Journal of Cachexia Sarcopenia and Muscle最新文献

{"title":"Association Analysis of the Circulating Proteome With Sarcopenia-Related Traits Reveals Potential Drug Targets for Sarcopenia","authors":"Simin Wen, Siqi Xu, Xizeng Zong, Shifeng Wen, Wende Xiao, Weipeng Zheng, Han Cen, Zhaohua Zhu, Jingyu Xie, Yan Zhang, Changhai Ding, Guangfeng Ruan","doi":"10.1002/jcsm.13720","DOIUrl":"https://doi.org/10.1002/jcsm.13720","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sarcopenia severely affects the physical health of the elderly. Currently, there is no specific drug available for sarcopenia. This study aims to identify pathogenic proteins and druggable targets for sarcopenia through Mendelian randomization (MR)–based analytical framework.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A sequential stepwise screening method that includes two-sample MR, Steiger filtering test and colocalization (MRSC) was applied to identify causal proteins associated with sarcopenia-related traits. In the MR analyses, 4372 circulating proteins with valid instrumental variables (IVs) from eight proteomic genome-wide association studies were utilized as exposures, and nine sarcopenia-related traits were utilized as outcomes. IVs were classified into cis–protein quantitative trait loci (pQTLs) and trans-pQTLs based on their positions. We conducted cis-only MRSC analyses and cis + trans MRSC analyses using cis-pQTLs and cis + trans pQTLs as IVs, respectively. Post-MRSC analyses were conducted on the prioritized findings of MRSC, including annotation of protein-altering variants (PAVs), assessment of overlap between pQTLs and expression quantitative trait loci (eQTLs), protein–protein interaction (PPI) analysis, pathway enrichment analysis and annotation of drug targets. Utilizing data from the UK Biobank, we performed an observational study to explore the associations between baseline circulating protein levels and the longitudinal changes in nine sarcopenia-related traits.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 181 causal associations for 65 proteins were prioritized by the cis-only MRSC analyses and 227 associations for 91 proteins were prioritized by the cis + trans MRSC analyses. Among the prioritized proteins, the majority of them employed non-PAVs as IVs and most of their cis-pQTLs overlapped with corresponding eQTLs and exhibited consistent directionality, with only one trans-pQTL overlapping with an eQTL. The PPI network of cis-only MRSC-prioritized proteins (<i>p</i> = 4.04 × 10<sup>−4</sup>) and cis + trans MRSC-prioritized proteins (<i>p</i> = 8.76 × 10<sup>−5</sup>) showed significantly more interactions than expected. Reactome, KEGG and GO pathway enrichment analyses for cis-only MRSC-prioritized proteins identified 52, 12 and 79 enriched pathways, respectively (adjusted <i>p</i> < 0.05). For proteins identified by cis + trans MRSC analyses, only 15 pathways were enriched through the GO pathway enrichment analyses. In the observational study, 197 circulating proteins were identified to be associated with one or more sarcopenia-related traits (<i>p</i> < 0.05","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13720","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404655","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":"Neuroimaging Findings in Nondemented Frail Individuals: A Systematic Review","authors":"Hamid Harandi, Soheil Mohammadi, Ali Jahanshahi, Mahsa Dolatshahi, Sogol Alikarami, Rasa Zafari, Cyrus A. Raji","doi":"10.1002/jcsm.13719","DOIUrl":"https://doi.org/10.1002/jcsm.13719","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Frailty is a chronic condition characterised by the progressive decline of multiple physiological functions. There is a critical need to investigate neuroimaging findings in nondemented frail individuals to better understand the underlying mechanisms and implications of frailty on brain health. This paper is aimed at reviewing neuroimaging studies assessing brain changes in nondemented frail individuals to understand the neuropsychological basis of frailty.