Journal of Cachexia Sarcopenia and Muscle最新文献

{"title":"Mitochondrial Adaptations in Skeletal Muscle Following Incretin-Based Therapies: In Vitro","authors":"Victoria Old, Melanie Davies, Matthew Denniff, Pratik Choudhary, Nicholas Eastley, Robert U. Ashford, Emma Watson","doi":"10.1002/jcsm.70254","DOIUrl":"10.1002/jcsm.70254","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Incretin-based therapies such as glucagon-like peptide-1 receptor agonists (GLP-1Ras), dual GLP-1/GIP agonists and amylin analogues have demonstrated significant weight loss benefits. However, their impact on skeletal muscle mitochondrial function, particularly under metabolic stress, remains unclear. This study aimed to investigate the effects of semaglutide (GLP-1RA), tirzepatide (dual GLP-1/GIP agonist) and cagrilintide (amylin analogue) on mitochondrial function in C2C12 skeletal muscle myotubes under both healthy and lipotoxic (palmitic acid-treated) conditions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Differentiated C2C12 myotubes were treated with doses of each drug for 48 h and 5 days. Mitochondrial respiration was assessed using the Seahorse XFp analyser, mitochondrial DNA (mtDNA) copy number and oxidative phosphorylation (OXPHOS) complex protein expression were measured by qPCR and western blotting. Key findings were repeated in primary human skeletal muscle cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Palmitic acid (PA) significantly impaired mitochondrial function, reducing basal oxygen consumption rate (OCR) by 22% (<i>p</i> = 0.0056) and ATP production by 25% (<i>p</i> = 0.0022). In healthy myotubes, semaglutide and cagrilintide transiently reduced basal respiration (↓21%–28%, <i>p</i> < 0.05) and ATP production (↓24%–31%, <i>p</i> < 0.01) at 48 h, along with reductions in Complexes I, III and IV protein expression, all of which resolved by 5 days. Tirzepatide significantly increased maximal respiration (↑20%–25%, <i>p</i> < 0.005) and spare respiratory capacity (↑22%–30%, <i>p</i> < 0.005) after 5 days. In PA-treated myotubes, semaglutide and cagrilintide acutely worsened mitochondrial impairment (↓ATP production by ~20%–25%, <i>p</i> < 0.01), but these effects resolved by Day 5. Tirzepatide initially suppressed mitochondrial function (↓ATP production, <i>p</i> = 0.0087) but reversed these effects by Day 5, significantly improving ATP production (↑27%–30%, <i>p</i> < 0.005), basal respiration (↑20%, <i>p</i> = 0.0152), and coupling efficiency. mtDNA content remained unchanged across all conditions. Similar responses were noted in human myotubes, with a transient reduction in respiration for semaglutide and cagrilintide (↓30%–62%, <i>p</i> < 0.05) at 48 h and a significant improvement in maximal respiration for tirzepatide at 5 days (↑42%–52%, <i>p</i> = 0.0022).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Incretin-based therapies exert distinct, time and d","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"17 2","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70254","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147477968","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":"Inhibition of N-Terminal Acetyltransferase C Mitigates Endoplasmic Reticulum Stress–Mediated Muscle Atrophy in Cancer Cachexia","authors":"Yusaku Kaneko, Tomohiro Hino, Shunta Taminishi, Yayoi Matoba, Daisuke Motooka, Atsushi Hoshino, Satoaki Matoba","doi":"10.1002/jcsm.70249","DOIUrl":"10.1002/jcsm.70249","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cancer cachexia is a complex syndrome marked by weight loss and muscle wasting, significantly impacting patient quality of life and survival. Mechanistically, it is characterized by suppressed protein synthesis and enhanced muscle catabolism, with the role of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) becoming increasingly evident. This study aimed to explore ER stress–tolerant factors in muscle wasting and evaluate their potential to prevent muscle loss in cancer