Backgroundβ‐Hydroxy‐β‐methyl butyrate (HMB) is a metabolite of the amino acid leucine, known for its ergogenic effects on body composition and strength. Despite these benefits, the magnitude of these effects remains unclear due to variability among studies. This umbrella review aims to synthesize meta‐analyses investigating the effects of HMB on body composition and muscle strength in adults.MethodsA comprehensive literature search was conducted in Scopus, PubMed and Web of Science without date or language restrictions until August 2024. The study protocol was registered at Prospero (No. CRD42023402740). Included studies evaluated the effects of HMB supplementation on body mass, fat mass (FM), fat‐free mass (FFM), muscle mass and performance outcomes. Effect sizes (ESs) and 95% confidence intervals (CIs) were calculated, and a random‐effects model was used for meta‐analysis. Standard methods assessed heterogeneity, sensitivity and publication bias. The methodological quality of included studies was assessed using the AMSTAR2 tool.ResultsEleven studies comprising 41 data sets were included, with participants aged 23–79 years. HMB supplementation significantly increased muscle mass (ES: 0.21; 95% CI: 0.06–0.35; p = 0.004), muscle strength index (ES: 0.27; 95% CI: 0.19–0.35; p < 0.001) and FFM (ES: 0.22; 95% CI: 0.11–0.34; p < 0.001). No significant changes were observed in FM (ES: 0.03; 95% CI: −0.04 to 0.35; p = 0.09) or body mass (ES: 0.09; 95% CI: −0.06 to 0.24; p = 0.22). The quality assessment revealed that five studies were of high quality, three were of low quality and three were of critically low quality.ConclusionsHMB supplementation may benefit individuals experiencing muscular atrophy due to physiological conditions, particularly enhancing muscle mass and strength without significant changes in fat mass or body weight.
{"title":"Ergogenic Benefits of β‐Hydroxy‐β‐Methyl Butyrate (HMB) Supplementation on Body Composition and Muscle Strength: An Umbrella Review of Meta‐Analyses","authors":"Mohammad Vesal Bideshki, Mehrdad Behzadi, Mehrdad Jamali, Parsa Jamilian, Meysam Zarezadeh, Bahram Pourghassem Gargari","doi":"10.1002/jcsm.13671","DOIUrl":"https://doi.org/10.1002/jcsm.13671","url":null,"abstract":"Backgroundβ‐Hydroxy‐β‐methyl butyrate (HMB) is a metabolite of the amino acid leucine, known for its ergogenic effects on body composition and strength. Despite these benefits, the magnitude of these effects remains unclear due to variability among studies. This umbrella review aims to synthesize meta‐analyses investigating the effects of HMB on body composition and muscle strength in adults.MethodsA comprehensive literature search was conducted in Scopus, PubMed and Web of Science without date or language restrictions until August 2024. The study protocol was registered at Prospero (No. CRD42023402740). Included studies evaluated the effects of HMB supplementation on body mass, fat mass (FM), fat‐free mass (FFM), muscle mass and performance outcomes. Effect sizes (ESs) and 95% confidence intervals (CIs) were calculated, and a random‐effects model was used for meta‐analysis. Standard methods assessed heterogeneity, sensitivity and publication bias. The methodological quality of included studies was assessed using the AMSTAR2 tool.ResultsEleven studies comprising 41 data sets were included, with participants aged 23–79 years. HMB supplementation significantly increased muscle mass (ES: 0.21; 95% CI: 0.06–0.35; <jats:italic>p</jats:italic> = 0.004), muscle strength index (ES: 0.27; 95% CI: 0.19–0.35; <jats:italic>p</jats:italic> < 0.001) and FFM (ES: 0.22; 95% CI: 0.11–0.34; <jats:italic>p</jats:italic> < 0.001). No significant changes were observed in FM (ES: 0.03; 95% CI: −0.04 to 0.35; <jats:italic>p</jats:italic> = 0.09) or body mass (ES: 0.09; 95% CI: −0.06 to 0.24; <jats:italic>p</jats:italic> = 0.22). The quality assessment revealed that five studies were of high quality, three were of low quality and three were of critically low quality.ConclusionsHMB supplementation may benefit individuals experiencing muscular atrophy due to physiological conditions, particularly enhancing muscle mass and strength without significant changes in fat mass or body weight.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"95 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chhanda Bose, Judit Megyesi, Oleg Karaduta, Sharda P. Singh, Sundararaman Swaminathan, Sudhir V. Shah