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A systematic review was conducted on studies focusing on neuroimaging modalities in frailty, including MRI, fMRI, DTI and PET. The review was based on PRISMA instructions and a two-step screening process. The studies evaluating neuroimaging findings of nondemented frail individuals, regardless of publication time or participant age, were included. Data were extracted from the included studies, and the quality of the studies as well as risk of bias was assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Out of 1604 studies screened, 22 eligible studies were included. Out of these, 10 studies had good quality, while others had fair quality according to the Newcastle Ottawa scale (NOS). Of these studies, 18 used Fried criteria or a modified version of it to diagnose frailty, while the Edmonton frailty score (EFS), Rockwood and Mitnitski frailty index and frailty index (FI) were implemented by the remaining studies. The MRI findings indicated significant differences in brain structure between nondemented frail and robust individuals, including an increased number and size of white matter hyperintensities, reduced grey matter volume, higher cerebrospinal fluid (CSF) volume and increased number of cerebral microbleeds (CMBs) in frail participants compared to the robust ones. The studies showed no significant difference between at-risk and robust groups regarding total intracranial volume (TIV). The number of CMBs was associated with prefrailty status and its severity. fMRI studies showed decreased intranetwork mean functional connectivity (FC) in nondemented frail individuals. DTI studies showed lower fractional anisotropy (FA), higher axial diffusivity (<span>AD</span>) and higher radial diffusivity (RD) in the nondemented frail group. The PET scan study showed that mean cortical beta-amyloid level was not associated with FI, but the accumulation of beta-amyloid in the anterior and posterior putamen and precuneus region significantly correlated with frailty and its severity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 ","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13719","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389341","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":"Association of Cumulative Exposure to Metabolic Score for Visceral Fat With the Risk of Cardiovascular Disease and All-Cause Mortality: A Prospective Cohort Study","authors":"Qian Liu, Haozhe Cui, Fei Si, Yuntao Wu, Jing Yu","doi":"10.1002/jcsm.13702","DOIUrl":"https://doi.org/10.1002/jcsm.13702","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Previous studies have demonstrated that metabolic score for visceral fat (METS-VF), a novel surrogate indicator assessing visceral fat, was associated with the risk of hypertension, diabetes mellitus, cardiovascular disease (CVD) and mortality, predicting the risks based on a single METS-VF measurement can increase limitations of the study. Few studies have investigated the association between cumulative exposure to METS-VF and risk of CVD and all-cause mortality. We aimed to examine the association of cumulative METS-VF with risk for CVD and all-cause mortality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>All participants in the study were from the Kailuan Study, which is a large, prospective cohort study, and began in 2006 years. Cumulative METS-VF was calculated by data from 2006 survey to 2010 survey and defined as the mean METS-VF for each pair of consecutive surveys multiplied by the time intervals between these two consecutive surveys. The optimal cut-off value for time-averaged cumulative METS-VF associated with CVD was determined using a survival-time method to calculate maximally selected rank statistics and was used to assess exposure of high METS-VF. A multivariate Cox proportional hazards regression model was used to assess the risk of CVD and all-cause mortality during 2010–2022 years (hazard ratio [HR] and 95% confidence interval [95% CI]).