cachexia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A genome-wide CRISPR screening was conducted in the context of ER stress–mediated growth inhibition of C2C12 myoblasts. The candidate genes resistant to ER stress were further evaluated in C2C12 myotubes treated with conditioned medium of Lewis lung adenocarcinoma (LLC) cells. Twelve-week-old male mice were administered LLC cells and shRNA against Naa35 via adeno-associated virus. Four weeks later, tibialis anterior (TA) muscles were analysed for muscle mass, grip strength and molecular changes with quantitative polymerase chain reaction, western blotting and histological analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>CRISPR screening identified Naa35, Naa38 and Naa30, all three components of N-terminal acetyltransferase C, as key molecules for resistance to ER stress. The atrophic muscles of mice bearing LLC demonstrated an elevation of UPR, as well as 1.64-fold upregulation of Naa35 protein (<i>p</i> = 0.0072). Among the three branches of the UPR, an ATF6 inhibitor, AEBSF, abolished upregulation of Naa35, Naa38 and Naa30, and an ATF6 activator, AA147, induced Naa35 expression in a dose-dependent manner (<i>p</i> < 0.001). In cells treated with LLC conditioned medium, Naa35 knockdown reduced the amount of cathepsin K (CTSK) protein, which subsequently resulted in the CTSK-mediated proteolysis of insulin receptor substrate 1. In LLC-bearing mice, Naa35 knockdown led to a 65.4% reduction in CTSK protein expression (<i>p</i> < 0.001) and preservation of the phosphorylation levels of protein kinase B (<i>p</i> < 0.0324) and anabolic-related S6 kinase (<i>p</i> < 0.0375). Concurrently, the expression of catabolism-related genes was repressed (MuRF1, <i>p</i> < 0.0015; MAFbx1, <i>p</i> < 0.0265). These alterations were associated with the restoration of TA muscle mass (2.52 ± 0.19 vs. 3.72 ± 0.45 mg/g, <i>p</i> = 0.0004), fibre area (1741 ± 992 vs. 2099 ± 1264 mm<sup>2</sup>, <i>p</i> < 0.0001), grip strength in all four limbs (0.0328 ± 0.0076 vs. 0.0506 ± 0.0130 N/g, <i>p</i> = 0.0295) and wire mesh hanging time (496 ± 331 vs. 1038 ± 370 s, <","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"17 2","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70249","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478380","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":"Multi-Parametric MRI Approach at 3 T and 7 T for Assessing Skeletal Muscle Pathology in Myofibrillar Myopathies: A Pilot Study","authors":"Claudius S. Mathy, Lena V. Gast, Christian Holtzhausen, Teresa Gerhalter, Christoph Stuprich, Matthias Türk, Rafael Heiss, Benjamin Marty, Frederik B. Laun, Julia V. Wanschitz, Simon Hametner, Arnd Dörfler, Michael Uder, Tobias Bäuerle, Armin M. Nagel, Rolf Schröder","doi":"10.1002/jcsm.70245","DOIUrl":"10.1002/jcsm.70245","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Myofibrillar myopathies (MFM) form a large group of clinically and genetically heterogeneous protein aggregate diseases. We investigated whether a novel quantitative MRI protocol can reveal new aspects of structural and biochemical muscle pathology in three classic MFM subtypes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>MRI of the lower legs was performed in nine MFM patients with filamin-C (<i>FLNC</i>; <i>n</i> = 5), desmin (<i>DES</i>, <i>n</i> = 2) and LIM domain binding 3 (<i>LDB3</i>; <i>n</i> = 2) gene mutations, one patient with non-MFM, filamin-C related distal myopathy (4 males, 6 females, 51.0 ± 7.7 years) and 10 age-matched healthy control subjects (5 males, 5 females, 50.0 ± 11.0 years). <sup>1</sup>H MRI at 3 T addressed fatty replacement and edema-like changes as well as quantitative measurements of proton density fat fraction (PDFF) and water T<sub>2</sub> relaxation times. <sup>39</sup>K/<sup>23</sup>Na MRI at 7 T was employed to determine apparent tissue potassium and tissue sodium concentrations (aTPC/aTSC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>T<sub>1</sub>-weighted and T<sub>2</sub>-weighted STIR