BackgroundA decline in skeletal muscle mass and function known as skeletal muscle sarcopenia is an inevitable consequence of aging. Sarcopenia is a major cause of decreased muscle strength, physical frailty and increased muscle fatigability, contributing significantly to an increased risk of physical disability and functional dependence among the elderly. There remains a significant need for a novel therapy that can improve sarcopenia and related problems in aging. Iron accumulation, especially catalytic iron (labile iron) through increased oxidative stress, could be one of the contributing factors to sarcopenia. Our study aimed to examine the effect of an iron chelator on age‐related sarcopenia in mice.MethodsWe investigated the effect of iron chelation (deferiprone, DFP) in sarcopenia, using mice with klotho deficiency (<jats:italic>kl/kl</jats:italic>), an established mouse model for aging. Four weeks old Klotho <jats:sup>−/−</jats:sup> male mice were treated with 25 mg/kg body weight of iron chelator deferiprone in drinking water for 8–14 weeks (<jats:italic>n</jats:italic> = 12/group, treated and untreated). At the end of the study, gastrocnemius, quadriceps and bicep muscles were dissected and used for western blot and immunohistochemistry analysis, histopathology and iron staining. Serum total iron, catalytic iron and cytokine ELISAs were performed with established methods.ResultsTreatment with DFP significantly reduced loss of muscle mass in gastrocnemius and quadriceps muscles (<jats:italic>p</jats:italic> < 0.0001). Total and catalytic iron content of serum and iron in muscles were significantly (both <jats:italic>p</jats:italic> < 0.0001) lower in the treated animals. The inhibitory factor of myogenesis, the myostatin protein in gastrocnemius muscles (<jats:italic>p</jats:italic> = 0.019) and serum (<jats:italic>p</jats:italic> = 0.003) were downregulated after 8 weeks of therapy accompanied by an increased in muscle contractile protein myosin heavy chain (~2.9 folds, <jats:italic>p</jats:italic> = 0.0004). Treatment decreased inflammation (serum IL6 and TNFα) (<jats:italic>p</jats:italic> < 0.0001, <jats:italic>p</jats:italic> = 0.005), respectively, and elevated insulin‐like growth factor levels (<jats:italic>p</jats:italic> = 0.472). This was associated with reduced DNA damage and reduced 8‐hydroxy 2 deoxyguanosine in muscle and HO‐1 protein (<jats:italic>p</jats:italic> < 0.001, <jats:italic>p</jats:italic> = 079), respectively. Significant weight loss (<jats:italic>p</jats:italic> < 0.001) and decreased water intake (<jats:italic>p</jats:italic> = 0.012) were observed in untreated mice compared to treatment group. Kaplan–Meier survival curves show the median life span of treated mice was 108 days as compared to 63 days for untreated mice (<jats:italic>p</jats:italic> = 0.0002).ConclusionsIn summary, our research findings indicate that deferiprone reduced age‐related sarcopenia in the muscles of <jats:italic>Klotho</
{"title":"Iron Chelation Prevents Age‐Related Skeletal Muscle Sarcopenia in Klotho Gene Mutant Mice, a Genetic Model of Aging","authors":"Chhanda Bose, Judit Megyesi, Oleg Karaduta, Sharda P. Singh, Sundararaman Swaminathan, Sudhir V. Shah","doi":"10.1002/jcsm.13678","DOIUrl":"https://doi.org/10.1002/jcsm.13678","url":null,"abstract":"BackgroundA decline in skeletal muscle mass and function known as skeletal muscle sarcopenia is an inevitable consequence of aging. Sarcopenia is a major cause of decreased muscle strength, physical frailty and increased muscle fatigability, contributing significantly to an increased risk of physical disability and functional dependence among the elderly. There remains a significant need for a novel therapy that can improve sarcopenia and related problems in aging. Iron accumulation, especially catalytic iron (labile iron) through increased oxidative stress, could be one of the contributing factors to sarcopenia. Our study aimed to examine the effect of an iron chelator on age‐related sarcopenia in mice.MethodsWe investigated the effect of iron chelation (deferiprone, DFP) in sarcopenia, using mice with klotho deficiency (<jats:italic>kl/kl</jats:italic>), an established mouse model for aging. Four weeks old Klotho <jats:sup>−/−</jats:sup> male mice were treated with 25 mg/kg body weight of iron chelator deferiprone in drinking water for 8–14 weeks (<jats:italic>n</jats:italic> = 12/group, treated and untreated). At the end of the study, gastrocnemius, quadriceps and bicep muscles were dissected and used for western blot and immunohistochemistry analysis, histopathology and iron staining. Serum total iron, catalytic iron and cytokine ELISAs were performed with established methods.ResultsTreatment with DFP significantly reduced loss of muscle mass in gastrocnemius and quadriceps muscles (<jats:italic>p</jats:italic> < 0.0001). Total and catalytic iron content of serum and iron in muscles were significantly (both <jats:italic>p</jats:italic> < 0.0001) lower in the treated animals. The inhibitory factor of myogenesis, the myostatin protein in gastrocnemius muscles (<jats:italic>p</jats:italic> = 0.019) and serum (<jats:italic>p</jats:italic> = 0.003) were downregulated after 8 weeks of therapy accompanied by an increased in muscle contractile protein myosin heavy chain (~2.9 folds, <jats:italic>p</jats:italic> = 0.0004). Treatment decreased inflammation (serum IL6 and