Journal of Cachexia Sarcopenia and Muscle最新文献

{"title":"Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer","authors":"Daria Neyroud, Andrew C. D'Lugos, Enrique J. Trevino, Chandler S. Callaway, Jacqueline Lamm, Orlando Laitano, Brittney Poole, Michael R. Deyhle, Justina Brantley, Lam Le, Andrew R. Judge, Sarah M. Judge","doi":"10.1002/jcsm.13668","DOIUrl":"10.1002/jcsm.13668","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cancer cachexia represents a debilitating muscle wasting condition that is highly prevalent in gastrointestinal cancers, including pancreatic ductal adenocarcinoma (PDAC). Cachexia is estimated to contribute to ~30% of cancer-related deaths, with deterioration of respiratory muscles suspected to be a key contributor to cachexia-associated morbidity and mortality. In recent studies, we identified fibrotic remodelling of respiratory accessory muscles as a key feature of human PDAC cachexia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To gain insight into mechanisms driving respiratory muscle wasting and fibrotic remodelling in response to PDAC, we conducted temporal histological and transcriptomic analyses on diaphragm muscles harvested from mice-bearing orthotopic murine pancreatic (KPC) tumours at time points reflective of precachexia (D8 and D10), mild–moderate cachexia (D12 and D14) and advanced cachexia (endpoint).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>During the precachexia phase, diaphragms showed significant leukocyte infiltration (+3-fold to +13-fold; D8—endpoint vs. Sham, <i>p</i> < 0.05) and transcriptomic enrichment of inflammatory processes associated with tissue injury that remained increased through endpoint. Diaphragm inflammation was followed by increases in PDGFR-ɑ<sup>+</sup> fibroadipogenic progenitors (+2.5 to +3.8-fold; D10—endpoint vs. Sham, <i>p</i> < 0.05), fibre atrophy (−16% to −24%, D12 to endpoint vs. Sham, <i>p</i> < 0.05), ECM expansion (+1.5 to +1.8-fold; D14—endpoint vs. Sham, <i>p</i> < 0.05), collagen accumulation (+3.8-fold; endpoint vs. Sham, <i>p</i> = 0.0013) and reductions in breathing frequency (−55%, <i>p</i> = 0.0074) and diaphragm excursion (−43%, <i>p</i> = 0.0006). These biological processes were supported by changes in the diaphragm transcriptome. Ingenuity pathway analysis predicted factors involved in inflammatory responses to tissue injury, including TGF-β1, angiotensin and PDGF BB, as top upstream regulators activated in diaphragms prior to and throughout cachexia progression, while PGC-1α and the insulin receptor were among the top upstream regulators predicted to be suppressed. The transcriptomic dataset further revealed progressive disturbances to networks involved in lipid, glucose and oxidative metabolism, activation of the unfolded protein response and neuromuscular junction remodelling associated with denervation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In summary, our data support leukocyte infiltration and expansion of P","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13668","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Prognostic Value of Sarcopenia in Clinical Outcomes in Cervical Cancer: A Systematic Review and Meta-Analysis","authors":"Fang Wang, Hongnan Zhen, Kang Yu, Pengju Liu","doi":"10.1002/jcsm.13674","DOIUrl":"10.1002/jcsm.13674","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sarcopenia is a condition characterized by inadequate muscle and function decline and is often associated with ageing and cancer. It is established that sarcopenia and muscle loss occurred during treatment are associated with the clinical outcomes of patients with cancer. This systematic review and meta-analysis aims to evaluate the association between sarcopenia at pretreatment and during treatment and overall survival or disease progression in patients with cervical cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The Web of Science, Embase, Medline and Cochrane Library databases were searched until 4 July 2024. Studies evaluating the prognostic effect of muscle mass at pretreatment or muscle change during treatment on survival or disease