imaging showed the highest degree of fat replacement in the soleus and gastrocnemius medialis muscle regions and the highest degree of edema-like changes in the extensor regions in all 10 myopathy patients. The lowest degree of fat replacement and edema-like changes was present in the gastrocnemius lateralis muscles. Marked fatty replacement of peroneus muscles was also present in DES-related MFM and <i>FLNC</i>-related distal myopathy. Muscular PDFF values were significantly increased in all MFM patients (<i>p</i> = 0.003 - < 0.001) with 60 and 35 of 63 muscles analysed showing increased mean PDFF (> 10% and > 50%). When excluding the muscles with PDFF > 50%, the median water T<sub>2</sub> was significantly increased in all muscle regions of MFM patients with the exception of the tibialis anterior and posterior muscles. Fat-corrected aTSC values in MFM patients were significantly increased compared to healthy controls (55.6 ± 16.3 mM vs. 23.2 ± 5.5 mM, <i>p</i> < 0.001) in all muscles but peroneus muscles, whereas fat-corrected aTPC values were reduced in all muscles except for gastrocnemius lateralis, tibialis posterior and peroneus muscles (75.4 ± 13.3 mM vs. 108.9 ± 9.9 mM, <i>p</i> < 0.001).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Quantitative PDFF measurements and water T<sub>2</sub> mapping serve as valuable tools to objectively quantify fat and ede","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"17 2","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70245","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478382","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":"Effects of Diactive-1–Supported Progressive Resistance Training on Body Composition in Youth With Type 1 Diabetes","authors":"Jacinto Muñoz-Pardeza, José Francisco López-Gil, Ignacio Hormazábal-Aguayo, Mikel Izquierdo, Cesar Agostinis-Sobrinho, Yasmin Ezzatvar, Antonio García-Hermoso","doi":"10.1002/jcsm.70257","DOIUrl":"10.1002/jcsm.70257","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Compared to their healthy peers, children and adolescents with type 1 diabetes are at an increased risk of adverse changes in body composition, including increased fat mass along with reductions in lean and bone mass. Although exercise has shown promise in improving body mass index in this population, the individual effects of resistance training on specific body composition parameters remain understudied. The aim of the study was to evaluate the effects of resistance training supported by the mHealth application Diactive-1 on body composition in children and adolescents with type 1 diabetes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Sixty-two participants with type 1 diabetes (aged 8–18 years old; 48% females) participated in a 24-week randomised controlled trial and were assigned to either the usual care group (<i>n</i> = 32) or the exercise group (<i>n</i> = 30). The intervention was delivered via the Diactive-1 app, which generates progressive overload resistance training programmes tailored to real-time glycaemia and provides educational support. Body composition was assessed using anthropometry and dual-energy X-ray absorptiometry, with fat, lean and bone measurements standardised by age, sex and ethnicity. Linear mixed models were used to evaluate between-group differences in change over time under both intention-to-treat (ITT) and per-protocol (PP) approaches.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>At 24 weeks, in the ITT analysis, the intervention group showed greater gains in lean mass (mean difference [MD] = 0.88 kg; 95% confidence interval [CI] 0.09 to 1.66; Hedges' <i>g</i> = 0.568) and whole-body bone mineral content less head (MD = 32.40 g; 95% CI 6.90 to 57.89; <i>g</i> = 0.644) compared with those in the usual care group. No changes were observed in anthropometric measures, fat mass–related regions or standardised variables (<i>p</i> > 0.05). The risk of probable sarcopenia was lower in the intervention group (relative risk [RR] = 0.17; 95% CI 0.04 to 0.73; Cohen's <i>h</i> = 0.987) than in the usual care group. Findings were directionally consistent in the PP analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This intervention increased bone-related outcomes and was associated with modest gains in lean mass and a lower risk of probable sarcopenia in youths with type 1 diabetes. These findings highlight the potential of the Diactive-1 app as an adjunct tool to support musculoskeletal health in youths with type 1 diabetes.