Journal of Cachexia, Sarcopenia and Muscle最新文献

{"title":"Myonuclear Domain-Associated and Central Nucleation-Dependent Spatial Restriction of Dystrophin Protein Expression.","authors":"Katarzyna Chwalenia,Vivi-Yun Feng,Nicole Hemmer,John C W Hildyard,Liberty E Roskrow,Richard J Piercy,Eric T Wang,Annemieke Aartsma-Rus,Maaike van Putten,Matthew J A Wood,Thomas C Roberts","doi":"10.1002/jcsm.70284","DOIUrl":"https://doi.org/10.1002/jcsm.70284","url":null,"abstract":"BACKGROUNDThe restoration of uniformly distributed dystrophin protein expression is an important consideration for the development of advanced therapeutics for Duchenne muscular dystrophy (DMD).METHODSWe have generated a novel genetic mouse model (mdx52-XistΔhs) that expresses variable and nonuniformly distributed dystrophin protein from birth as a consequence of skewed X-chromosome inactivation. mdx52-XistΔhs myofibers are heterokaryons containing a mixture of myonuclei expressing either wild-type or mutant dystrophin alleles in a mutually exclusive manner, resulting in dystrophin protein being spatially restricted to corresponding dystrophin-expressing myonuclear domains. This phenotype models the situation in female dystrophinopathy and dystrophic muscle in which dystrophin has been incompletely restored by partially effective experimental therapeutics. Dystrophin distribution was assessed in mdx52-XistΔhs muscle sections and isolated single myofibers by immunostaining and RNA-FISH analysis.RESULTSTotal dystrophin expression increased by ~2.8-fold (p < 0.010) in aged (60-week-old) mdx52-XistΔhs mice relative to 6-week-old adults, suggestive of an aging-associated accumulation of dystrophin-expressing myonuclei through positive selection, although this was insufficient to resolve sarcolemmal dystrophin patchiness. Nonuniformly distributed dystrophin conferred partial protection against pathology-related muscle turnover in an expression-level-dependent manner in both adult and aged mdx52-XistΔhs mice compared to mice expressing no dystrophin. Isolated mdx52-XistΔhs myofibers exhibited patchy 'zebra-like' banding of dystrophin sarcolemmal coverage that colocalized with β-dystroglycan but not neuronal nitric oxide synthase, which was uniformly distributed. Systematic classification of isolated mdx52-XistΔhs myofibers revealed unexpected and profound differences associated with central nucleation, with dystrophin found to be absent in centrally nucleated myofibers and myofiber segments. Muscle injury alone was insufficient to recapitulate this phenomenon, suggesting that it is a feature of the dystrophic environment. Dmd mRNA was found to be present throughout centrally nucleated segments, and proteins such as titin and F-actin were uniformly distributed, suggesting that dystrophin is specifically repressed at the protein level in these regions. The microtubule network was moderately disrupted in mdx52-XistΔhs 'zebra-banded' fibers, but this effect was not different between dystrophin-positive and dystrophin-negative myofiber subdomains. By contrast, centrally nucleated mdx52-XistΔhs myofibers exhibited severe microtubule network disruption.CONCLUSIONSThese findings reveal new insights into the importance of dystrophin spatial localization and identify a previously unappreciated barrier to effective therapeutic dystrophin restoration, particularly within regenerated or centrally nucleated myofibers.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"21 1","pages":"e70284"},"PeriodicalIF":8.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147625690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Automated CT-Based Muscle Density Predicts Mortality Regardless of Muscle Area.","authors":"Adam J Kuchnia,Glen M Blake,Matthew H Lee,Jevin Lortie,Rachel Fenske,John W Garrett,Perry J Pickhardt","doi":"10.1002/jcsm.70268","DOIUrl":"https://doi.org/10.1002/jcsm.70268","url":null,"abstract":"BACKGROUNDAbdominal CT-based assessments of skeletal muscle may provide important prognostic information for all-cause mortality in aging adults. We aimed to evaluate whether AI-segmented muscle area and muscle density predict long-term survival in a large, retrospective adult population.METHODSThis retrospective study included 151 141 adult patients who underwent an abdominal CT