progression for patients with cervical cancer were included. Study quality was evaluated with the Newcastle–Ottawa Scale (NOS). Forest plots and summary effect models were used to show the effect size of sarcopenia on clinical outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The search strategy yielded 1721 studies in four databases. Eleven and seven studies were included in the quantitative analysis of pretreatment sarcopenia and muscle change on clinical outcomes, respectively. A total of 1907 patients underwent pretreatment muscle assessment, but 1016 were monitored for muscle changes; however, none of the studies involved measures of muscle strength or function. Meta-analysis showed a significant association between pretreatment sarcopenia and OS [hazard ratio (HR) 1.58, 95% confidence interval (CI): 1.16–2.14, <i>p</i> = 0.003] and PFS (HR 1.63, 95%CI 1.16–2.29, <i>p</i> = 0.005) according to data of univariate analysis. In the meta-analysis of the multivariate data, pretreatment sarcopenia remained associated with poor OS (HR 3.09, 95% CI: 2.07–4.61, <i>p</i> < 0.00001) and PFS (HR: 1.55, 95%CI 1.06–2.28, <i>p</i> = 0.03). Additionally, muscle loss was significantly associated with OS (HR 5.18, 95%CI 3.54–7.56, <i>p</i> < 0.00001) and PFS (HR 2.62, 95%CI 1.63–4.22, <i>p</i> < 0.00001). Subgroup analysis showed that the association between pretreatment sarcopenia and OS, as well as PFS, was influenced by muscle mass measurements and cut-off values, whereas muscle loss consistently predicted worse OS and PFS when stratified by varying degrees of reduction. The NOS scores of all included studies were ≥ 6.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Pretreatment sarcopenia and muscle change during treatment are significantly associated with bot","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13674","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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,&nbsp;Mehrdad Behzadi,&nbsp;Mehrdad Jamali,&nbsp;Parsa Jamilian,&nbsp;Meysam Zarezadeh,&nbsp;Bahram Pourghassem Gargari","doi":"10.1002/jcsm.13671","DOIUrl":"10.1002/jcsm.13671","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>β-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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A 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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Eleven 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; <i>p</i> = 0.004), muscle strength index (ES: 0.27; 95% CI: 0.19–0.35; <i>p</i> &lt; 0.001) and FFM (ES: 0.22; 95% CI: 0.11–0.34; <i>p</i> &lt; 0.001). No significant changes were observed in FM (ES: 0.03; 95% CI: −0.04 to 0.35; <i>p</i> = 0.09) or body mass (ES: 0.09; 95% CI: −0.06 to 0.24; <i>p</i> = 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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>HMB 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.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13671","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cut-Off Points for Low Relative 30-s Sit-to-Stand Power and Their Associations With Adverse Health Conditions","authors":"Mikel Garcia-Aguirre,&nbsp;Ivan Baltasar-Fernandez,&nbsp;Julian Alcazar,&nbsp;Jose Losa-Reyna,&nbsp;Ana Alfaro-Acha,&nbsp;Ignacio Ara,&nbsp;Leocadio Rodriguez-Mañas,&nbsp;Luis M. Alegre,&nbsp;Francisco J. Garcia-Garcia","doi":"10.1002/jcsm.13676","DOIUrl":"10.1002/jcsm.13676","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A total of 1475 community-dwelling older adults (65–98 years; 45% men) from the Toledo Study for Healthy Aging were included. Relative STS power was assessed using the 30-s STS test and the Alcazar's equation. Adverse health conditions considered encompassed frailty, depression, disability in basic (BADL) and instrumental activities of daily living (IADL), cognitive impairment and low habitual gait speed (HGS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Relative STS power decreased linearly at an average rate of 1.0% year⁻¹ in men and 1.5% year⁻¹ in women. The cut-off points for low relative STS power were 2.53 and 2.01 W·kg⁻¹ for