</p>\u0000 </section>\u0000 \u0000 ","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"17 2","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70257","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478381","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":"Phospholipid Glutathione Peroxidase Overexpression Mitigates Cancer Cachexia by Protecting Muscle Mass and Lowering Inflammation","authors":"Elizabeth Duggan, Jordan D. Fuqua, Bo Hagy, Constantin Georgescu, Benjamin F. Miller, Holly Van Remmen, Jacob L. Brown","doi":"10.1002/jcsm.70255","DOIUrl":"10.1002/jcsm.70255","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cancer cachexia is a muscle wasting syndrome that occurs in ~80% of cancer patients and is the primary cause of death for 22%–30% of cancer patients. The primary challenge associated with cancer cachexia is that effective therapies to treat the associated muscle loss and dysfunction are lacking. Research exploring whether reactive oxygen species (ROS, i.e., superoxide anion and hydrogen peroxide) contributes to cancer cachexia has had mixed results. Lipid peroxidation is an underexplored component of oxidative stress that may contribute to cancer cachexia as markers of lipid peroxidation such as 4-hydroxyneoneal (4-HNE) and MDA (Malondialdehyde) are higher in muscle from tumour-bearing mice when compared to controls. Phospholipid hydroperoxide glutathione peroxidase (GPx4) is an antioxidant enzyme that reduces lipid hydroperoxides. We hypothesized that reducing lipid peroxidation via GPx4 overexpression would mitigate cancer cachexia in tumour-bearing mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>One million Lewis lung carcinoma (LLC) cells or phosphate-buffered saline was injected into the hind flank of wildtype or GPx4 transgenic (Tg) mice at 6 months of age and the tumour developed for 4 weeks. Muscle mass, contractile function, mitochondrial respiration, RNA-sequencing, inflammation and the oxylipin profile were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Muscle mass and myofiber cross-sectional area were reduced ~25% in wildtype tumour-bearing mice compared to control mice but not changed in GPx4 Tg tumour-bearing mice. GPx4 overexpression (~3-fold) did not raise maximal or specific muscle force generation in LLC-tumour-bearing mice. Muscle mitochondrial respiration was reduced in wildtype tumour-bearing mice by ~40% when compared to control mice but not altered in tumour-bearing GPx4 Tg mice. Quadricep RNA seq analysis revealed that expression of inflammatory genes was elevated in wildtype tumour-bearing mice when compared to control mice, and the expression of these genes was reduced in tumour-bearing GPx4 Tg mice compared to wildtype tumour-bearing mice. Next, we found that protein content of IL-6 was ~5-fold greater in muscle from wildtype tumour-bearing mice compared to control mice, and GPx4 overexpression prevented this increase in IL-6. We assessed the muscle oxylipin profile and found that many oxylipins generated by 12/15-Lox were elevated in tumour-bearing mice but not impacted by GPx4 overexpression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our results show that GPx","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"17 2","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70255","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483519","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":"Impaired Adipose Anabolism in Pancreatic Cancer Cachexia Is Reversed by HuR Inhibition","authors":"Paige