TNFα) (<jats:italic>p</jats:italic> < 0.0001, <jats:italic>p</jats:italic> = 0.005), respectively, and elevated insulin‐like growth factor levels (<jats:italic>p</jats:italic> = 0.472). This was associated with reduced DNA damage and reduced 8‐hydroxy 2 deoxyguanosine in muscle and HO‐1 protein (<jats:italic>p</jats:italic> < 0.001, <jats:italic>p</jats:italic> = 079), respectively. Significant weight loss (<jats:italic>p</jats:italic> < 0.001) and decreased water intake (<jats:italic>p</jats:italic> = 0.012) were observed in untreated mice compared to treatment group. Kaplan–Meier survival curves show the median life span of treated mice was 108 days as compared to 63 days for untreated mice (<jats:italic>p</jats:italic> = 0.0002).ConclusionsIn summary, our research findings indicate that deferiprone reduced age‐related sarcopenia in the muscles of <jats:italic>Klotho</","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"36 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Radu Tanacli, Patrick Doeblin, Alessandro Faragli, Jan‐Hendrik Hassel, Christian Stehning, Ursula Plöckinger, Athanasia Ziagaki, Sebastian Kelle
BackgroundDespite a phenylalanine (Phe) restrictive diet, most adult patients with ‘classical’ phenylketonuria (PKU) maintain life‐long Phe concentrations above the normal range and receive tyrosine (Tyr) and protein‐enriched diets to maintain acceptable concentrations and ensure normal development. While these interventions are highly successful in preventing adverse neuropsychiatric complications, their long‐ term consequences are incompletely explored. We observed early cardiomyopathic characteristics and associated hemodynamic changes in adult PKU patients and present here the results of a longitudinal evaluation of cardiac phenotype.MethodsFifteen adult patients with PKU (age: 39.8 ± 8.1 years, 9 males and 6 females) underwent a comprehensive follow‐up cardiac magnetic resonance (CMR) imaging assessment after a mean follow‐up interval of 8.3 ± 0.3 years from the initial baseline visit. The CMR protocol included left (LV) and right (RV) ventricular and left atrial (LA) volumetric assessment, LV parametric mapping (precontrast and postcontrast T1 and T2 maps, extracellular volume [ECV]), multilayer LV myocardial strain, systolic and diastolic hemodynamic forces and RV and LA strain and aortic distensibility evaluation. Plasma concentrations of Phe, tyrosine (Tyr) and other biochemical markers of disease were retrospectively collected. For comparison, a group of 20 matched control subjects undergoing an identical CMR protocol was included.ResultsOn average, the LV end‐diastolic volume (EDV) (158 ± 29 vs. 143 ± 29 mL, <jats:italic>p</jats:italic> = 0.013) and end‐systolic volume (ESV) (68 ± 18 vs. 62 ± 18 mL, <jats:italic>p</jats:italic> = 0.011) were lower at follow‐up. In contrast, LV mass (LVM) (72 ± 25 vs. 82 ± 29 g, <jats:italic>p</jats:italic> < 0.001) and the ratio LVM/EDV (0.46 ± 0.12 vs. 0.58 ± 0.23 g/mL, <jats:italic>p</jats:italic> = 0.005) were increased, and T1 times were longer (940 ± 42 vs. 1010 ± 35 ms, <jats:italic>p</jats:italic> < 0.001). LV EF (57 ± 6 vs. 57 ± 7%, <jats:italic>p</jats:italic> = 0.90), longitudinal (GLS) and circumferential (GCS) systolic strain remained unchanged, but early diastolic hemodynamic (HD) forces were more markedly negative (−19.4 ± 7.0 vs. −26.5 ± 12.2%, <jats:italic>p</jats:italic> = 0.012), while LA strain 43.8 ± 11.3 vs. 37.3 ± 9.6%, <jats:italic>p</jats:italic> = 0.031) and aortic distensibility (6.38 ± 1.75 vs. 5.21 ± 1.17 10<jats:sup>−3</jats:sup> mmHg<jats:sup>−1</jats:sup>, <jats:italic>p</jats:italic> = 0.008) decreased at follow‐up. Compared with controls, PKU patients maintain reduced systolic function with lower LV EF and impaired GCS and have more markedly negative early diastolic HD pressures. A higher decrease in Phe concentration (ΔPhe) was associated with longer T1 times, ΔT1 (<jats:italic>β</jats:italic> = −0.78, <jats:italic>p</jats:italic> < 0.001), increased ECV, ΔECV (<jats:italic>β</jats:italic> = −0.61, <jats:italic>p</jats:italic> = 0.016) and a decrease in systol
{"title":"Large Variations in Phenylalanine Concentrations Associate Adverse Cardiac Remodelling in Adult Patients With Phenylketonuria—A Long‐Term CMR Study","authors":"Radu Tanacli, Patrick Doeblin, Alessandro Faragli, Jan‐Hendrik Hassel, Christian Stehning, Ursula Plöckinger, Athanasia Ziagaki, Sebastian Kelle","doi":"10.1002/jcsm.13667","DOIUrl":"https://doi.org/10.1002/jcsm.13667","url":null,"abstract":"BackgroundDespite a phenylalanine (Phe) restrictive diet, most adult patients with ‘classical’ phenylketonuria (PKU) maintain life‐long Phe concentrations above the normal range and receive tyrosine (Tyr) and protein‐enriched diets to maintain acceptable concentrations and ensure normal development. While these interventions are highly successful in preventing adverse neuropsychiatric