degeneration and/or regeneration. Six-month-old female Apc(Min/+) body weight decreased 21% compared with C57BL/6 mice and was not the result of blunted growth. Apc(Min/+) gastrocnemius muscle was reduced 45%, and soleus mean fiber cross-sectional area decreased 24% vs. C57BL/6 mice. Soleus muscle morphology demonstrated pathology of myofibers undergoing degeneration and/or regeneration. These data demonstrate that the Apc(Min/+) mouse becomes cachectic by 6 mo of age and that skeletal muscle degeneration and regeneration may be related to the muscle loss.
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Affiliation(s)
- Kristen A Mehl
- Division of Applied Physiology, Dept. of Exercise Science, University of South Carolina, Columbia, SC 29208, USA
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Giordano A, Calvani M, Petillo O, Grippo P, Tuccillo F, Melone MAB, Bonelli P, Calarco A, Peluso G. tBid induces alterations of mitochondrial fatty acid oxidation flux by malonyl-CoA-independent inhibition of carnitine palmitoyltransferase-1. Cell Death Differ 2005; 12:603-13. [PMID: 15846373 DOI: 10.1038/sj.cdd.4401636] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Recent studies suggest a close relationship between cell metabolism and apoptosis. We have evaluated changes in lipid metabolism on permeabilized hepatocytes treated with truncated Bid (tBid) in the presence of caspase inhibitors and exogenous cytochrome c. The measurement of beta-oxidation flux by labeled palmitate demonstrates that tBid inhibits beta-oxidation, thereby resulting in the accumulation of palmitoyl-coenzyme A (CoA) and depletion of acetyl-carnitine and acylcarnitines, which is pathognomonic for inhibition of carnitine palmitoyltransferase-1 (CPT-1). We also show that tBid decreases CPT-1 activity by a mechanism independent of both malonyl-CoA, the key inhibitory molecule of CPT-1, and Bak and/or Bax, but dependent on cardiolipin decrease. Overexpression of Bcl-2, which is able to interact with CPT-1, counteracts the effects exerted by tBid on beta-oxidation. The unexpected role of tBid in the regulation of lipid beta-oxidation suggests a model in which tBid-induced metabolic decline leads to the accumulation of toxic lipid metabolites such as palmitoyl-CoA, which might become participants in the apoptotic pathway.
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Affiliation(s)
- A Giordano
- Institute of Protein Biochemistry--IBP, CNR, Naples, Italy
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Grohmann M, Foulstone E, Welsh G, Holly J, Shield J, Crowne E, Stewart C. Isolation and validation of human prepubertal skeletal muscle cells: maturation and metabolic effects of IGF-I, IGFBP-3 and TNFalpha. J Physiol 2005; 568:229-42. [PMID: 16081485 PMCID: PMC1474756 DOI: 10.1113/jphysiol.2005.093906] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
We have developed a primary skeletal muscle cell culture model derived from normal prepubertal children to investigate the effects of insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and tumour necrosis factor alpha (TNFalpha) on growth, differentiation and metabolism. Cells of myoblast lineage were characterized morphologically by desmin staining and differentiated successfully into multinucleated myotubes. Differentiation was confirmed biochemically by an increase in creatine kinase (CK) activity and IGFBP-3 secretion over time. IGF-I promoted whilst TNFalpha inhibited myoblast proliferation, differentiation and IGFBP-3 secretion. IGF-I partially rescued the cells from the inhibiting effects of TNFalpha. Compared to adult myoblast cultures, children's skeletal muscle cells demonstrated higher basal and day 7 CK activities, increased levels of IGFBP-3 secretion, diminished IGF-I/TNFalpha action and absence of the inhibitory effect of exogenous IGFBP-3 on differentiation. Additional studies demonstrated that TNFalpha increased basal glucose transport via GLUT1, nitric oxide synthase and p38MAPK-dependent mechanisms. These studies provide baseline data to study the interactivity effects of growth factors and cytokines on differentiation and metabolism in muscle in relation to important metabolic disorders such as obesity, type II diabetes or chronic wasting diseases.
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Affiliation(s)
- Malcolm Grohmann
- Department of Exercise and Sport Science, Manchester Metropolitan University, Hassall Road, Alsager, UK.
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Abstract
The key points of this article are anorexia and cachexia are: A major cause of cancer deaths. Several drugs are available to treat anorexia and cachexia. Dyspnea in cancer usually is caused by several factors. Treatment consists of reversing underlying causes, empiric bronchodilators, cortico-steroids--and in the terminally ill patients-opioids, benzodiazepines,and chlorpromazine. Delirium is associated with advanced cancer. Empiric treatment with neuroleptics while evaluating for reversible causes is a reasonable approach to management. Nausea and vomiting are caused by extra-abdominal factors (drugs,electrolyte abnormalities, central nervous system metastases) or intra-abdominal factors (gastroparesis, ileus, gastric outlet obstruction, bowel obstruction). The pattern of nausea and vomiting differs depending upon whether the cause is extra- or intra-abdominal. Reversible causes should be sought and empiric metoclopramide or haloperidol should be initiated. Fatigue may be caused by anemia, depression, endocrine abnormalities,or electrolyte disturbances that should be treated before using empiric methylphenidate. Constipation should be treated with laxatives and stool softeners. Both should start with the first opioid dose.