C. Arneson-Wissink, Katherine Pelz, Beth Worley, Heike Mendez, Peter Pham, Parham Diba, Peter R. Levasseur, Grace McCarthy, Alex Chitsazan, Jonathan R. Brody, Aaron J. Grossberg","doi":"10.1002/jcsm.70253","DOIUrl":"10.1002/jcsm.70253","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cachexia is defined by chronic loss of fat and muscle, is a frequent complication of pancreatic ductal adenocarcinoma (PDAC) and negatively impacts patient outcomes. Nutritional supplementation cannot fully reverse tissue wasting, and the mechanisms underlying this phenotype are unclear. This work aims to define the relative contributions of catabolism and anabolism to adipose wasting in PDAC-bearing mice. Human antigen R (HuR) is an RNA-binding protein recently shown to suppress adipogenesis. We hypothesize that fat wasting results from a loss of adipose anabolism driven by increased HuR activity in adipocytes of PDAC-bearing mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Adult C57BL/6J mice received orthotopic PDAC cell (<i>Kras</i><sup><i>G12D</i></sup>; <i>p53</i><sup><i>R172H/+</i></sup>; <i>Pdx1-cre</i>) (PDAC) or PBS (sham) injections. Mice exhibiting moderate cachexia (9 days after injection) were fasted for 24 h, or fasted 24 h and refed 24 h before euthanasia. A separate cohort of PDAC mice were treated with an established HuR inhibitor (KH-3, 100 mg/kg) and subjected to the fast/refeed paradigm. We analysed body mass, gross fat pad mass and adipose tissue mRNA expression. We quantified lipolytic rate as the normalized quantity of glycerol released from 3T3-L1 adipocytes in vitro and gonadal fat pads (gWAT) ex vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>3T3-L1 adipocytes treated with PDAC cell conditioned media (CM) had lower expression of lipolysis and lipogenesis genes than control cells and did not display elevated lipolysis as measured by liberated glycerol. PDAC gWAT cultured ex vivo displayed decreased lipolysis compared to sham gWAT (−54.7%). PDAC and sham mice lost equivalent fat mass after a 24 h fast; however, PDAC mice could not restore inguinal fat pads (iWAT) (−40.5%) or gWAT (−31.8%) mass after refeeding. RNAseq revealed 572 differentially expressed genes in gWAT from PDAC compared to sham mice. Downregulated genes (<i>n</i> = 126) were associated with adipogenesis (adj <i>p</i> = 0.05), and expression of adipogenesis master regulators <i>Pparg</i> and <i>Cebpa</i> were reduced in gWAT from PDAC mice. Immunohistochemistry revealed increased HuR staining in gWAT (+74.9%) and iWAT (+41.2%) from PDAC mice. Inhibiting HuR binding restored lipogenesis in refed animals with a concomitant increase in iWAT mass (+131.7%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our work highlights deficient adipose anabolism as a driver of reduced lipid content in 3T3-L1 adipocytes treat","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"17 2","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70253","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478378","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":"Frailty and Recurrent Cardiovascular Events in Patients With Obstructive Sleep Apnoea: The SAVE Study","authors":"Shoujiang You,&nbsp;Danni Zheng,&nbsp;Katie Harris,&nbsp;Kelly A. Loffler,&nbsp;R. Doug McEvoy,&nbsp;Ruth Peters,&nbsp;Qiang Li,&nbsp;Ferran Barbé,&nbsp;Linan Chen,&nbsp;Xiaoying Chen,&nbsp;Yongjun Cao,&nbsp;Chun-Feng Liu,&nbsp;Geraldo Lorenzi-Filho,&nbsp;Mark Woodward,&nbsp;John Chalmers,&nbsp;Craig S. Anderson,&nbsp;the SAVE Investigators","doi":"10.1002/jcsm.70252","DOIUrl":"10.1002/jcsm.70252","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Frailty is a common syndrome in patients with cardiovascular disease (CVD). Whether frailty modifies the risk of recurrent cardiovascular events in patients with established CVD and obstructive sleep apnoea (OSA) is uncertain. We aimed to determine associations of frailty and the risk of recurrent cardiovascular events in adults with moderate–severe OSA and established