men and women, respectively. The prevalence of low relative STS power was significantly lower in older men compared with older women (43.5% vs. 50.0%, respectively; <i>p</i> = 0.005). In men, low relative STS power was associated with frailty (OR [95% CI] = 4.4 [2.4–8.0]), cognitive impairment (OR [95% CI] = 1.7 [1.0–2.7]), disability in BADL (OR [95% CI] = 4.5 [1.5–13.8]) and low HGS (OR [95% CI] = 3.4 [1.9–5.9]). In women, low relative STS power was associated with frailty (OR [95% CI] = 5.2 [3.5–7.7]), disability in BADL (OR [95% CI] = 4.3 [1.8–9.9]) and IADL (OR [95% CI] = 3.1 [2.2–4.3]) and low HGS (OR [95% CI] = 6.1 [2.8–13.1]). No associations were found between low relative STS power and disability in IADL or depression in men, nor between low relative STS power and cognitive impairment or depression in women.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Relative STS power decreased with increasing age in both men and women. The provided sex-specific cut-off points for low relative STS power using the 30-s STS test adequately identified older people with frailty and were associated with an increased risk of experiencing adverse conditions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13676","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reference Values of Handgrip and Lower Extremity Strength for Vietnamese Men and Women: The Vietnam Osteoporosis Study","authors":"Kiet T. Do,&nbsp;Duy K. Hoang,&nbsp;Quan N. Luong,&nbsp;Huy G. Nguyen,&nbsp;An T. Do,&nbsp;Lan T. Ho-Pham,&nbsp;Tuan V. Nguyen","doi":"10.1002/jcsm.13689","DOIUrl":"10.1002/jcsm.13689","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>To establish the reference ranges for muscle strength among Vietnamese individuals.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The study involved 4096 individuals, including 1419 men and 2677 women aged 18 years and above, from the Vietnam Osteoporosis Study. Muscle strength was assessed using a Baseline hand dynamometer for handgrip strength and a Back-Leg-Chest dynamometer for leg strength. We calculated mean values, standard deviations, interquartile ranges, and peak muscle strength (<i>p</i>MS) for both handgrip and leg strength across various ages. Reference curves were created with the Generalised Additive Model for Location Scale and Shape, and polynomial regression models were employed to analyse the relationship between muscle strength and age.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Advancing age was significantly associated with lower muscle strength. Peak muscle strength typically occurred between ages 30 and 40, with earlier peaks in women, especially in leg strength. Men consistently showed higher muscle strength than women, with variations depending on the measurement site. Specifically, average handgrip strength was 36.4 kg ± 8.4 (mean ± SD) for men and 23.2 kg ± 6.0 for women (<i>p</i> &lt; 0.001). Leg strength averaged 63.9 kg ± 27.2 for men and 29.5 kg ± 13.9 for women (<i>p</i> &lt; 0.001). Additionally, we produced a percentile chart illustrating muscle weakness ranges based on the 25th percentile of muscle strength and the appendicular skeletal muscle mass index (ASMI) for the Vietnamese population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These data provide reference ranges for evaluating muscle strength in the Vietnamese population, offering crucial insights for identifying individuals at risk of falls or sarcopenia in clinical settings.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13689","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iron Chelation Prevents Age-Related Skeletal Muscle Sarcopenia in Klotho Gene Mutant Mice, a Genetic Model of Aging","authors":"Chhanda Bose,&nbsp;Judit Megyesi,&nbsp;Oleg Karaduta,&nbsp;Sharda P. Singh,&nbsp;Sundararaman Swaminathan,&nbsp;Sudhir V. Shah","doi":"10.1002/jcsm.13678","DOIUrl":"10.1002/jcsm.13678","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A 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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We investigated the effect of iron chelation (deferiprone, DFP) in sarcopenia, using