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Affiliation(s)
- Ruth L Lagman
- The Harry R. Horvitz Center for Palliative Medicine, Cleveland Clinic Taussig Cancer Center, The Cleveland Clinic Foundation, 9500 Euclid Avenue, M76 Cleveland, OH 44195, USA.
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Peluso G, Petillo O, Margarucci S, Grippo P, Melone MAB, Tuccillo F, Calvani M. Differential carnitine/acylcarnitine translocase expression defines distinct metabolic signatures in skeletal muscle cells. J Cell Physiol 2005; 203:439-46. [PMID: 15515015 DOI: 10.1002/jcp.20239] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Import of acylcarnitine into mitochondrial matrix through carnitine/acylcarnitine-translocase (CACT) is fundamental for lipid catabolism. To probe the effect of CACT down-expression on lipid metabolism in muscle, human myocytes were stably transfected with CACT-antisense construct. In presence of low concentration of palmitate, transfected cells showed decreased palmitate oxidation and acetyl-carnitine content, increased palmitoyl-carnitine level, and reduced insulin-dependent decrease of fatty acylcarnitine-to-fatty acyl-CoA ratio. The augmented palmitoyl-carnitine synthesis, also in the presence of insulin, could be related to an altered regulation of carnitine-palmitoyl-transferase 1 (CPT 1) by malonyl-CoA, whose synthesis is dependent by the availability of cytosolic acetyl-groups. Indeed, all the described effects were completely overcome by CACT neo-expression by recombinant adenovirus vector or by addition of acetyl-carnitine to cultures. Acetyl-carnitine effect was related to an increase of malonyl-CoA and was abolished by down-expression, via antisense RNA strategy, of acetyl-CoA carboxylase-beta, the mitochondrial membrane enzyme involved in the direct CPT 1 inhibition via malonyl-CoA synthesis. Thus, in our experimental model the modulation of CACT expression has consequences for CPT 1 activity, while the biologic effects of acetyl-carnitine are not associated with a generic supply of energy compounds but to the anaplerotic property of the molecule.
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Affiliation(s)
- Gianfranco Peluso
- National Cancer Institute-INT Fondazione G. Pascale, via Mariano Semmola, 80131 Naples, Italy.
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Szewczyk NJ, Jacobson LA. Signal-transduction networks and the regulation of muscle protein degradation. Int J Biochem Cell Biol 2005; 37:1997-2011. [PMID: 16125109 DOI: 10.1016/j.biocel.2005.02.020] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2004] [Revised: 01/18/2005] [Accepted: 02/22/2005] [Indexed: 02/05/2023]
Abstract
Protein degradation in muscle functions in maintaining normal physiological homeostasis and adapting to new homeostatic states, and is required for muscle wasting or atrophy in various pathological states. The interplay between protein synthesis and degradation to maintain homeostasis is complex and responds to a variety of autocrine and intercellular signals from neuronal inputs, hormones, cytokines, growth factors and other regulatory molecules. The intracellular events that connect extracellular signals to the molecular control of protein degradation are incompletely understood, but likely involve interacting signal-transduction networks rather than isolated pathways. We review some examples of signal-transduction systems that regulate protein degradation, including effectors of proteolysis inducing factor (PIF), insulin and insulin-like growth factor (IGF) and their receptors, and fibroblast growth factor (FGF) and its receptors.
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Affiliation(s)
- Nathaniel J Szewczyk
- Department of Biological Sciences, University of Pittsburgh, 304 Langley Hall, Pittsburgh, PA 15260, USA
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Libera LD, Vescovo G. Muscle wastage in chronic heart failure, between apoptosis, catabolism and altered anabolism: a chimaeric view of inflammation? Curr Opin Clin Nutr Metab Care 2004; 7:435-41. [PMID: 15192447 DOI: 10.1097/01.mco.0000134374.24181.5b] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF THE REVIEW The mechanisms involved in determining skeletal muscle wastage and cachexia in heart failure are complex and not unequivocal. There are however three different mechanisms that are in some way related to each other and play a very important role. These are inflammation, the catabolic/anabolic imbalance and apoptosis. We have tried to link these pathophysiological processes with the aim of giving a holistic view. RECENT FINDINGS Recent experiments have demonstrated that a major determinant of muscle atrophy in congestive heart failure is apoptosis of skeletal myocytes. Apoptosis is triggered by tumour necrosis factor alpha and its second messenger sphingosine. The source of tumour necrosis factor alpha has to be searched for in inflammation, which may have its origin in the bowel, in the heart, in peripheral hypoxic tissues or in neurohormonal activation. It has also been shown that the growth hormone/insulin-like growth factor 1 axis regulates contractile protein synthesis (transition from slow to fast fibres) and apoptosis, through calcineurin, FK506-FK506-binding protein, mitogen-activated protein kinase and nuclear factor kappaB. Tumour necrosis factor alpha also intervenes in this interplay by activating nuclear factor kappaB. SUMMARY According to these new pathophysiological insights, some strategies aiming to prevent or revert congestive heart failure myopathy with pharmacological interventions blocking inflammation, tumour necrosis factor alpha and apoptosis have been proposed. Future perspectives are based on stem cell implantation, transcription and gene therapy, for instance by overexpression of insulin-like growth factor 1.
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