CVD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Post hoc analyses of the international Sleep Apnea Cardiovascular Endpoints (SAVE) trial where participants from 89 clinical centres in seven countries with moderate-to-severe OSA and established CVD were randomised to usual care plus continuous positive airway pressure (CPAP) treatment or usual care alone. Participants were categorised using the Rockwood frailty index (FI) into three groups: nonfrail (FI ≤ 0.210), moderately frail (FI 0.211–0.310) and severely frail (FI ≥ 0.311). Cox proportional hazards models were used to assess associations of FI and both composite and individual cardiovascular outcomes over an average follow-up period of 3.7 years.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>There were 2653 OSA participants (mean age 61.3 [SD 7.8] years, and 507 [19.1%] were female) with established CVD included with a mean FI of 0.290 (SD 0.125). There were 783 (29.5%) and 1006 (37.9%) classified as moderately and severely frail, respectively. Compared to those without frailty, those with severe frailty had increased risks of the composite cardiovascular endpoint (hazard ratio [HR], 2.41; 95% confidence interval [CI], 1.88–3.11), and separately for stroke (HR, 2.40; 95% CI, 1.54–3.74), hospitalisation for unstable angina (HR, 2.94; 95% CI, 1.98–4.35), all-cause mortality (HR, 1.77; 95% CI, 1.01–3.11) and CVD death (HR, 2.51; 95% CI, 1.13–5.60), during a mean 3.7 years of follow-up. There was a similar level of adherence to CPAP treatment (<i>p</i> = 0.488) across baseline frailty groups and no heterogeneity in the effect of CPAP treatment on composite and separate cardiovascular events.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In the SAVE cohort of adults with co-occurring OSA and CVD, a higher FI was associated with significantly higher risk of recurrent cardiovascular events. Frailty did not modify CPAP treatment adherence or the effect of CPAP on recurrent cardiovascular events.</p>\u0000 \u0000 <p>Trial Registration: ClinicalTrials.gov identifier: NCT00738179.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"17 2","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70252","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478876","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":"Deficient Cardiolipin Remodelling Alters Muscle Fibre Composition and Neuromuscular Connectivity in Barth Syndrome","authors":"Catalina Matias,&nbsp;Paige L. Snider,&nbsp;Elizabeth A. Sierra Potchanant,&nbsp;Joshua R. Huot,&nbsp;Rahul Raghav,&nbsp;Michael T. Chin,&nbsp;Simon J. Conway,&nbsp;Jeffrey J. Brault","doi":"10.1002/jcsm.70246","DOIUrl":"10.1002/jcsm.70246","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;Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by mutations in the &lt;i&gt;TAFAZZIN&lt;/i&gt; gene, which disrupts cardiolipin (CL) remodelling and mitochondrial function. While cardiac manifestations of BTHS are well characterized in male patients, the mechanisms underlying skeletal muscle weakness and fatigability are poorly understood.&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 neuromuscular and mitochondrial alterations in a novel murine model (&lt;i&gt;Taz&lt;/i&gt;&lt;sup&gt;&lt;i&gt;PM&lt;/i&gt;&lt;/sup&gt;) carrying a patient-derived D75H point mutation knocked into the &lt;i&gt;Tafazzin locus&lt;/i&gt;. This mutation preserves protein abundance but abolishes enzymatic activity. Skeletal muscle function was assessed via weightlifting and hanging tests. Muscle fibre composition and neuromuscular junction (NMJ) integrity were evaluated using immunofluorescence, western blotting and in vivo electrophysiology. Mitochondrial morphology was examined by transmission electron microscopy, and bioenergetics were quantified using ultra-performance liquid chromatography. Stress signalling was assessed by western blotting.