complications, their long‐ term consequences are incompletely explored. We observed early cardiomyopathic characteristics and associated hemodynamic changes in adult PKU patients and present here the results of a longitudinal evaluation of cardiac phenotype.MethodsFifteen adult patients with PKU (age: 39.8 ± 8.1 years, 9 males and 6 females) underwent a comprehensive follow‐up cardiac magnetic resonance (CMR) imaging assessment after a mean follow‐up interval of 8.3 ± 0.3 years from the initial baseline visit. The CMR protocol included left (LV) and right (RV) ventricular and left atrial (LA) volumetric assessment, LV parametric mapping (precontrast and postcontrast T1 and T2 maps, extracellular volume [ECV]), multilayer LV myocardial strain, systolic and diastolic hemodynamic forces and RV and LA strain and aortic distensibility evaluation. Plasma concentrations of Phe, tyrosine (Tyr) and other biochemical markers of disease were retrospectively collected. For comparison, a group of 20 matched control subjects undergoing an identical CMR protocol was included.ResultsOn average, the LV end‐diastolic volume (EDV) (158 ± 29 vs. 143 ± 29 mL, <jats:italic>p</jats:italic> = 0.013) and end‐systolic volume (ESV) (68 ± 18 vs. 62 ± 18 mL, <jats:italic>p</jats:italic> = 0.011) were lower at follow‐up. In contrast, LV mass (LVM) (72 ± 25 vs. 82 ± 29 g, <jats:italic>p</jats:italic> < 0.001) and the ratio LVM/EDV (0.46 ± 0.12 vs. 0.58 ± 0.23 g/mL, <jats:italic>p</jats:italic> = 0.005) were increased, and T1 times were longer (940 ± 42 vs. 1010 ± 35 ms, <jats:italic>p</jats:italic> < 0.001). LV EF (57 ± 6 vs. 57 ± 7%, <jats:italic>p</jats:italic> = 0.90), longitudinal (GLS) and circumferential (GCS) systolic strain remained unchanged, but early diastolic hemodynamic (HD) forces were more markedly negative (−19.4 ± 7.0 vs. −26.5 ± 12.2%, <jats:italic>p</jats:italic> = 0.012), while LA strain 43.8 ± 11.3 vs. 37.3 ± 9.6%, <jats:italic>p</jats:italic> = 0.031) and aortic distensibility (6.38 ± 1.75 vs. 5.21 ± 1.17 10<jats:sup>−3</jats:sup> mmHg<jats:sup>−1</jats:sup>, <jats:italic>p</jats:italic> = 0.008) decreased at follow‐up. Compared with controls, PKU patients maintain reduced systolic function with lower LV EF and impaired GCS and have more markedly negative early diastolic HD pressures. A higher decrease in Phe concentration (ΔPhe) was associated with longer T1 times, ΔT1 (<jats:italic>β</jats:italic> = −0.78, <jats:italic>p</jats:italic> < 0.001), increased ECV, ΔECV (<jats:italic>β</jats:italic> = −0.61, <jats:italic>p</jats:italic> = 0.016) and a decrease in systol","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"6 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mikel Garcia-Aguirre, Ivan Baltasar-Fernandez, Julian Alcazar, Jose Losa-Reyna, Ana Alfaro-Acha, Ignacio Ara, Leocadio Rodriguez-Mañas, Luis M. Alegre, Francisco J. Garcia-Garcia
Despite muscle power derived from the 5-rep sit-to-stand (STS) test having been demonstrated to be a valuable biomarker in older individuals, there is limited information regarding muscle power derived from the 30-s STS test, a widely used test in the clinical setting. This study aimed (i) to compare relative 30-s STS power values between older men and women, (ii) to identify cut-off points for low relative 30-s STS power, (iii) to compare the prevalence of low relative STS power between sexes and (iv) to evaluate the association of low relative 30-s STS power with adverse conditions in older people.
{"title":"Cut-Off Points for Low Relative 30-s Sit-to-Stand Power and Their Associations With Adverse Health Conditions","authors":"Mikel Garcia-Aguirre, Ivan Baltasar-Fernandez, Julian Alcazar, Jose Losa-Reyna, Ana Alfaro-Acha, Ignacio Ara, Leocadio Rodriguez-Mañas, Luis M. Alegre, Francisco J. Garcia-Garcia","doi":"10.1002/jcsm.13676","DOIUrl":"https://doi.org/10.1002/jcsm.13676","url":null,"abstract":"Despite muscle power derived from the 5-rep sit-to-stand (STS) test having been demonstrated to be a valuable biomarker in older individuals, there is limited information regarding muscle power derived from the 30-s STS test, a widely used test in the clinical setting. This study aimed (i) to compare relative 30-s STS power values between older men and women, (ii) to identify cut-off points for low relative 30-s STS power, (iii) to compare the prevalence of low relative STS power between sexes and (iv) to evaluate the association of low relative 30-s STS power with adverse conditions in older people.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"55 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kiet T. Do, Duy K. Hoang, Quan N. Luong, Huy G. Nguyen, An T. Do, Lan T. Ho-Pham, Tuan V. Nguyen
Falls and sarcopenia are significant public health issues in Vietnam. Despite muscle strength being a critical predictor for these conditions, reference data on muscle strength within the Vietnamese population are lacking.