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We included 41 756 participants (mean age, [52.72 ± 11.64] years, 78.53% males and 21.47% females). All participants were divided into four groups: Q1 (reference group), Q2, Q3 and Q4 according to the quartiles of cumulative METS-VF, and exposure duration of high METS-VF was quantified as 0, 2, 4, and 6 years. During the median follow-up of 12.01 years, 4008 (9.60%) CVD events and 3944 all-cause mortality events occurred. After adjusting for potential covariates, compared to participants in Q1 group, the HRs of incident CVD and all-cause mortality were 1.55 (95% CI, 1.38–1.74) and 1.59 (95% CI, 1.40–1.81) for those in Q2 group, 2.13 (95% CI, 1.91–2.38) and 2.67 (95% CI 2.37–3.01) for those in Q3 group, 2.78 (95% CI, 2.49–3.17) and 4.90 (95% CI 4.36–5.50) for those in Q4 group. The HRs for CVD and all-cause mortality were increased with exposure duration of high METS-VF increasing. The result of ROC curve analysis showed that cumulative METS-VF had the highest predictive for CVD among 4 indexes including cumulative METS-VF, cumulative waist circumference, cumulative body mass index and cumulative WHtR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13702","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389342","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":"Circulating Extracellular Vesicles in Alcoholic Liver Disease Affect Skeletal Muscle Homeostasis and Differentiation","authors":"Laura Barberi, Cristiana Porcu, Caterina Boccia, Marianna Cosentino, Carmine Nicoletti, Barbara Peruzzi, Francesca Iosi, Flavia Forconi, Giulia Bagnato, Gabriella Dobrowolny, Simone Di Cola, Lucia Lapenna, Gianluca Cera, Manuela Merli, Antonio Musarò","doi":"10.1002/jcsm.13675","DOIUrl":"https://doi.org/10.1002/jcsm.13675","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The mechanisms underlying muscle alteration associated to alcoholic liver disease (ALD) are not fully understood and the physiopathologic mediators of the liver–muscle interplay remains elusive. We investigated the role of circulating extracellular vesicles (EVs) in ALD as potential mediators of muscle atrophy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We established a mouse model of sarcopenia associated to ALD, by feeding mice with an alcoholic diet for 8 weeks. We investigated the effects of hepatic and circulating EVs isolated from these mice (EtOH mice; <i>n</i> = 7 females) on muscle cell cultures, comparing them with EVs from mice fed with a standard diet (CD mice; <i>n</i> = 6 females). Additionally, we examined the impact of circulating EVs from patients with alcohol-related cirrhosis (7 males and 2 females, mean age 55.4 years) on primary human muscle cells, comparing them with EVs from age-matched healthy subjects (6 males and 3 females). We analysed the miRNA profile of the EVs to identify potential mediators of ALD-associated sarcopenia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We demonstrated that circulating EVs were internalized by muscle cells and that EVs from ALD mice and cirrhotic patients caused alteration in the myogenic program. Molecular analysis revealed that serum EVs from ALD mice reduced protein synthesis in C2C12 cells, decreasing levels of p-AKT/AKT (−54.6%; <i>p</i> < 0.05), p-mTOR/mTOR (−54.5%; <i>p</i> < 0.05) and p-GSK3(Ser9)/GSK3 (−30.63%). Similarly, hepatic EVs induced defects in muscle differentiation, with reduced levels of p-AKT/AKT (−39.1%; <i>p</i> < 0.05), p-mTOR/mTOR (−30.1%; <i>p</i> < 0.05) and p-GSK3(Ser9)/GSK3 (−40%). C2C12 cells treated with either serum or hepatic EtOH-EVs exhibited upregulated expression of muscle-specific atrophy markers Atrogin-1 (+61.2% and +189.5%, respectively; <i>p</i> < 0.05) and MuRF1 (+260.4% and +112.5%, respectively; <i>p</i> < 0.05), along with an increased LC3-II/-I ratio (+131.5% and +40.2%, respectively; <i>p</i> < 0.05), indicating enhanced autophagy. MiRNA analysis revealed that both circulating and hepatic EVs from ALD mice showed elevated expression of miR-21, miR-155, miR-223 and miR-122 (+230% and +292%, respectively; <i>p</i> < 0.01) suggesting their potential role in sarcopenia.