&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;Male &lt;i&gt;Taz&lt;/i&gt;&lt;sup&gt;&lt;i&gt;PM&lt;/i&gt;&lt;/sup&gt; mice exhibited seven-fold elevated total monolysocardiolipin and five-fold reduced mature CL levels, confirming deficient transacylase activity. These mice exhibited lower muscle strength and endurance, 32% smaller muscle fibres of all types and a shift towards fast-twitch type 2B fibres, which are more susceptible to fatigue. Electrophysiological analysis revealed a 60% reduction in motor unit number and an increase in average single motor unit potential, indicating motor neuron remodelling. NMJ protein analysis showed decreased MUSK and DOK7 and increased CHRNA1, suggesting impaired NMJ integrity. Despite mitochondrial structural abnormalities and reduced expression of key mitochondrial proteins (NDUFB8, MCU, TMEM65), resting ATP, phosphocreatine and adenine nucleotide ratios were unchanged in both glycolytic and oxidative muscles. However, stress signalling pathways were markedly activated, including phosphorylation of eIF2α, increased CHOP, DELE1, p53 expression and altered Wnt/β-catenin signalling components.&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;Whole-body deficiency of tafazzin enzymatic activity, as occurs in BTHS, is sufficient to result in widespread neuromuscular remodelling, including fibre size/type shifts, motor unit loss, NMJ dysregulation and stress pathway activation, without overt energetic failure at","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"17 2","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70246","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147465946","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":"IL-15 Links Muscle–Kidney Crosstalk to Preserving Podocyte Mitochondrial Fusion and Attenuating Diabetic Nephropathy","authors":"Yin Li,&nbsp;Jialing Rao,&nbsp;Weiyan Lai,&nbsp;Yuxiang Sun,&nbsp;Hongchun Lin,&nbsp;Jun Zhang,&nbsp;Zengchun Ye,&nbsp;Zhaoyong Hu,&nbsp;Hui Peng","doi":"10.1002/jcsm.70256","DOIUrl":"10.1002/jcsm.70256","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>High glucose induces mitochondrial dysfunction in podocytes, contributing to the development of diabetic nephropathy (DN). There is increasing evidence that muscles play a protective role by secreting myokines into the kidneys. Here, we investigated how skeletal muscle influences podocyte health via muscle–kidney crosstalk.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To increase myokine release, we overexpressed PGC-1α specifically in skeletal muscle (mPGC-1α) and crossed these mice with db/m mice to generate diabetic mPGC-1α:db/db mice. In parallel, db/db mice were treated intraperitoneally with recombinant murine interleukin-15 (IL-15). Mechanistic studies were performed using isolated primary podocytes and cultured podocyte cell lines.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared with db/db controls, mPGC-1α:db/db mice exhibited reduced urinary albumin excretion (<i>p</i> &lt; 0.001), mesangial matrix expansion (<i>p</i> &lt; 0.001), glomerular basement membrane thickening (<i>p</i> &lt; 0.001) and urinary podocin excretion (<i>p</i> &lt; 0.001), along with increased podocyte number (<i>p</i> &lt; 0.001). Podocytes from mPGC-1α:db/db mice showed higher expression of Nephrin and COX IV (<i>p</i> &lt; 0.05) and upregulation of multiple mitochondrial function-related genes, notably OPA1 (<i>p</i> &lt; 0.05). Skeletal muscle from mPGC-1α:db/db mice displayed elevated IL-15 mRNA (<i>p</i> &lt; 0.05) and protein (<i>p</i> &lt; 0.01) levels, accompanied by increased plasma IL-15 concentrations (<i>p</i> &lt; 0.05). IL-15 treatment enhanced podocyte mitochondrial respiration, including basal oxygen consumption rate (OCR, <i>p</i> &lt; 0.05), ATP-coupled respiration (<i>p</i> &lt; 0.05) and maximal respiration (<i>p</i> &lt; 0.05). IL-15 preserved mitochondrial fusion under high-glucose conditions by increasing OPA1 expression (<i>p</i> &lt; 0.05) and promoted OPA1 transcription via histone H3 acetylation at its promoter (<i>p</i> &lt; 0.