{"title":"Reference Values of Handgrip and Lower Extremity Strength for Vietnamese Men and Women: The Vietnam Osteoporosis Study","authors":"Kiet T. Do, Duy K. Hoang, Quan N. Luong, Huy G. Nguyen, An T. Do, Lan T. Ho-Pham, Tuan V. Nguyen","doi":"10.1002/jcsm.13689","DOIUrl":"https://doi.org/10.1002/jcsm.13689","url":null,"abstract":"Falls and sarcopenia are significant public health issues in Vietnam. Despite muscle strength being a critical predictor for these conditions, reference data on muscle strength within the Vietnamese population are lacking.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"45 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matthew J. Burke, Braiden M. Blatt, James A. Teixeira, Dennis O. Pérez-López, Yongping Yue, Xiufang Pan, Chady H. Hakim, Gang Yao, Roland W. Herzog, Dongsheng Duan
Adeno-associated virus (AAV) 8 and 9 are in clinical trials for treating neuromuscular diseases such as Duchenne muscular dystrophy (DMD). Muscle consists of myofibres of different types and sizes. However, little is known about the fibre type and fibre size tropism of AAV in large mammals.
{"title":"Adeno-Associated Virus 8 and 9 Myofibre Type/Size Tropism Profiling Reveals Therapeutic Effect of Microdystrophin in Canines","authors":"Matthew J. Burke, Braiden M. Blatt, James A. Teixeira, Dennis O. Pérez-López, Yongping Yue, Xiufang Pan, Chady H. Hakim, Gang Yao, Roland W. Herzog, Dongsheng Duan","doi":"10.1002/jcsm.13681","DOIUrl":"https://doi.org/10.1002/jcsm.13681","url":null,"abstract":"Adeno-associated virus (AAV) 8 and 9 are in clinical trials for treating neuromuscular diseases such as Duchenne muscular dystrophy (DMD). Muscle consists of myofibres of different types and sizes. However, little is known about the fibre type and fibre size tropism of AAV in large mammals.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"15 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BackgroundRecent studies provide strong evidence for a key role of skeletal muscle pathophysiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In a 2021 review article on the pathophysiology of ME/CFS, we postulated that hypoperfusion and ischemia can result in excessive sodium and calcium overload in skeletal muscles of ME/CFS patients to cause mitochondrial damage. Since then, experimental evidence has been provided that supports this concept.MethodsWe collect, summarize and discuss the current state of knowledge for the key role of skeletal muscle pathophysiology. We try to explain which risk factors and mechanisms are responsible for a subgroup of patients with post COVID syndrome (PCS) to develop ME/CFS (PC‐ME/CFS).ResultsMitochondrial dysfunction is a long‐held assumption to explain cardinal symptoms of ME/CFS. However, mitochondrial dysfunction could not be convincingly shown in leukocytes. By contrast, recent studies provide strong evidence for mitochondrial dysfunction in skeletal muscle tissue in ME/CFS. An electron microscopy study could directly show damage of mitochondria in skeletal muscle of ME/CFS patients with a preferential subsarcolemmal localization but not in PCS. Another study shows signs of skeletal muscle damage and regeneration in biopsies taken one day after exercise in PC‐ME/CFS. The simultaneous presence of necroses and signs of regeneration supports the concept of repeated damage. Other studies correlated diminished hand grip strength (HGS) with symptom severity and prognosis. A MRI study showed that intracellular sodium in muscles of ME/CFS patients is elevated and that levels correlate inversely with HGS. This finding corroborates our concept of sodium and consecutive calcium overload as cause of muscular and mitochondrial damage caused by enhanced proton‐sodium exchange due to anaerobic metabolism and diminished activity of the sodium‐potassium‐ATPase. The histological investigations in ME/CFS exclude ischemia by microvascular obstruction, viral presence or immune myositis. The only known exercise‐induced mechanism of damage left is sodium induced calcium overload. If ionic disturbance and mitochondrial dysfunction is severe enough the patient may be captured in a vicious circle. This energy deficit is the most likely cause of exertional intolerance and post exertional malaise and is further aggravated by exertion.ConclusionBased on this pathomechanism, future treatment approaches should focus on normalizing the cause of ionic disbalance. Current treatment strategies targeting hypoperfusion have the potential to improve the dysfunction of ion transporters.