examination for any indication between 2000 and 2021. A validated automated AI-based algorithm measured L3-level muscle area (cm2) and muscle density in Hounsfield units (HU). Demographic and clinical data (age, sex, BMI and date of death) were extracted from electronic health records. Survival analyses included Kaplan-Meier curves and multivariable hazard ratio (HR) models to determine the relationship between these muscle metrics and mortality.RESULTSAmong the 138 535 adults (66 468 men and 72 067 women) included, 28 489 died over the 20-year period post-CT, yielding an overall 20-year survival rate of 0.620 (95% CI: 0.611-0.629). Of these, 9343 deaths occurred within the first year [survival rate: 0.933 (95% CI: 0.932-0.934)]. Mean and median follow-up time was 6.4 and 4.9 years, respectively. Lower muscle density significantly predicted higher mortality when each patient's measurement was expressed by its percentile within the age and sex-matched population (HR up to 3.5 in women and 4.0 in men), with decreasing mortality throughout the higher percentiles. Lower muscle area showed a more modest effect on mortality in both sexes when expressed in percentiles. Individuals with high muscle density demonstrated the most favourable survival and those with low density demonstrated the worst survival. Low muscle density significantly predicted mortality across all age groups and both sexes. Conversely, muscle area predicted mortality in all age groups in men, albeit to a lesser degree and did not predict mortality in any age group among women.CONCLUSIONSAutomated CT-based measurements of muscle density are superior to muscle area in predicting all-cause mortality in a large, heterogeneous adult population. Incorporating AI-driven muscle density assessments into routine clinical practice could substantially improve patient risk stratification and management, of particular relevance for aging and sarcopenic patients.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"9 1","pages":"e70268"},"PeriodicalIF":8.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147585634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal Deterioration in Nutritional Status Associated With Increased Risk of Sarcopenia in Community-Dwelling Aged Adults: A Prospective Cohort Study.","authors":"Ho Jun Lim,Seung Shin Park,Mi Ji Kim,Hak Chul Jang,Sung Hye Kong,Chang Won Won","doi":"10.1002/jcsm.70270","DOIUrl":"https://doi.org/10.1002/jcsm.70270","url":null,"abstract":"BACKGROUNDThe association between changes in nutritional status over time and the risk of sarcopenia in older adults is unclear. This study investigated the impact of baseline nutritional status and its 4-year changes on the development of sarcopenia and severe sarcopenia.METHODSWe conducted a prospective, multicentre longitudinal cohort study and 1661 community-dwelling adults aged 70-84 years without baseline sarcopenia were included for analysis. Nutritional status was assessed using the Mini Nutritional Assessment (MNA), categorized as normal, at risk of malnutrition or malnutrition (24-30, 17-23.5 and < 17 points, respectively). Changes in nutritional status were classified as improved, unchanged or deteriorated. Primary outcomes were new-onset sarcopenia and severe sarcopenia. Sarcopenia was defined by the Asian Working Group for Sarcopenia (AWGS) 2019 criteria. Cox regression models using changes in nutritional status as a time-varying covariate were used to estimate hazard ratios (HRs), adjusted for age, sex, body mass index, smoking, alcohol use, fall history, education, comorbidities and activities of daily living. In sensitivity analyses, the Fine and Gray subdistribution hazard model was performed to estimate subdistribution HRs (sHRs), which accounts for death as a competing risk.RESULTSThe mean age of participants was 76.3 ± 3.6 years, and 46.9% were male. At baseline, 77.3% had normal nutritional status, 21.8% were at risk of malnutrition, and 0.9% were malnourished. After mean follow-up of 6.8 years, deterioration in nutritional status was associated with increased risk of sarcopenia (HR 1.77 [95% confidence interval, 1.25-2.51], p = 0.001) and severe sarcopenia (HR 1.97 [1.23-3.16], p = 0.005) compared to those with unchanged nutritional status among total