</p>\u0000 \u0000 <p>Human muscle cells exposed to EVs from cirrhotic patients exhibited reduced protein synthesis and upregulated Atrogin-1 (+113%; <i>p</i> < 0.05) and MuRF1 (+86.3%; <i>p</i> < 0.05), indicating proteasome activation. Circulating EVs of alcoholic patients showed upregulat","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13675","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362511","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":"Multiomics Analysis Reveals Therapeutic Targets for Chronic Kidney Disease With Sarcopenia","authors":"Meiqiu Wang, Lianghui You, Xu He, Yingchao Peng, Ren Wang, Zhiqiang Zhang, Jiaping Shu, Pei Zhang, Xiaoyi Sun, LiLi Jia, Zhengkun Xia, Chenbo Ji, Chunlin Gao","doi":"10.1002/jcsm.13696","DOIUrl":"10.1002/jcsm.13696","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The presence of sarcopenia in patients with chronic kidney disease (CKD) is associated with poor prognosis. The mechanism underlying CKD-induced muscle wasting has not yet been fully explored. This study investigates the influence of renal secretions on muscles using multiomics sequencing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The kidney transcriptome analysis by RNA-seq and protein profiling by tandem mass tag (TMT), serum TMT and muscle TMT were performed in CKD established using 0.2% adenine and control mice. Spp1 recombinant protein was used to study its effect on myotube atrophy in vitro. In animal experiments on CKD, pharmacological inhibition of Spp1 was used to explore the role of Spp1 in skeletal muscle wasting. Transcriptome analysis was performed to identify differentially expressed genes (DEGs) in the gastrocnemius muscle following Spp1 pharmacological inhibition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the renal transcriptome and TMT, 503 and 377 proteins/genes respectively were co-upregulated and co-downregulated. In the serum TMT of CKD and normal control (NC) mice, 22 upregulated and 7 downregulated differentially expressed proteins (DEPs) showed the same expression patterns as those in the kidney transcriptome and TMT analysis. Based on bioinformatics analysis and reported studies, we selected Spp1 for further validation. Spp1 recombinant protein was added to C2C12 myotubes in vitro, and the results indicated that Spp1 significantly increased the protein levels of the muscle atrophy marker (Murf-1) and promoted the smaller myotubes (all <i>p</i> < 0.05). Compared with NC mice, Spp1 mRNA and protein levels were significantly upregulated in the kidneys of CKD mice, and the serum concentration of Spp1 was also markedly increased (all <i>p</i> < 0.05). In animal experiments, pharmacological inhibition of Spp1 increased the weights of gastrocnemius and tibialis anterior muscles (<i>p</i> < 0.05) and improved muscle atrophy phenotype. Transcriptome analysis showed that DEGs in the gastrocnemius muscle following Spp1 pharmacological inhibition were enriched in protein digestion and absorption, glucagon signalling pathway, apelin signalling pathway and ECM-receptor interaction pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study is the first to establish a regulatory network of kidney-muscle crosstalk to explore the potential mechanism of CKD-related sarcopenia. Employing multiomics analysis, cellular assessment and animal experiments, we have identified that","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13696","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192523","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":"Targeting Drug Delivery System to Skeletal Muscles: A Comprehensive Review of Different Approaches","authors":"Xiaofang Li,&nbsp;Jintao Xu,&nbsp;Shanshan Yao,&nbsp;Ning Zhang,&nbsp;Bao-Ting Zhang,&nbsp;Zong-Kang Zhang","doi":"10.1002/jcsm.13691","DOIUrl":"10.1002/jcsm.13691","url":null,"abstract":"<p>The skeletal muscle is one of the largest organs in the body and is responsible for the mechanical activity required for posture, movement and breathing. The effects of current pharmaceutical therapies for skeletal muscle diseases are far from satisfactory; approximately 24% of Duchenne muscular dystrophy (DMD) trials have been terminated because of unsatisfactory outcomes. The lack of a skeletal muscle-targeting strategy is a major reason for these unsuccessful trials, contributing to low efficiency and severe side effects. The development of targeting strategies for skeletal muscle-specific drug delivery has shown the potential for increasing drug concentrations in the skeletal muscle, minimising off-target effects, and thereby improving the therapeutic effects of drugs. Over the past few decades, novel methods for specifically delivering cargo to skeletal muscles have been developed. In this review, we categorise targeting methods into four types: peptides, antibodies, small molecules and aptamers. Most research has focused on peptide and antibody ligands, and there are several well-established drugs in this category; however, drawbacks such as protease degradation and immunogenicity limit their use. Aptamers and small molecules have low immunogenicity and are simple to chemically produce. However, small molecule ligands generally exhibit lower affinity because of their small size and high mobility. Aptamers are promising ligands for skeletal muscle-targeting delivery systems. Additionally, if the active site of the cargo is located inside the cell, an internalisation pathway becomes necessary. The order of internalisation ligands and targeting ligands in the complex is a crucial factor, because an inappropriate order could lead to much lower targeting and internalisation efficiencies. Moreover, ligand density also merits consideration, as increasing the density of the targeting ligands may result in steric hindrance, which could impact the accessibility of the receptor and cause enlargement of the targeted ligands. More efforts are required to optimise drug delivery systems that specifically recognise skeletal muscle, with the aim of enhancing quality of life and promoting patient well-being.</p>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13691","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192484","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":"Long-Term Impact of Physical Activity on Mortality in Adults With Multimorbidity: A 12-Year Cohort Longitudinal Study From the Survey on Health, Ageing and Retirement in Europe","authors":"Nicola Veronese,&nbsp;Francesco Saverio Ragusa,&nbsp;André Hajek,&nbsp;Brendon Stubbs,&nbsp;Lee Smith,&nbsp;Mario Barbagallo,&nbsp;Ligia Juliana Dominguez,&nbsp;Luigi Fontana,&nbsp;Pinar Soysal,&nbsp;Shaun Sabico,&nbsp;Nasser M. Al-Daghri","doi":"10.1002/jcsm.13695","DOIUrl":"10.1002/jcsm.13695","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;While physical activity (PA) is known to reduce mortality in the general population, this relationship in individuals with multimorbidity (≥ 2 chronic conditions) is unclear. This longitudinal study aimed to investigate whether there is a long-term association between PA levels and mortality rates over a 12-year period in adults with multimorbidity.&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;Data were obtained from eight waves of the Survey of Health, Ageing and Retirement in Europe (SHARE), from 28 European countries. PA levels were self-reported via computer-assisted personal interviews. Mortality during the follow-up period was assessed using data obtained from caregivers through end-of-life interview. Multimorbidity was identified based on the presence of two or more 15 self-reported chronic diseases/conditions. Cox's regression analysis, adjusted for potential confounders, was used to assess the association between PA level and mortality. &lt;i&gt;p&lt;/i&gt;-values were calculated using the Jonckheere–Terpstra test for continuous variables and the Mantel–Haenszel Chi-square test for categorical variables, stratified by PA level.