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Skeletal muscle-derived IL-15 mediates renal protection by maintaining mitochondrial fusion in podocytes during DN progression. Targeting this pathway may offer a therapeutic strategy to preserve kidney function and slow progression to end-stage renal disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"17 2","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70256","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471083","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":"Evaluation of Dysphagia in Myositis and Muscular Dystrophy Using Real-Time MRI and Quantitative Muscle Ultrasound","authors":"Rachel Zeng,&nbsp;Anke Rietveld,&nbsp;Omar Al-Bourini,&nbsp;Rosemarie H. M. J. M. Kroon,&nbsp;Arno Olthoff,&nbsp;Matthias Weidenmüller,&nbsp;Per-Ole Carstens,&nbsp;Isabel Kommerell,&nbsp;Saskia G. Schütz,&nbsp;Corinne G. C. Horlings,&nbsp;Johanna G. Kalf,&nbsp;Bert J. M. de Swart,&nbsp;Baziel G. M. van Engelen,&nbsp;Tim Friede,&nbsp;Sabine Hofer,&nbsp;Jens Frahm,&nbsp;Ali Seif Amir Hosseini,&nbsp;Jens Schmidt,&nbsp;Christiaan G. J. Saris","doi":"10.1002/jcsm.70187","DOIUrl":"10.1002/jcsm.70187","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;Swallowing dysfunction—dysphagia—is a frequent and debilitating symptom in neuromuscular disorders, leading to malnutrition, cachexia, aspiration pneumonia, and death. Identification of the underlying pathophysiological mechanisms is important for diagnosis and treatment. As standard assessments have limitations, novel imaging techniques are needed. We here studied the utility of real-time MRI and quantitative muscle ultrasound for characterizing dysphagia in two different neuromuscular disorders.&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;This prospective cohort study included 18 patients with inclusion body myositis (IBM, 33% female, age 68.9 ± 7.7 years) and 13 with oculopharyngeal muscular dystrophy (OPMD, 62% female, age 55.9 ± 7.0 years) from two European Neuromuscular research centers (Nijmegen, NL; Göttingen, DE). Swallowing function was studied using real-time MRI (RT-MRI), FEES (flexible endoscopic evaluation of swallowing), and clinical assessments. T1-mapping and quantitative muscle ultrasound (QMUS) were used to analyse tissue properties in swallowing muscles. Outcomes were compared between the two muscle diseases. RT-MRI values were also compared with 22 age- and sex-matched non-myopathic controls.&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;RT-MRI revealed significantly prolonged oral transit times in OPMD vs. controls (difference between means = 581.2 ms, 95% CI 225.9–936.4, &lt;i&gt;p&lt;/i&gt; = 0.002). Pharyngeal transit time was significantly prolonged in IBM vs. controls (difference between means = 1132.8 ms, 95% CI 482.2–1783, &lt;i&gt;p&lt;/i&gt; = 0.001). A cricopharyngeal bar as a well-established morphological indicator of dysphagia was identified in 80% of patients with IBM compared with 53% in OPMD. Fatty degeneration of the tongue in OPMD significantly correlated between MRI-T1 values and ultrasound echogenicity (Spearman's ρ = −0.52, &lt;i&gt;p&lt;/i&gt; = 0.005). ROC revealed excellent discrimination between diseases by combining RT-MRI, T1-mapping and QMUS (AUC = 0.95, 95% CI 0.86–1.00), while FEES and clinical assessments failed to differentiate specific patterns of dysphagia.&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;This study supports the value of novel MRI and ultrasound techniques for clinical use by identifying the pathophysiology and severity of impaired swallowing. Differentiating the phenotypes of dysphagia can aid in the diagnosis and treatment of affected patients. RT-MRI and QMUS may serve as outcome measures for swallowing in clinical trials.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 &lt;/","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"17 2","pages":""},"PeriodicalIF":9.1,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70187","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147439336","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}