participants. Among those with normal nutritional status at baseline, deterioration in nutritional status was also associated with increased risk of sarcopenia (HR 2.07 [95% confidence interval, 1.37-3.12], p = 0.001) and severe sarcopenia (HR 1.95 [1.08-3.53], p = 0.028). Prevalence of low muscle mass differed significantly by measurement device (Hologic 64.8%, GE Lunar 37.2%, BIA 24.2%, p < 0.001); however, the longitudinal association between nutritional status and sarcopenia risk remained consistent in sensitivity analysis.CONCLUSIONBaseline nutritional risk and deterioration in nutritional status are robust predictors of future sarcopenia and severe sarcopenia in community-dwelling older adults. Improving nutritional status over time may significantly reduce the risk of progressing to severe sarcopenia. Clinical strategies to monitor and enhance nutrition are essential for preventing sarcopenia.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"6 1","pages":"e70270"},"PeriodicalIF":8.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147583917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of 5 Years of Aerobic Exercise on Sarcopenia in Older Adults-Secondary Outcomes of the Generation 100 Study.","authors":"Guro Birgitte Stene,Maria Jose Lequerica,Dorthe Stensvold,Trude Rakel Balstad,Stian Lydersen,Ulrik Wisløff,Jorunn Lægdheim Helbostad","doi":"10.1002/jcsm.70279","DOIUrl":"https://doi.org/10.1002/jcsm.70279","url":null,"abstract":"BACKGROUNDEarly prevention of sarcopenia through exercise is vital to health, independence and mortality risk in older adults; however, there is a scarcity of evidence concerning the long-term effects of aerobic exercise alone. We tested the primary hypothesis that a 5-year decline in key defining components of sarcopenia is less in an aerobic exercise group compared with a control group. Secondly, we tested the same hypothesis using a model of 'clinically defined sarcopenia'.METHODSNorwegian community dwelling older adults (n = 1567; aged 70-75 years at inclusion) participated in the Generation 100 Study. They were randomized in a 1:1:2 ratio-stratified by sex and cohabitation status to either moderate intensity continuous training (MICT, n = 387) or high intensity interval training (HIIT, n = 400), or to a control group following the Norwegian physical activity guidelines (CON, n = 780). Key defining components of sarcopenia were grip strength (kilograms), skeletal muscle index (kg/m2) and gait speed (m/s). Clinically defined sarcopenia was based on the European Working Group on Sarcopenia in Older People and recent normative data for the Norwegian population. An intention to treat linear mixed model and an ordinal logistic regression mixed model were used to examine the effects of aerobic exercise on sarcopenia on the 1, 3 and 5 years follow-up. p values for the main hypothesis were adjusted using the Benjamini-Hochberg correction.RESULTSMean age across groups was 72 years of age, including ~50% women, ~50% with higher education, 86%-90% with good or very good health and 73%-76% considered physically active. Compared with CON, grip strength declined less for HIIT at Year 1 (estimated difference of 0.98 kg; p < 0.001) and Year 3 (estimated difference of 0.03 kg; p = 0.016). At Year 3, HIIT increased their gait speed by 0.01 m/s (estimated difference between HIIT vs. CON of 0.03 m/s; p = 0.016). At Year 5, all groups declined from baseline (CON -0.07; MICT -0.10 and HIIT -0.04 m/s). Participants determined as having 'clinically defined sarcopenia' at baseline, Years 3 and 5 were: 22%, 58% and 63% (CON); 20%, 55% and 67% (MICT) and 19%, 50% and 56% (HIIT). Odds for developing clinically defined sarcopenia were significantly lower for HIIT (OR = 0.51; p = 0.018 at Year 3; OR = 0.47; p = 0.009 at Year 5) as compared with CON. No effects were found for MICT.CONCLUSIONSThe study demonstrates that in addition to having a protective cardiovascular effect, HIIT also has a beneficial effect on muscle strength and physical performance in a relatively healthy population of older adults.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"29 2 1","pages":"e70279"},"PeriodicalIF":8.