{"title":"Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence","authors":"Carmen Scheibenbogen, Klaus J. Wirth","doi":"10.1002/jcsm.13669","DOIUrl":"https://doi.org/10.1002/jcsm.13669","url":null,"abstract":"BackgroundRecent studies provide strong evidence for a key role of skeletal muscle pathophysiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In a 2021 review article on the pathophysiology of ME/CFS, we postulated that hypoperfusion and ischemia can result in excessive sodium and calcium overload in skeletal muscles of ME/CFS patients to cause mitochondrial damage. Since then, experimental evidence has been provided that supports this concept.MethodsWe collect, summarize and discuss the current state of knowledge for the key role of skeletal muscle pathophysiology. We try to explain which risk factors and mechanisms are responsible for a subgroup of patients with post COVID syndrome (PCS) to develop ME/CFS (PC‐ME/CFS).ResultsMitochondrial dysfunction is a long‐held assumption to explain cardinal symptoms of ME/CFS. However, mitochondrial dysfunction could not be convincingly shown in leukocytes. By contrast, recent studies provide strong evidence for mitochondrial dysfunction in skeletal muscle tissue in ME/CFS. An electron microscopy study could directly show damage of mitochondria in skeletal muscle of ME/CFS patients with a preferential subsarcolemmal localization but not in PCS. Another study shows signs of skeletal muscle damage and regeneration in biopsies taken one day after exercise in PC‐ME/CFS. The simultaneous presence of necroses and signs of regeneration supports the concept of repeated damage. Other studies correlated diminished hand grip strength (HGS) with symptom severity and prognosis. A MRI study showed that intracellular sodium in muscles of ME/CFS patients is elevated and that levels correlate inversely with HGS. This finding corroborates our concept of sodium and consecutive calcium overload as cause of muscular and mitochondrial damage caused by enhanced proton‐sodium exchange due to anaerobic metabolism and diminished activity of the sodium‐potassium‐ATPase. The histological investigations in ME/CFS exclude ischemia by microvascular obstruction, viral presence or immune myositis. The only known exercise‐induced mechanism of damage left is sodium induced calcium overload. If ionic disturbance and mitochondrial dysfunction is severe enough the patient may be captured in a vicious circle. This energy deficit is the most likely cause of exertional intolerance and post exertional malaise and is further aggravated by exertion.ConclusionBased on this pathomechanism, future treatment approaches should focus on normalizing the cause of ionic disbalance. Current treatment strategies targeting hypoperfusion have the potential to improve the dysfunction of ion transporters.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"20 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yifan Shi, Da Zhou, Haoyang Wang, Longchang Huang, Xuejin Gao, Gulisudumu Maitiabula, Li Zhang, Xinying Wang
BackgroundSkeletal muscle remodelling can cause clinically important changes in muscle phenotypes. Satellite cells (SCs) myogenic potential underlies the maintenance of muscle plasticity. Accumulating evidence shows the importance of succinate in muscle metabolism and function. However, whether succinate can affect SC function and subsequently coordinate muscle remodelling to exercise remains unexplored.MethodsA mouse model of high‐intensity interval training (HIIT) was used to investigate the effects of succinate on muscle remodelling and SC function by exercise capacity test and biochemical methods. Mice with succinate receptor 1 (SUCNR1)‐specific knockout in SCs were generated as an in vivo model to explore the underlying mechanisms. RNA sequencing of isolated SCs was performed to identify molecular changes responding to succinate‐SUCNR1 signalling. The effects of identified key molecules on the myogenic capacity of SCs were investigated using gain‐ and loss‐of‐function assays in vitro. To support the translational application, the clinical efficacy of succinate was explored in muscle‐wasting mice.ResultsAfter 21 days of HIIT, mice supplemented with 1.5% succinate exhibited striking gains in grip strength (+0.38 ± 0.04 vs. 0.26 ± 0.03 N, <jats:italic>p</jats:italic> < 0.001) and endurance (+276.70 ± 55.80 vs. 201.70 ± 45.31 s, <jats:italic>p</jats:italic> < 0.05), accompanied by enhanced muscle hypertrophy and neuromuscular junction regeneration (<jats:italic>p</jats:italic> < 0.001). The myogenic capacity of SCs was significantly increased in gastrocnemius muscle of mice supplemented with 1% and 1.5% succinate (+16.48% vs. control, <jats:italic>p</jats:italic> = 0.008; +47.25% vs. control, <jats:italic>p</jats:italic> < 0.001, respectively). SUCNR1‐specific deletion in SCs abolished the modulatory influence of succinate on muscle adaptation in response to exercise, revealing that SCs respond to succinate–SUCNR1 signalling, thereby facilitating muscle remodelling. SUCNR1 signalling markedly upregulated genes associated with stem cell differentiation and phosphorylation pathways within SCs, of which p38α mitogen‐activated protein kinase (MAPK; fold change = 6.7, <jats:italic>p</jats:italic> < 0.001) and protein kinase C eta (PKCη; fold change = 12.5, <jats:italic>p</jats:italic> < 0.001) expressions were the most enriched, respectively. Mechanistically, succinate enhanced the myogenic capacity of isolated SCs by activating the SUCNR1–PKCη–p38α MAPK pathway. Finally, succinate promoted SC differentiation (1.5‐fold, <jats:italic>p</jats:italic> < 0.001), ameliorating dexamethasone‐induced muscle atrophy in mice (<jats:italic>p</jats:italic> < 0.001).ConclusionsOur findings reveal a novel function of succinate in enhancing SC myogenic capacity via SUCNR1, leading to enhanced muscle adaptation in response to exercise. These findings provide new insights for developing pharmacological strategies to overcome muscle atrophy–rel