&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;The study included 9216 participants with multimorbidity (mean age 69 ± 10.1 years; 58.7% were women). Among those with multimorbidity, individuals with high PA level were significantly younger, more frequently men, less impaired in activities of daily living, less educated and less frequently obese than those with very low level of PA (&lt;i&gt;p&lt;/i&gt; &lt; 0.0001 for all comparisons). Over the 12 years of follow-up, mortality incidence was three times higher in individuals with multimorbidity and very low PA levels than those with multimorbidity and high levels of PA. After adjusting for confounders, the risk of mortality was significantly lower for participants with moderately low PA levels (HR = 0.64; 95% CI: 0.59–0.71; &lt;i&gt;p&lt;/i&gt; &lt; 0.0001), moderately high PA levels (HR = 0.53; 95% CI: 0.47–0.60; &lt;i&gt;p&lt;/i&gt; &lt; 0.0001) and high PA levels (HR = 0.49; 95% CI: 0.43–0.55; &lt;i&gt;p&lt;/i&gt; &lt; 0.0001) compared to those with very low PA levels.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Findings from the present study suggest that people with multimorbidity who had lower levels of PA were three times more likely to die prematurely after 12 years than adults with multimorbidity and higher levels of PA at baseline. These findings underscore the importance of promoting physical activity in adults with multimorbidity to reduce the risk of premature mortal","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13695","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143192494","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":"Skeletal Muscle Mitochondrial and Autophagic Dysregulation Are Modifiable in Spinal Muscular Atrophy","authors":"Andrew I. Mikhail,&nbsp;Sean Y. Ng,&nbsp;Donald Xhuti,&nbsp;Magda A. Lesinski,&nbsp;Jennifer Chhor,&nbsp;Marc-Olivier Deguise,&nbsp;Yves De Repentigny,&nbsp;Joshua P. Nederveen,&nbsp;Rashmi Kothary,&nbsp;Mark A. Tarnopolsky,&nbsp;Vladimir Ljubicic","doi":"10.1002/jcsm.13701","DOIUrl":"10.1002/jcsm.13701","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;Spinal muscular atrophy (SMA) is a health- and life-limiting neuromuscular disorder. Although varying degrees of mitochondrial abnormalities have been documented in SMA skeletal muscle, the influence of disease progression on pathways that govern organelle turnover and dynamics are poorly understood. Thus, the purpose of this study was to investigate skeletal muscle mitochondria during SMA disease progression and determine the effects of therapeutic modalities on organelle biology.&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;&lt;i&gt;Smn&lt;/i&gt;&lt;sup&gt;&lt;i&gt;2B/+&lt;/i&gt;&lt;/sup&gt; and &lt;i&gt;Smn&lt;/i&gt;&lt;sup&gt;&lt;i&gt;2B/−&lt;/i&gt;&lt;/sup&gt; severe SMA-like mice were used to investigate mitochondrial turnover and dynamics signalling. Muscles were analysed at postnatal day 9 (P9), P13 or P21 to address pre-symptomatic, early symptomatic and late symptomatic periods of the disorder. Additionally, we utilized an acute dose of exercise and urolithin A (UA) to stimulate organelle remodelling in skeletal muscle of SMA mice in vivo and in SMA patient-derived myotubes in vitro, respectively.&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;&lt;i&gt;Smn&lt;/i&gt;&lt;sup&gt;&lt;i&gt;2B/+&lt;/i&gt;&lt;/sup&gt; and &lt;i&gt;Smn&lt;/i&gt;&lt;sup&gt;&lt;i&gt;2B/−&lt;/i&gt;&lt;/sup&gt; mice demonstrated similar levels of muscle mitochondrial oxidative phosphorylation (OxPhos) proteins throughout disease progression. In contrast, at P21 the mRNA levels of upstream factors important for the transcription of mitochondrial genes encoded by the nuclear and mitochondrial DNA, including &lt;i&gt;nuclear respiratory factor 2&lt;/i&gt;, &lt;i&gt;sirtuin 1&lt;/i&gt;, &lt;i&gt;mitochondrial transcription factor A&lt;/i&gt; and &lt;i&gt;tumour protein 53&lt;/i&gt;, were upregulated (+31%–195%, &lt;i&gt;p&lt;/i&gt; &lt; 0.05) in &lt;i&gt;Smn&lt;/i&gt;&lt;sup&gt;&lt;i&gt;2B/−&lt;/i&gt;&lt;/sup&gt; mice relative to &lt;i&gt;Smn&lt;/i&gt;&lt;sup&gt;&lt;i&gt;2B/+&lt;/i&gt;&lt;/sup&gt;. Early and late symptomatic skeletal muscle from SMA-like mice showed greater autophagosome formation as denoted by more phosphorylated autophagy related 16-like 1 (p-ATG16L1&lt;sup&gt;Ser278&lt;/sup&gt;) puncta (+60%–80%, &lt;i&gt;p&lt;/i&gt; &lt; 0.05), along with a build-up of