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147619412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calprotectin and Sarcopenia in COPD: Biomarker, Bystander or Target?","authors":"Irena Sarc,Ramon Langen,Harry Reinier Gosker,Mitja Lainscak","doi":"10.1002/jcsm.70283","DOIUrl":"https://doi.org/10.1002/jcsm.70283","url":null,"abstract":"","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"58 1 1","pages":"e70283"},"PeriodicalIF":8.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147524492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validity of Bioelectrical Impedance Analysis for the Assessment of Body Composition in Patients With Systemic Sclerosis.","authors":"Lucas Denardi Dória,Rafaela Cavalheiro do Espírito Santo,Vanessa Hax,André Luiz Mallmann,Leonardo Peterson Dos Santos,Stephanie Pilotti,Daniel Nóbrega de Moraes,Bruno Eduardo Lara Da Silva,Vinícius Hammel Lovison,Ronaldo Legati Junior,Poliana Espíndola Correia,Tayane Muniz Fighera,Fernando Gerchman,Poli Mara Spritzer,Ricardo Machado Xavier,Rafael Mendonça da Silva Chakr","doi":"10.1002/jcsm.70273","DOIUrl":"https://doi.org/10.1002/jcsm.70273","url":null,"abstract":"BACKGROUNDSystemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and progressive fibrosis. Reduced muscle mass is common and contributes to myopenia, sarcopenia and adverse clinical outcomes. Dual-energy X-ray absorptiometry (DXA) is the most widely used method in clinical research and is recommended by international guidelines as the reference standard for muscle mass evaluation in sarcopenia. However, its accessibility in routine clinical practice is limited. Bioelectrical impedance analysis (BIA) is a validated method for assessing body composition due to its affordability, ease of use and non-invasive nature. Nevertheless, variability across devices and assessment protocols may influence measurement accuracy, underscoring the need for validation in specific clinical populations. This study compared body composition measured by BIA and DXA and evaluated the diagnostic accuracy of BIA for detecting myopenia in SSc.METHODSIn this cross-sectional study, patients with SSc underwent body composition assessment by BIA (InBody 370 s) and DXA (Lunar Prodigy Primo). Fat mass (FM), fat mass index (FMI), fat-free mass (FFM), fat-free mass index (FFMI), appendicular skeletal muscle mass (ASM), appendicular skeletal muscle mass index (ASMI) and ASM adjusted by body mass index (ASM/BMI) were assessed. Myopenia was defined according to established muscle mass criteria. Agreement was evaluated using Bland-Altman analysis and Lin's concordance correlation coefficient (CCC). Diagnostic performance was assessed using receiver operating characteristic (ROC) curves.RESULTSOne hundred patients with SSc were included (91% women; mean age 60.1 ± 11.5 years; median disease duration 11.5 [5.0-20.3] years). Disease subtypes comprised 23% diffuse cutaneous, 61% limited cutaneous and 16% sine scleroderma. BIA demonstrated excellent agreement with DXA (CCC > 0.900) for ASM/BMI [Δ = 0.032; 95% CI 0.019-0.045], FM (Δ = -0.401; 95% CI -0.804 to 0.003), FMI (Δ = -0.190; 95% CI -0.366 to -0.015) and FFM (Δ = -0.010; 95% CI -0.415 to 0.395). Good concordance (CCC 0.750-0.900) was observed for ASM (Δ = 0.803; 95% CI 0.518-1.088). In women, ROC analysis showed high discriminative ability, with AUCs of 0.956 (95% CI 0.908-1.000) for ASM, 0.878 (95% CI 0.763-0.993) for ASMI and 0.969 (95% CI 0.935-1.000) for ASM/BMI. The optimal ASM/BMI cut-off (0.506) yielded 100% sensitivity and 90.1% specificity (PPV 55.6%, NPV 100%).CONCLUSIONBIA showed high agreement with DXA and strong diagnostic accuracy for detecting myopenia in SSc, particularly in women. These findings support BIA as an accessible tool for body composition assessment in SSc when standardized conditions and validated sex-specific cut-offs are applied.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"105 1","pages":"e70273"},"PeriodicalIF":8.