{"title":"Succinate Regulates Exercise‐Induced Muscle Remodelling by Boosting Satellite Cell Differentiation Through Succinate Receptor 1","authors":"Yifan Shi, Da Zhou, Haoyang Wang, Longchang Huang, Xuejin Gao, Gulisudumu Maitiabula, Li Zhang, Xinying Wang","doi":"10.1002/jcsm.13670","DOIUrl":"https://doi.org/10.1002/jcsm.13670","url":null,"abstract":"BackgroundSkeletal muscle remodelling can cause clinically important changes in muscle phenotypes. Satellite cells (SCs) myogenic potential underlies the maintenance of muscle plasticity. Accumulating evidence shows the importance of succinate in muscle metabolism and function. However, whether succinate can affect SC function and subsequently coordinate muscle remodelling to exercise remains unexplored.MethodsA mouse model of high‐intensity interval training (HIIT) was used to investigate the effects of succinate on muscle remodelling and SC function by exercise capacity test and biochemical methods. Mice with succinate receptor 1 (SUCNR1)‐specific knockout in SCs were generated as an in vivo model to explore the underlying mechanisms. RNA sequencing of isolated SCs was performed to identify molecular changes responding to succinate‐SUCNR1 signalling. The effects of identified key molecules on the myogenic capacity of SCs were investigated using gain‐ and loss‐of‐function assays in vitro. To support the translational application, the clinical efficacy of succinate was explored in muscle‐wasting mice.ResultsAfter 21 days of HIIT, mice supplemented with 1.5% succinate exhibited striking gains in grip strength (+0.38 ± 0.04 vs. 0.26 ± 0.03 N, <jats:italic>p</jats:italic> < 0.001) and endurance (+276.70 ± 55.80 vs. 201.70 ± 45.31 s, <jats:italic>p</jats:italic> < 0.05), accompanied by enhanced muscle hypertrophy and neuromuscular junction regeneration (<jats:italic>p</jats:italic> < 0.001). The myogenic capacity of SCs was significantly increased in gastrocnemius muscle of mice supplemented with 1% and 1.5% succinate (+16.48% vs. control, <jats:italic>p</jats:italic> = 0.008; +47.25% vs. control, <jats:italic>p</jats:italic> < 0.001, respectively). SUCNR1‐specific deletion in SCs abolished the modulatory influence of succinate on muscle adaptation in response to exercise, revealing that SCs respond to succinate–SUCNR1 signalling, thereby facilitating muscle remodelling. SUCNR1 signalling markedly upregulated genes associated with stem cell differentiation and phosphorylation pathways within SCs, of which p38α mitogen‐activated protein kinase (MAPK; fold change = 6.7, <jats:italic>p</jats:italic> < 0.001) and protein kinase C eta (PKCη; fold change = 12.5, <jats:italic>p</jats:italic> < 0.001) expressions were the most enriched, respectively. Mechanistically, succinate enhanced the myogenic capacity of isolated SCs by activating the SUCNR1–PKCη–p38α MAPK pathway. Finally, succinate promoted SC differentiation (1.5‐fold, <jats:italic>p</jats:italic> < 0.001), ameliorating dexamethasone‐induced muscle atrophy in mice (<jats:italic>p</jats:italic> < 0.001).ConclusionsOur findings reveal a novel function of succinate in enhancing SC myogenic capacity via SUCNR1, leading to enhanced muscle adaptation in response to exercise. These findings provide new insights for developing pharmacological strategies to overcome muscle atrophy–rel","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"29 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marie E. Esper, Caroline E. Brun, Alexander Y. T. Lin, Peter Feige, Marie J. Catenacci, Marie‐Claude Sincennes, Morten Ritso, Michael A. Rudnicki
BackgroundDuchenne muscular dystrophy (DMD) is a devastating disease characterized by progressive muscle wasting that leads to diminished lifespan. In addition to the inherent weakness of dystrophin‐deficient muscle, the dysfunction of resident muscle stem cells (MuSC) significantly contributes to disease progression.MethodsUsing the <jats:italic>mdx</jats:italic> mouse model of DMD, we performed an in‐depth characterization of disease progression and MuSC function in dystrophin‐deficient skeletal muscle using immunohistology, isometric force measurements, transcriptomic analysis and transplantation assays. We examined the architectural and functional changes in <jats:italic>mdx</jats:italic> skeletal muscle from 13 and 52 weeks of age and following acute cardiotoxin (CTX) injury. We also studied MuSC dynamics and function under homeostatic conditions, during regeneration post‐acute injury, and following engraftment using a combination of histological and transcriptomic analyses.ResultsDystrophin‐deficient skeletal muscle undergoes progressive changes with age and delayed regeneration in response to acute injury. Muscle hypertrophy, deposition of collagen and an increase in small myofibres occur with age in the <jats:italic>tibialis anterior</jats:italic> (TA) and diaphragm muscles in <jats:italic>mdx</jats:italic> mice. Dystrophic <jats:italic>mdx</jats:italic> mouse