molecules indicative of damaged mitochondria such as BCL2 interacting protein 3, Parkin and PTEN-induced kinase 1 (+100%–195%, &lt;i&gt;p&lt;/i&gt; &lt; 0.05). Furthermore, we observed a fragmented mitochondrial phenotype at P21 that was concomitant with abnormal splicing of &lt;i&gt;Optic atrophy 1&lt;/i&gt; transcripts (−53%, &lt;i&gt;p&lt;/i&gt; &lt; 0.05). A single dose of exercise augmented the expression of &lt;i&gt;citrate synthase&lt;/i&gt; (+43%, &lt;i&gt;p&lt;/i&gt; &lt; 0.05) and corrected the over-assembly of autophagosomes (−64%, &lt;i&gt;p&lt;/i&gt; &lt; 0.05). In patient muscle cells, UA treatment stimulated autophagic flux, increased the expression of OxPhos proteins (+15%–47%, &lt;i&gt;p&lt;/i&gt; &lt; 0.05) and improved m","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13701","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083699","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":"Rapid Quantitative Assessment of Muscle Sodium Dynamics After Exercise Using 23Na-MRI in Dysferlinopathy and Healthy Controls","authors":"Mary A. Neal,&nbsp;Carla F. Bolano-Diaz,&nbsp;Mark Richardson,&nbsp;Jassi Michell-Sodhi,&nbsp;Robert Muni-Lofra,&nbsp;Meredith K. James,&nbsp;Kieren G. Hollingsworth,&nbsp;Heather Hilsden,&nbsp;Ian Wilson,&nbsp;Andrew M. Blamire,&nbsp;Volker Straub,&nbsp;Peter E. Thelwall,&nbsp;Jordi Diaz-Manera","doi":"10.1002/jcsm.13709","DOIUrl":"10.1002/jcsm.13709","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;Dysferlin plays a key role in cell membrane repair; its absence or malfunction in patients with dysferlin-deficient limb girdle muscular dystrophy leads to muscle fibre death. Muscle magnetic resonance (MR) imaging allows non-invasive and repeatable measurements that can report on pathological changes observed in dysferlinopathy patients (DP). We aimed to demonstrate the feasibility of utilising volume-localised &lt;sup&gt;23&lt;/sup&gt;Na spectroscopy as a novel approach to characterise muscle Na&lt;sup&gt;+&lt;/sup&gt; content and biexponential T&lt;sub&gt;2&lt;/sub&gt;* at rest, and dynamically post-exercise, in patients with dysferlinopathy and in matched healthy controls.&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;Adult DP and age and sex matched healthy volunteers (HV) were recruited and scanned on a 3 T clinical MR scanner. Following baseline scans, participants performed physiotherapist-guided isometric dorsiflexion contractions until &lt;i&gt;tibialis anterior&lt;/i&gt; (TA) muscle exhaustion. Dynamic volume-localised sodium-23 (&lt;sup&gt;23&lt;/sup&gt;Na)- and proton (&lt;sup&gt;1&lt;/sup&gt;H)-MR scans were acquired serially for 35 min post-exercise. MR data were analysed to determine TA lipid content, change in TA sodium content, biexponential sodium T&lt;sub&gt;2&lt;/sub&gt;* properties and TA water &lt;sup&gt;1&lt;/sup&gt;H T&lt;sub&gt;2&lt;/sub&gt;.&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;Ten DP (mean age ± standard deviation [SD]: 38.0 ± 10.8 years; 80% female) and 10 HV (mean age ± SD: 38.9 ± 11.5 years) were scanned. Baseline muscle water &lt;sup&gt;1&lt;/sup&gt;H T&lt;sub&gt;2&lt;/sub&gt; and sodium concentration were significantly higher in DP compared to matched controls (&lt;sup&gt;1&lt;/sup&gt;H T&lt;sub&gt;2 DP&lt;/sub&gt; [SD] = 33.8 [2.7] ms, &lt;sup&gt;1&lt;/sup&gt;H T&lt;sub&gt;2 HV&lt;/sub&gt; = 29.3 [1.1] ms, &lt;i&gt;p&lt;/i&gt; &lt; 0.001; [&lt;sup&gt;23&lt;/sup&gt;Na]&lt;sub&gt;DP&lt;/sub&gt; = 36.2 [11.4] mM, [&lt;sup&gt;23&lt;/sup&gt;Na]&lt;sub&gt;HV&lt;/sub&gt; = 19.6 [3.1] mM, &lt;i&gt;p&lt;/i&gt; &lt; 0.001). &lt;sup&gt;1&lt;/sup&gt;H T&lt;sub&gt;2&lt;/sub&gt; and sodium content in healthy controls showed significant post-exercise elevation with a slower time-to-peak for sodium content compared to &lt;sup&gt;1&lt;/sup&gt;H T&lt;sub&gt;2&lt;/sub&gt;. &lt;sup&gt;1&lt;/sup&gt;H T&lt;sub&gt;2&lt;/sub&gt; and sodium content change post-exercise was highly variable in the DP group. Notably, &lt;sup&gt;23&lt;/sup&gt;Na dynamics in one DP with normal muscle fat fraction were similar to HV. Biexponential &lt;sup&gt;23&lt;/sup&gt;Na