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147518488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibro-Adipogenic Progenitors Regulate Orofacial Neuromuscular Junction Regeneration via Myostatin.","authors":"Ruizhi Li,Ruojing Liu,Yixuan Huang,Yijue Wang,Xu Cheng,Jingtao Li,Shujuan Zou,Xing Yin","doi":"10.1002/jcsm.70264","DOIUrl":"https://doi.org/10.1002/jcsm.70264","url":null,"abstract":"BACKGROUNDOrofacial and limb muscles differ in embryonic origin and regenerative capacity. Neuromuscular junction (NMJ) regeneration is critical for muscle restoration both histologically and functionally. The relative potential of orofacial and limb muscles to form postsynaptic apparatuses remains elusive. While the role of fibro-adipogenic progenitors (FAPs) in NMJ regeneration has been discussed in limb muscles, it remains unexplored in orofacial muscles.METHODSNMJ regeneration was triggered by freeze injury in masseter (MAS) and tibialis anterior (TA) muscles and assessed using histological and functional tests. FAPs transplantation experiments and coculture with muscle stem cells (MuSCs) were performed to investigate their effects on postsynaptic apparatus formation. Transcriptome profiling of FAPs identified the key secretory molecule involved in NMJ regulation. The effect of this molecule was further investigated using in vitro gain- and loss-of-function assays, conditional knockout transgenic mice and pharmacological blockade.RESULTSImmunohistochemistry showed extensive fibrosis surrounded by regenerated myofibres in MAS, whereas no fibrosis but regenerated myofibres in TA. Restored myofibre calibre and resolved fibrosis in the regenerated lesion periphery are observed in both muscles, yet regenerated NMJs remained markedly below the intact level at 30 days post-injury (dpi) only in MAS (-52.1%, p < 0.001). Interestingly, transplantation of FAPs isolated from MAS reduced the number of postsynaptic acetylcholine receptors (AChRs) on regenerated myofibres in recipient TA muscle (-61.3%, p < 0.001). Conditioned medium of FAPs isolated from MAS at 7 dpi impaired AChR clustering on myotubes, decreasing the AChR/myotube area ratio (p < 0.001). RNA-seq analysis of 7 dpi MAS and TA FAPs identified myostatin (Mstn) as the key differentially expressed gene. Mstn transcripts in MAS FAPs were 1.7-fold higher than those in TA FAPs (p < 0.001). In vitro knockdown of Mstn in FAPs isolated from 7 dpi MAS reversed its negative effect on AChR clustering, as evidenced by a 4-fold increase in the AChR/myotube area ratio (p < 0.01). The number of nascent AChR clusters in injured MAS of FAP-specific Mstn knockout mice was higher than that of injured floxed controls (2.7-fold, p < 0.001). Pharmacological blockade of MSTN enhanced postsynaptic AChR neogenesis in MAS.CONCLUSIONSWe demonstrated differential NMJ regeneration in MAS and TA muscle. Injury-activated MAS FAPs impede postsynaptic apparatus formation by secreting pathophysiological levels of MSTN. Lowering MSTN levels in injured MAS might enhance its regeneration through nerve-muscle signalling.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 1","pages":"e70264"},"PeriodicalIF":8.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147585695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated Kallistatin Induces Myosteatosis and Exercise Intolerance by Antagonizing AdipoR1-Mediated AMPK Signalling.","authors":"Fuyan Hong,Zhenzhen Fang,Gang Shen,Yan Wang,Yunhua Li,Youbin Zhong,Junze Dai,Chengwei Zhang,Jing Zhang,Wencan Chen,Weiwei Qi,Xia Yang,Guoquan Gao,Ti Zhou","doi":"10.1002/jcsm.70261","DOIUrl":"https://doi.org/10.1002/jcsm.70261","url":null,"abstract":"BACKGROUNDPathological intramuscular lipid deposition (myosteatosis) and exercise intolerance are hallmarks of metabolic disorders, including diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD), yet their underlying mechanisms remain unclear. Our previous work has confirmed that hypertriglyceridemia-driven kallistatin (KAL) elevation is present in the peripheral blood of patients with MASLD and diabetes and is a causative factor in hepatic steatosis and MASH pathogenesis. Here, we aim to evaluate this elevated KAL on myosteatosis and exercise function.METHODSWe first established rat models of myosteatosis via a high-fat diet or high-fructose water intake and measured serum KAL levels by immunoblotting. KAL transgenic (KAL-TG) mice were generated and subjected to longitudinal analyses, including Oil Red O staining for lipid deposition, exercise tolerance tests, indirect calorimetry for energy expenditure, mitochondrial DNA copy number quantification, ATP measurement, immunoblotting and quantitative PCR. For mechanistic analyses, mouse