Journal of Cachexia, Sarcopenia and Muscle最新文献

{"title":"Longitudinal Study of Frailty Phenotype in Relation to Chronic Kidney Disease Incidence.","authors":"Yong-Xiang Ruan,Da-Chuan Guo,Wen-Hao Liu,Jia-Man Ou,Qi Guo,Jing-Wei Gao,Yang-Wei Cai,Mao-Xiong Wu,Xiao-Tian Liang,Jie-Wen Cai,Pin-Ming Liu,Jing-Feng Wang,Hai-Feng Zhang,Yang-Xin Chen","doi":"10.1002/jcsm.70287","DOIUrl":"https://doi.org/10.1002/jcsm.70287","url":null,"abstract":"BACKGROUNDThe longitudinal relationship between frailty phenotype and CKD development, and the modifying role of genetic CKD risk in this association, remains unclear. Research on simple, noninvasive and quantifiable CKD prediction models incorporating frailty is limited.METHODSWe analysed 214 502 CKD-free participants from the UK Biobank cohort. Frailty was assessed using a modified phenotype with five components: weight loss, exhaustion, low grip strength, low physical activity and slow gait speed, to match UK Biobank data. Self-reported walking pace and weight change served as proxies where objective measures were unavailable. A polygenic risk score for CKD was calculated based on 258 single nucleotide polymorphisms. Cox proportional hazards models were used to assess the association between the frailty phenotype and new-onset CKD. The interaction between frailty and genetic risk on CKD outcomes was also examined. A noninvasive CKD prediction model, integrating frailty, age, gender, diabetes, hypertension, BMI and smoking status, was developed and validated internally using the UK Biobank and externally using CHARLS cohorts.RESULTSAmong the 214 502 CKD-free participants with a median age of 57 (49-62) years, 50.3% were female. A total of 109 290 individuals (51.0%) were classified as non-frail, 96 941 (45.2%) as pre-frail and 8271 (3.9%) as frail. Over the course of a median follow-up period of 12.9 years, we documented 8079 (3.8%) cases of CKD. Compared with non-frailty, the hazard ratio (HR) for new-onset CKD in prefrailty and frailty was 1.143 (95% CI, 1.090-1.199, p < 0.001) and 1.606 (95% CI, 1.474-1.749, p < 0.001) in the multivariate model, respectively. Each one-point increase in frailty score was associated with a higher risk of CKD (HR = 1.142; 95% CI, 1.116-1.170, p < 0.001) in the multivariable model. Participants with frailty and high genetic risk had the greatest risk of CKD (HR = 1.981; 95% CI, 1.733-2.266, p < 0.001) compared with those without frailty and low genetic risk. In the simple CKD prediction model incorporating frailty, it demonstrated an AUC of 0.734 at 5 years, 0.745 at 8 years and 0.749 at 10 years in internal testing. External validation also showed consistent discrimination and calibration with an AUC of 0.740.CONCLUSIONSPre-frail and frail phenotypes were associated with a higher risk of developing CKD, showing a dose-response relationship. A noninvasive prediction model incorporating frailty and clinical parameters exhibited stable discriminative performance over a decade in both European and Asian cohorts.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"6 1","pages":"e70287"},"PeriodicalIF":8.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147731664","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":"Adipose Tissue and Lipid Dysregulation Contributions to Cachexia, Sarcopenia and Muscle Function.","authors":"Joseph D Abraham,Stephan von Haehling,Stefan D Anker","doi":"10.1002/jcsm.70299","DOIUrl":"https://doi.org/10.1002/jcsm.70299","url":null,"abstract":"","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"13 1","pages":"e70299"},"PeriodicalIF":8.