T&lt;sub&gt;2&lt;/sub&gt;* was measured at baseline in HV (T&lt;sub&gt;2&lt;/sub&gt;*&lt;sub&gt;slow&lt;/sub&gt; = 13.4 [2.3] ms, T&lt;sub&gt;2&lt;/sub&gt;*&lt;sub&gt;fast&lt;/sub&gt; = 2.2 [1.3] ms), and DP (T&lt;sub&gt;2&lt;/sub&gt;*&lt;sub&gt;slow&lt;/sub&gt; = 14.0 [1.5] ms and T&lt;sub&gt;2&lt;/sub&gt;*&lt;sub&gt;fast&lt;/sub&gt; = 1.0 [0.5] m). Equivalent measurements post-exercise revealed an increase in the fraction of the slow-relaxing component in HV (&lt;i&gt;p&lt;/i&gt; &lt; 0.05), consiste","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13709","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083702","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":"Melatonin Ameliorates Age-Related Sarcopenia via the Gut–Muscle Axis Mediated by Serum Lipopolysaccharide and Metabolites","authors":"Ling-Shan Zhou,&nbsp;Yuan Yang,&nbsp;Li Mou,&nbsp;Xin Xia,&nbsp;Min Liu,&nbsp;Ling-Jie Xu,&nbsp;Rong Liu,&nbsp;Jun-Ping Liu,&nbsp;Hai-Yan Zhang,&nbsp;Xiao-Jun Ao,&nbsp;Chang-Jiang Liu,&nbsp;Qian Xiao,&nbsp;Shi-Xiong Liu","doi":"10.1002/jcsm.13722","DOIUrl":"10.1002/jcsm.13722","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;Sarcopenia affects the quality of life and increases adverse outcomes in the elderly. However, as a potential safe and effective remedy to many age-related disorders, little is known about the protective effect of melatonin against sarcopenia, especially the underlying mechanisms of pathophysiology related to the gut–muscle axis.&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;The young (4 months) and old-aged (24 months) wild-type C57BL/6J male mice were included in this study, of which the old-aged mice in the experimental group were treated with 10 mg/kg/day of melatonin for 16 weeks. After that, muscle strength, muscle mass and the cross-sectional area (CSA) of the gastrocnemius muscle fibres were measured. Then, the putative pathways, based on the data obtained from 16S rDNA sequencing of the gut microbiota, RNA sequencing of gastrocnemius muscle and serum untargeted metabolomics, were screened out by the integrated multiomics analysis and validated using immunohistochemistry, ELISA and TUNEL staining. C2C12 myoblasts were treated with LPS. Flow cytometric analysis and western blotting were applied to detect cell apoptosis and protein expressions of Tnfrsf12a and caspase8, respectively. In addition, the mediation analysis was carried out to infer the causal role of the microbiome in contributing to the skeletal muscle through metabolites.&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;Melatonin treatment ameliorated age-related declines in muscle strength (&lt;i&gt;p&lt;/i&gt; &lt; 0.05), muscle mass (&lt;i&gt;p&lt;/i&gt; &lt; 0.01) and CSA of the gastrocnemius muscle fibres (&lt;i&gt;p&lt;/i&gt; &lt; 0.01), as well as changed the gut microbial composition (beta-diversity analysis; &lt;i&gt;R&lt;/i&gt; = 0.513, &lt;i&gt;p&lt;/i&gt; = 0.005). The integrated multiomics analysis implied two main mechanisms about the impact of melatonin-related modifications in the gut microbiota on sarcopenia. First, a lower serum lipopolysaccharide (LPS) level associated with the altered gut microbiota was observed in melatonin-treated mice (&lt;i&gt;p&lt;/i&gt; &lt; 0.001) and was most relevant to the transcription level of Tnfrsf12a in skeletal muscle (&lt;i&gt;R&lt;/i&gt; = 0.926, &lt;i&gt;p&lt;/i&gt; &lt; 0.001). Further bioinformatics analyses and in vitro experiments showed that LPS could contribute to skeletal muscle apoptosis by regulating the Tnfrsf12a/caspase-8 signalling pathway. Second, melatonin significantly altered serum metabolites (variable importance on projection (VIP) &gt; 1.5, &lt;i&gt;p&lt;/i&gt; &lt; 0.05). Mediation models showed that changes in the gut microbiome also influenced skeletal muscle through these metabolites (27 linkages; BH-adjusted &lt;i&gt;p&lt;/i&gt; &lt; 0.05).&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":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13722","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083685","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}