C2C12 myotubes were treated with recombinant KAL or KAL adenovirus, with or without co-treatment with AICAR, AdipoRon or AdipoR1 siRNA. Additionally, we evaluated the potential ameliorative effects of KAL knockout and target agonists on myosteatosis.RESULTSSerum KAL levels were significantly elevated in rat models of myosteatosis. Conversely, genetic ablation of KAL ameliorated diet-induced muscle lipid deposition. KAL-TG mice developed myosteatosis (muscle TG [μmol/g]: WT: 54.26 ± 14.56 [95% CI: 38.99-69.54]; KAL-TG: 85.13 ± 11.53 [95% CI: 73.03-97.24], p < 0.01) and exhibited exercise intolerance (p < 0.05 for all) from 6 months of age. Mechanistically, KAL bound to sarcolemmal adiponectin receptor 1 (AdipoR1), suppressing AMPK activity. This led to reduced phosphorylation of acetyl-CoA carboxylase (ACC) (p < 0.05), enhancing lipogenesis and downregulated the PGC-1α/NRF1 axis (p < 0.05), impairing mitochondrial biogenesis and reducing ATP production (p < 0.05). Pharmacological activation of AdipoR1 (AdipoRon) and fenofibrate attenuated myosteatosis and restored exercise capacity in KAL-TG mice (p < 0.05).CONCLUSIONSAbnormal elevation of KAL drives metabolic myopathy and exercise intolerance by antagonizing the AdipoR1-AMPK axis. Our findings offer dual strategies: repurposing AdipoR1 agonists (e.g., AdipoRon) or reducing circulating KAL (e.g., via genetic ablation or triglyceride-lowering agents such as fenofibrate), both applicable to diabetes/MASLD-related metabolic myopathy.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"25 1","pages":"e70261"},"PeriodicalIF":8.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147585693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Muscle Weakness and the Irisin-BDNF and Oxidative Stress Axis in the 60-Day Pseudorandomised Controlled AGBRESA Bed Rest Study.","authors":"Alessandra Bosutti, Bergita Ganse, Edwin Mulder, Markus Gruber, Maria Venegas-Carro, Jochen Zange, Jörn Rittweger, Moritz Eggelbusch, Rob C I Wüst, Paul Hendrickse, Hans Degens","doi":"10.1002/jcsm.70250","DOIUrl":"10.1002/jcsm.70250","url":null,"abstract":"<p><strong>Background: </strong>Muscle atrophy and weakness are among the most detrimental consequences of disuse, microgravity, hospitalisation and ageing. Oxidative modifications of myofibrillar proteins generated by oxidative stress may contribute to the reduced force- and power-generating capacity of skeletal muscles. As part of the 60-day AGBRESA bed rest (BR) study, we studied (1) how microgravity-induced disuse affected markers of systemic and muscle oxidative stress, (2) how these related to muscle function and (3) to what extent artificial gravity (AG) attenuated these changes. Since the myokine irisin may protect against muscle deterioration in disuse, we additionally assessed serum irisin levels.</p><p><strong>Methods: </strong>Sixteen men and eight women (33 ± 9 years) participated in the AGBRESA study. Participants were pseudorandomly assigned to a control group (BR only), or a continuous or intermittent centrifugation group (n = 8 in each group) to assess the efficacy of daily 30-min AG in attenuating the adverse effects of BR-induced disuse. Muscle function, muscle protein carbonyls, serum irisin and key modulators of oxidative stress and cell protection in muscle and blood were assessed before, on Day 6, and at the end of BR.</p><p><strong>Results: </strong>BR caused a reduction in peak torque during maximal voluntary isometric knee extension and knee flexion (p < 0.001) that was greater in women than in men (knee extension, w: -39.7 ± 3.5%, m: -25.1 ± 2.4%; knee flexion, w: -32.9 ± 4.5%, m: -10.2 ± 3.5%, p ≤ 0.002) and faster electrically evoked twitch muscle contractions of plantar flexor and knee extensor muscles (half relaxation time and % peak rate of relaxation, p ≤ 0.003). AG attenuated the BR-induced increase in evoked twitch contraction speed in the knee extensors (group × time interactions: half relaxation time, p = 0.009; % peak rate of relaxation, p = 0.030), and the loss of evoked twitch peak torque of plantar flexors (AG - 25%, Controls -48%, group × time interactions, p = 0.020). Neither BR nor AG affected the circulating levels of systemic oxidative stress and muscle carbonyl concentration and serum irisin levels. However, participants with the highest serum irisin and brain-derived neurotrophic factor levels showed lower levels of 8-iso-PGF2α, a marker of systemic oxidative stress (r = -0.486, p = 0.019; r = -0.512, p = 0.012, respectively) and circulating levels of the C-terminal agrin fragment, a biomarker of neuromuscular junction fragmentation.