TA muscles become hypertrophic with age, whereas diaphragm atrophy is evident in 1‐year‐old <jats:italic>mdx</jats:italic> mice. Maximum tetanic force is comparable between genotypes in the TA, but maximum specific force is reduced by up to 38% between 13 and 52 weeks in the <jats:italic>mdx</jats:italic> mouse. Following acute injury, myofibre hyperplasia and hypotrophy and delayed recovery of maximum tetanic force occur in the <jats:italic>mdx</jats:italic> TA. We also find defective MuSC polarity and reduced numbers of myocytes in <jats:italic>mdx</jats:italic> muscle following acute injury. We observed a 50% and 30% decrease in PAX7<jats:sup>+</jats:sup> and MYOG<jats:sup>+</jats:sup> cells, respectively, at 5 days post CTX injury (5 dpi) in the <jats:italic>mdx</jats:italic> TA. A similar decrease in <jats:italic>mdx</jats:italic> progenitor cell proportion is observed by single cell RNA sequencing of myogenic cells at 5 dpi. The global expression of commitment‐related genes is also reduced at 5 dpi. We find a 46% reduction in polarized PARD3 in <jats:italic>mdx</jats:italic> MuSCs. Finally, <jats:italic>mdx</jats:italic> MuSCs exhibit elevated PAX7<jats:sup>+</jats:sup> cell engraftment with significantly fewer donor‐derived myonuclei in regenerated myofibres.ConclusionsOur study provides evidence that dystrophin deficiency in MuSCs and myofibres together contributes to progression of DMD. Ongoing muscle damage stimulates MuSC activation; however, aberrant intrinsic MuSC polarity and stem cell commitment deficits due to the loss of dystrophin impair muscle regeneration. Our st
{"title":"Intrinsic Muscle Stem Cell Dysfunction Contributes to Impaired Regeneration in the mdx Mouse","authors":"Marie E. Esper, Caroline E. Brun, Alexander Y. T. Lin, Peter Feige, Marie J. Catenacci, Marie‐Claude Sincennes, Morten Ritso, Michael A. Rudnicki","doi":"10.1002/jcsm.13682","DOIUrl":"https://doi.org/10.1002/jcsm.13682","url":null,"abstract":"BackgroundDuchenne muscular dystrophy (DMD) is a devastating disease characterized by progressive muscle wasting that leads to diminished lifespan. In addition to the inherent weakness of dystrophin‐deficient muscle, the dysfunction of resident muscle stem cells (MuSC) significantly contributes to disease progression.MethodsUsing the <jats:italic>mdx</jats:italic> mouse model of DMD, we performed an in‐depth characterization of disease progression and MuSC function in dystrophin‐deficient skeletal muscle using immunohistology, isometric force measurements, transcriptomic analysis and transplantation assays. We examined the architectural and functional changes in <jats:italic>mdx</jats:italic> skeletal muscle from 13 and 52 weeks of age and following acute cardiotoxin (CTX) injury. We also studied MuSC dynamics and function under homeostatic conditions, during regeneration post‐acute injury, and following engraftment using a combination of histological and transcriptomic analyses.ResultsDystrophin‐deficient skeletal muscle undergoes progressive changes with age and delayed regeneration in response to acute injury. Muscle hypertrophy, deposition of collagen and an increase in small myofibres occur with age in the <jats:italic>tibialis anterior</jats:italic> (TA) and diaphragm muscles in <jats:italic>mdx</jats:italic> mice. Dystrophic <jats:italic>mdx</jats:italic> mouse TA muscles become hypertrophic with age, whereas diaphragm atrophy is evident in 1‐year‐old <jats:italic>mdx</jats:italic> mice. Maximum tetanic force is comparable between genotypes in the TA, but maximum specific force is reduced by up to 38% between 13 and 52 weeks in the <jats:italic>mdx</jats:italic> mouse. Following acute injury, myofibre hyperplasia and hypotrophy and delayed recovery of maximum tetanic force occur in the <jats:italic>mdx</jats:italic> TA. We also find defective MuSC polarity and reduced numbers of myocytes in <jats:italic>mdx</jats:italic> muscle following acute injury. We observed a 50% and 30% decrease in PAX7<jats:sup>+</jats:sup> and MYOG<jats:sup>+</jats:sup> cells, respectively, at 5 days post CTX injury (5 dpi) in the <jats:italic>mdx</jats:italic> TA. A similar decrease in <jats:italic>mdx</jats:italic> progenitor cell proportion is observed by single cell RNA sequencing of myogenic cells at 5 dpi. The global expression of commitment‐related genes is also reduced at 5 dpi. We find a 46% reduction in polarized PARD3 in <jats:italic>mdx</jats:italic> MuSCs. Finally, <jats:italic>mdx</jats:italic> MuSCs exhibit elevated PAX7<jats:sup>+</jats:sup> cell engraftment with significantly fewer donor‐derived myonuclei in regenerated myofibres.ConclusionsOur study provides evidence that dystrophin deficiency in MuSCs and myofibres together contributes to progression of DMD. Ongoing muscle damage stimulates MuSC activation; however, aberrant intrinsic MuSC polarity and stem cell commitment deficits due to the loss of dystrophin impair muscle regeneration. Our st","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"83 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to ‘Hepatic signal transducer and activator of transcription‐3 signalling drives early‐stage pancreatic cancer cachexia via suppressed ketogenesis’","authors":"","doi":"10.1002/jcsm.13687","DOIUrl":"https://doi.org/10.1002/jcsm.13687","url":null,"abstract":"","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"133 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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