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147753123","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":"PACS2 Alleviates Sepsis-Induced Myopathy by Activating ERK-MAPK Signalling Pathway to Suppress ER-Phagy.","authors":"Xuexin Li, Zu-An Shi, Fei He, Guo Mu, Feixiang Wang, Bowen Sun, Xiaobin Wang, Li Liu","doi":"10.1002/jcsm.70308","DOIUrl":"10.1002/jcsm.70308","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Sepsis-induced myopathy (SIM) is a common and life-threatening complication, but its underlying mechanisms remain poorly understood. PACS2, a key resident protein at mitochondria-associated endoplasmic reticulum membranes (MAMs), regulates ER homeostasis under various pathological conditions. However, whether sepsis disrupts PACS2-dependent MAM integrity, thereby triggering ER dysfunction and muscle wasting, remains unexplored.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We established a sepsis mouse model via cecal ligation and puncture (CLP) and assessed muscle function using compound muscle action potential (CMAP) recording and grip strength measurements. Muscle atrophy was evaluated by H&E staining and Western blotting. PACS2 expression was determined by Western blotting, immunohistochemistry and qRT-PCR. MAM integrity was assessed by immunofluorescence co-localization of IP3R and VDAC1, and ER-phagy (reticulophagy) activation was evaluated by transmission electron microscopy, Western blotting and fluorescence microscopy. To investigate the functional role of PACS2, adeno-associated virus (AAV)-mediated PACS2 overexpression was performed in mouse tibialis anterior muscle and gastrocnemius muscles, followed by RNA-sequencing analysis. The MAPK pathway proteins p-ERK, p-P38 and p-JNK levels were assessed by Western blotting, and the involvement of ERK-MAPK signalling was tested pharmacologically via intraperitoneal injection of the ERK inhibitor SCH772984.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Septic mice developed progressive skeletal muscle atrophy (p &lt; 0.001) and dysfunction (p &lt; 0.01), accompanied by 56% reduction in PACS2 expression at 96 h post-CLP (p &lt; 0.01), 25% decrease in MAM integrity (p &lt; 0.05) and subsequent activation of FAM134B-mediated ER-phagy (p &lt; 0.01). AAV-mediated PACS2 overexpression significantly alleviated muscle atrophy by restoring MAM integrity by 28% (p &lt; 0.01), reducing FAM134B expression by 43% (p &lt; 0.01) and attenuating ER-phagy (p &lt; 0.01). Co-immunoprecipitation revealed no detectable direct protein-protein interaction between PACS2 and FAM134B. Transcriptome sequencing and Western blotting analysis demonstrated that PACS2 overexpression specifically activated the ERK-MAPK signalling pathway (55% increase in p-ERK, p &lt; 0.01) without affecting p-P38 or p-JNK levels (p&gt;0.05), which suppressed FAM134B-mediated ER-phagy (p &lt; 0.05) and ameliorated muscle atrophy (p &lt; 0.05) by inhibiting nuclear translocation of TFEB (p &lt; 0.01). Pharmacological ERK inhibition with SCH772984 abolished the protective effects of PACS2 by promoting TFEB nuclear translocation (p &lt; 0.001) and TFEB-mediated FAM134B expression (p &lt; 0.001).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our findings demonstrate that SIM is closely associated with disrupted MAM integrity. PACS2 plays a critical role in maintaining MAM structural integrity and regulating FAM134B-mediated ER-phagy through the ERK-MAPK-TFEB signalling axis, thereby providing nov","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 3","pages":"e70308"},"PeriodicalIF":9.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13156248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855733","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 Cancer Cachexia: A Mechanistic Evaluation of Anti-GDF-15 Antibody-Based Combination Therapies.","authors":"Danna M Breen, Stephanie Joaquim, Brianna LaCarubba Paulhus, Donald Bennett, Barbara Bernardo, Susie Collins, Ryan M Esquejo, Ja Young Kim-Muller, Laura Lin, Matthew Peloquin, Zhidan Wu, Shuxi Qiao, John C Stansfield, Bei B Zhang, Michelle I Rossulek","doi":"10.1002/jcsm.70312","DOIUrl":"10.1002/jcsm.70312","url":null,"abstract":"<p><strong>Background: </strong>In a recent Phase 2 trial in patients with cancer cachexia, the anti-GDF-15 antibody ponsegromab resulted in increased body weight, appetite, muscle mass and physical activity. This study provides compelling evidence that targeting the GDF-15 pathway may offer a viable therapeutic strategy, while raising new mechanistic questions about how GDF-15 neutralization could be optimally integrated with other interventions to reverse the multifactorial cachexia syndrome. This series of experiments aimed to evaluate the effects of anti-GDF-15 antibody treatment in combination with muscle anabolic (anti-myostatin antibody) or appetite stimulant (ghrelin receptor agonist anamorelin) modulators using mouse cancer cachexia models.