</p><p><strong>Conclusions: </strong>AG exposure attenuated some of the BR-induced changes in twitch contractile properties. Neither BR nor AG induced significant alterations in systemic oxidative stress, or muscle protein carbonylation, suggesting that the main contribution to the BR-induced loss of muscle strength during the AGBRESA study was not oxidative stress.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 2","pages":"e70250"},"PeriodicalIF":9.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13140337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508274","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":"KARIs, Ghrelin Receptor Agonists With Excellent Brain Permeability, Increase Food Intake and Attenuate the Muscle Loss in Mice.","authors":"Hee Ji Yoon,Wan Hui Han,Sang Bo Kim,Won Gyeong Lee,Seo Young Choi,Byung Jo Choi,Minyeong Pang,Min-Koo Choi,Jihoon Lee,Im-Sook Song,Min Hee Park,Hee Kyung Jin,Jae-Sung Bae","doi":"10.1002/jcsm.70277","DOIUrl":"https://doi.org/10.1002/jcsm.70277","url":null,"abstract":"BACKGROUNDGhrelin regulates appetite, gastrointestinal motility and growth hormone (GH) secretion through activation of the growth hormone secretagogue receptor (GHSR-1a) in hypothalamic neurons, with downstream effects on adipose tissue and skeletal muscle. Although ghrelin and synthetic GHSR-1a agonists have been investigated for the treatment of anorexia, sarcopenia and cancer cachexia, their clinical utility has been limited by unfavourable pharmacokinetics. We recently discovered a novel class of small-molecule compounds, termed KARIs, which act as potent GHSR-1a agonists with excellent brain permeability. Here, we evaluated their efficacy as GHSR-1a agonists in vitro and in vivo.METHODGHSR-1a agonistic effects of KARIs were assessed using calcium influx and competitive binding assays in human GHSR-1a-expressing cells, and molecular docking simulations were conducted. Pharmacokinetic properties of KARIs (1 mg/kg i.v, 10 mg/kg p.o) were compared with anamorelin (3 mg/kg i.v., 30 mg/kg p.o.). In vivo efficacy was evaluated in mouse models of postoperative ileus (POI; 10, 20 or 30 mg/kg), age-related sarcopenia (10 mg/kg/day for 4 weeks) and cancer cachexia (10 or 30 mg/kg/day from Days 9 to 24 after CT26 tumour induction).RESULTSKARIs directly interacted with key GHSR-1a residues (Phe279) and increased calcium influx (EC50: KARI 101 = 1.83 ± 1.05 μM; KARI 201 = 3.36 ± 1.09 μM). KARIs showed higher oral bioavailability (BA: KARI 101 = 63%; KARI 201 = 68%) and brain distribution (KARI 101 = 2.2; KARI 201 = 3.7) than anamorelin (BA = 45%, brain distribution = 0.1). KARIs significantly activated hypothalamic neurons (KARI 101 p = 0.029, KARI 201 p = 0.0152), resulting in increased food intake and improved gastric emptying and colonic transit in POI mice. In aged mice, KARIs markedly elevated plasma GH levels and restored gastrocnemius muscle mass (KARI 101 p = 0.0018, KARI 201 p = 0.0006) and improved rota-rod performance (p < 0.0001) by downregulating expression of atrophic genes and upregulating myogenic genes. In cancer cachexia mice, KARIs improved food intake and preserved skeletal muscle mass at lower doses (gastrocnemius, 10 mg/kg; p < 0.0001) than synthetic GHSR - 1a agonist (anamorelin, 30 mg/kg) and enhanced functional recovery (rota-rod test, 10 mg/kg; KARI 101 p = 0.045, KARI 201 p = 0.003) without affecting tumour growth.CONCLUSIONSKARIs are potent, brain-penetrant GHSR-1a agonists with favourable pharmacokinetics compared to anamorelin. They enhance appetite, preserve skeletal muscle mass and improve physical performance in models of aging and cancer cachexia, supporting their potential as next-generation therapies for anorexia and muscle wasting.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"21 1","pages":"e70277"},"PeriodicalIF":8.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147585692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}