mice with klotho deficiency (&lt;i&gt;kl/kl&lt;/i&gt;), an established mouse model for aging. Four weeks old Klotho &lt;sup&gt;−/−&lt;/sup&gt; male mice were treated with 25 mg/kg body weight of iron chelator deferiprone in drinking water for 8–14 weeks (&lt;i&gt;n&lt;/i&gt; = 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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Treatment with DFP significantly reduced loss of muscle mass in gastrocnemius and quadriceps muscles (&lt;i&gt;p&lt;/i&gt; &lt; 0.0001). Total and catalytic iron content of serum and iron in muscles were significantly (both &lt;i&gt;p&lt;/i&gt; &lt; 0.0001) lower in the treated animals. The inhibitory factor of myogenesis, the myostatin protein in gastrocnemius muscles (&lt;i&gt;p&lt;/i&gt; = 0.019) and serum (&lt;i&gt;p&lt;/i&gt; = 0.003) were downregulated after 8 weeks of therapy accompanied by an increased in muscle contractile protein myosin heavy chain (~2.9 folds, &lt;i&gt;p&lt;/i&gt; = 0.0004). Treatment decreased inflammation (serum IL6 and TNFα) (&lt;i&gt;p&lt;/i&gt; &lt; 0.0001, &lt;i&gt;p&lt;/i&gt; = 0.005), respectively, and elevated insulin-like growth factor levels (&lt;i&gt;p&lt;/i&gt; = 0.472). This was associated with reduced DNA damage and reduced 8-hydroxy 2 deoxyguanosine in muscle and HO-1 protein (&lt;i&gt;p&lt;/i&gt; &lt; 0.001, &lt;i&gt;p&lt;/i&gt; = 079), respectively. Significant weight loss (&lt;i&gt;p&lt;/i&gt; &lt; 0.001) and decreased water intake (&lt;i&gt;p&lt;/i&gt; = 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 (&lt;i&gt;p&lt;/i&gt; = 0.0002).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 ","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13678","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adeno-Associated Virus 8 and 9 Myofibre Type/Size Tropism Profiling Reveals Therapeutic Effect of Microdystrophin in Canines","authors":"Matthew J. Burke,&nbsp;Braiden M. Blatt,&nbsp;James A. Teixeira,&nbsp;Dennis O. Pérez-López,&nbsp;Yongping Yue,&nbsp;Xiufang Pan,&nbsp;Chady H. Hakim,&nbsp;Gang Yao,&nbsp;Roland W. Herzog,&nbsp;Dongsheng Duan","doi":"10.1002/jcsm.13681","DOIUrl":"10.1002/jcsm.13681","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We evaluated fibre type- and size-specific transduction properties of AAV8 and AAV9 in 17 dogs that received systemic gene transfer (dose 1.94 ± 0.52 × 10¹⁴ vg/kg; injected at 2.86 ± 0.30 months; harvested at 20.79 ± 3.30 months). For AAV8, two DMD dogs and three carrier dogs received an alkaline phosphatase (AP) reporter vector, and five DMD dogs received a four-repeat microdystrophin (uDys) vector. For AAV9, one normal and one DMD dog received the AP vector, and five DMD dogs received a five-repeat uDys vector. Association between AAV transduction and the fibre type/size was studied in three muscles that showed mosaic transgene expression, including the biceps femoris, teres major and latissimus dorsi.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Transgene expression was detected in 30%–45% of myofibres. In the AP reporter vector–injected dogs, neither AAV8 nor AAV9 showed a statistically significant fibre type preference. Interestingly, AP expression was enriched in smaller fibres. In uDys-treated DMD dogs, slow and fast myofibres were equally transduced. Notably, uDys-expressing myofibres were significantly larger than uDys-negative myofibres irrespective of the AAV serotype (<i>p</i> &lt; 0.0001). In AAV8 uDys vector–injected dogs, the mini-Feret diameter was 15%, 16% and 23% larger in uDys-positive slow, fast and hybrid fibres, respectively; the cross-sectional area was 30%, 34% and 46% larger in uDys-positive slow, fast and hybrid fibres, respectively. In AAV9 uDys vector–injected dogs, the mini-Feret diameter was 12%, 13% and 25% larger in uDys-positive slow, fast and hybrid fibres, respectively; the cross-sectional area was 25%, 28% and 59% larger in uDys-positive slow, fast and hybrid fibres, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our studies suggest that AAV8 and AAV9 transduce fast and slow myofibres at equivalent efficiency. Importantly, uDys therapy effectively