</p><p><strong>Methods: </strong>The effects of anti-GDF-15 monoclonal antibody alone and in combination with an anti-myostatin antibody or anamorelin fumarate were examined in GDF-15-dependent (HT-1080 and RENCA) and partially dependent (TOV21G) mouse tumour models. Comprehensive assessments included food intake, body weight, body composition (including fat, lean and muscle mass), muscle function and treadmill running. Circulating myostatin was measured in patient samples from an advanced NSCLC clinical study.</p><p><strong>Results: </strong>Anti-myostatin antibody treatment had limited efficacy in improving cachexia in mouse tumour models with high circulating GDF-15 (HT-1080 and RENCA), but improved cachexia (when combined with anti-GDF-15 antibody) in a tumour model with low circulating GDF-15 levels (TOV21G). In the TOV21G model, combining anti-myostatin and anti-GDF-15 antibodies led to even greater increases in body weight and hindlimb muscle mass compared with anti-GDF-15 antibody alone (p < 0.001 for muscle mass); however, the increase in muscle strength and treadmill running did not reach statistical significance over monotherapy. When anamorelin was combined with anti-GDF-15 antibody, body weight was elevated compared with the HT-1080 tumour-bearing vehicle group (p < 0.0001) but did not reach statistical significance over anti-GDF-15 antibody alone. Similar observations of the combination treatment were found for food intake, fat mass and gastrocnemius (p < 0.05). Circulating myostatin was negatively correlated with weight loss in patients with cancer (p < 0.01).</p><p><strong>Conclusion: </strong>These data provide proof-of-principle that mechanistically distinct approaches targeting muscle anabolism and appetite may act additively with GDF-15 neutralization, particularly in cancer cachexia settings with lower GDF-15 dependence.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov identifier: NCT01360554.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 3","pages":"e70312"},"PeriodicalIF":9.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13170096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147925039","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":"Novel Long-Acting Ghrelin Analogue PEP-064 Restores Energy Balance in C26 and Lewis Lung Carcinoma-Induced cachexia in Mice.","authors":"J E Hunt, C Lund, B Chen, A R Diaz, O Dmytriyeva, J Marcotorchino, K Löbner, K Mörl, N R Andersen, Z K J Ogueboule, E Frank, J Stöhr, D Meseguer, V Panajotova, J Roux, C Clemmensen, L Sylow, M Schneeberger, A G Beck-Sickinger, S L Pedersen, K Fosgerau","doi":"10.1002/jcsm.70318","DOIUrl":"10.1002/jcsm.70318","url":null,"abstract":"<p><strong>Background: </strong>Cancer cachexia is a debilitating syndrome marked by involuntary weight loss resulting from reduced food intake and intricate metabolic reprogramming. Despite its high prevalence, cancer cachexia remains undertreated, with a lack of effective and approved pharmacotherapies. Ghrelin has emerged as a therapeutic target for cancer cachexia due to its beneficial effects on energy balance. However, the clinical application of ghrelin is hampered by its short half-life. In this study, we introduce PEP-064, a novel stabilized, long-acting and efficacious ghrelin analogue and assess its effects on C26-induced and Lewis lung carcinoma (LLC)-induced cachexia in mice.