prevented dystrophic myofibre atrophy. Our study provides important insight into systemic muscle AAV delivery in large mammals and supports further development of uDys gene therapy for DMD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13681","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large Variations in Phenylalanine Concentrations Associate Adverse Cardiac Remodelling in Adult Patients With Phenylketonuria—A Long-Term CMR Study","authors":"Radu Tanacli,&nbsp;Patrick Doeblin,&nbsp;Alessandro Faragli,&nbsp;Jan-Hendrik Hassel,&nbsp;Christian Stehning,&nbsp;Ursula Plöckinger,&nbsp;Athanasia Ziagaki,&nbsp;Sebastian Kelle","doi":"10.1002/jcsm.13667","DOIUrl":"10.1002/jcsm.13667","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Despite 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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Fifteen 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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;On average, the LV end-diastolic volume (EDV) (158 ± 29 vs. 143 ± 29 mL, &lt;i&gt;p&lt;/i&gt; = 0.013) and end-systolic volume (ESV) (68 ± 18 vs. 62 ± 18 mL, &lt;i&gt;p&lt;/i&gt; = 0.011) were lower at follow-up. In contrast, LV mass (LVM) (72 ± 25 vs. 82 ± 29 g, &lt;i&gt;p&lt;/i&gt; &lt; 0.001) and the ratio LVM/EDV (0.46 ± 0.12 vs. 0.58 ± 0.23 g/mL, &lt;i&gt;p&lt;/i&gt; = 0.005) were increased, and T1 times were longer (940 ± 42 vs. 1010 ± 35 ms, &lt;i&gt;p&lt;/i&gt; &lt; 0.001). LV EF (57 ± 6 vs. 57 ± 7%, &lt;i&gt;p&lt;/i&gt; = 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%, &lt;i&gt;p&lt;/i&gt; = 0.012), while LA strain 43.8 ± 11.3 vs. 37.3 ± 9.6%, &lt;i&gt;p&lt;/i&gt; = 0.031) and aortic distensibility (6.38 ± 1.75 vs. 5.21 ± 1.17 10&lt;sup&gt;−3&lt;/sup&gt; mmHg&lt;sup&gt;−1&lt;/sup&gt;, &lt;i&gt;p&lt;/i&gt; = 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","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13667","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence","authors":"Carmen Scheibenbogen,&nbsp;Klaus J. Wirth","doi":"10.1002/jcsm.13669","DOIUrl":"10.1002/jcsm.13669","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Recent 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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We 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).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Mitochondrial 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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Based on this pathomechani","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13669","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Succinate Regulates Exercise-Induced Muscle Remodelling by Boosting Satellite Cell Differentiation Through Succinate Receptor 1","authors":"Yifan Shi,&nbsp;Da Zhou,&nbsp;Haoyang Wang,&nbsp;Longchang Huang,&nbsp;Xuejin Gao,&nbsp;Gulisudumu Maitiabula,&nbsp;Li Zhang,&nbsp;Xinying Wang","doi":"10.1002/jcsm.13670","DOIUrl":"10.1002/jcsm.13670","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Skeletal 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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A 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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;After 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, &lt;i&gt;p&lt;/i&gt; &lt; 0.001) and endurance (+276.70 ± 55.80 vs. 201.70 ± 45.31 s, &lt;i&gt;p&lt;/i&gt; &lt; 0.05), accompanied by enhanced muscle hypertrophy and neuromuscular junction regeneration (&lt;i&gt;p&lt;/i&gt; &lt; 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, &lt;i&gt;p&lt;/i&gt; = 0.008; +47.25% vs. control, &lt;i&gt;p&lt;/i&gt; &lt; 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, &lt;i&gt;p&lt;/i&gt; &lt; 0.001) and protein kinase C eta (PKCη; fold change = 12.5, &lt;i&gt;p&lt;/i&gt; &lt; 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, &lt;i&gt;p&lt;/i&gt; &lt; 0.001), ameliorating dexamethasone-induced muscle atrophy in mice (&lt;i&gt;p&lt;/i&gt; &lt; 0.001).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13670","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}