</p><p><strong>Methods: </strong>The in vivo efficacy of PEP-064 was evaluated in healthy CD-1 mice after repeated dosing for 7 days and in the C26 and LLC cancer cachexia mouse models. Additionally, the pharmacokinetic profile and whole brain neuronal activity mapping were conducted in healthy mice following a single subcutaneous injection of PEP-064. Growth hormone secretion was measured in healthy rats following a single administration of PEP-064.</p><p><strong>Results: </strong>In healthy mice, PEP-064 exhibited a dose-dependent (100, 300 and 1000 nmol/kg) increase in both delta body weight (BW) and total food intake (FI) compared to the vehicle (BW: 2.7 g vs. 3.5, 4.8 and 5.3 g; FI: 50 g vs. 57 g, 60 and 70 g). In the C26 model, PEP-064 protected against loss of tumour-free (TF) BW (-1.2 g vs. 1.7 g, p < 0.0001), increased food intake (33 g vs. 41 g, p < 0.01), prevented losses in fat (-1.1 g vs. 0.9 g, p < 0.0001) and lean mass (-0.07 g vs. 0.4 g, p < 0.05) without affecting tumour growth. In the LLC model, PEP-064 induced hyperphagia (52.2 g vs. 61.6 g, p < 0.0001) and protected against TF-BW loss (-1.4 g vs. - 0.01 g, p < 0.05) and fat mass loss (-0.9 g vs. 0.8 g, p < 0.0001). In mice, PEP-064 had a T_1/2 of 6.6 h and a T_max at 4 h. PEP-064 increased neuronal activity (c-Fos) in the hypothalamic and amygdala regions, with the tuberal nucleus of the hypothalamus showing the highest increase compared to the vehicle (p < 0.05). Lastly, circulating growth hormone was increased 20 min after subcutaneous PEP-064 dosing, peaking at 30 min at 93 ng/mL and returning to approximately baseline by 120 min.</p><p><strong>Conclusions: </strong>The novel, long-acting and efficacious ghrelin analogue, PEP-064, restored energy balance in cancer cachexia by increasing food intake and body weight, preserving lean mass and increasing adiposity, without affecting tumour growth. Considering the unmet medical need for safe and effective treatments for cachexia, our study demonstrates the feasibility of a long-acting ghrelin approach for treating cancer cachexia.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 3","pages":"e70318"},"PeriodicalIF":9.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13240157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148136061","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":"Systemic Drivers and Molecular Mechanisms of Sarcopenia in Aetiology-Specific End-Stage Liver Disease.","authors":"Thomas Nicholson,Sophie L Allen,Jonathan I Quinlan,Amritpal Dhaliwal,Michael Macleod,Joshua Price,Jon Hazeldine,Michael S Sagmeister,Caitlin Ditchfield,Kirsty C McGee,Felicity R Williams,Ahmed M Elsharkawy,Matthew J Armstrong,Carolyn A Greig,Janet M Lord,Leigh Breen,Simon W Jones","doi":"10.1002/jcsm.70294","DOIUrl":"https://doi.org/10.1002/jcsm.70294","url":null,"abstract":"BACKGROUNDPatients with end-stage liver disease (ESLD) often present with sarcopenia, defined as loss of skeletal muscle mass and quality, which is associated with reduced quality of life and increased mortality. However, the molecular mechanisms driving sarcopenia in ESLD are not fully understood and there are currently no therapeutic interventions. This study aimed to identify potential circulating factors contributing to sarcopenia progression in ESLD by assessing their role in driving transcriptomic alterations in skeletal muscle.METHODSQuadriceps muscle tissue, plasma and serum were obtained from ESLD patients (n = 24) and age/sex-matched healthy controls (HC; n = 18) (Clinical Trial ID: NCT04734496, Ethical Approval 18/WM/0167). Total RNA from snap-frozen vastus lateralis muscle biopsies underwent RNA sequencing (Illumina). Serum concentrations of 60 cytokines were profiled by Luminex and ELISA, with comparisons made both between ESLD and HC, and across ESLD aetiologies (alcohol-related, NAFLD, viral hepatitis, other). In vitro, primary human myotubes (from non-ESLD aged donors, NRES #16/SS/0172) were treated with 10% ESLD or HC plasma (24 h, n = 6 per group) followed by RNA sequencing (BGI Genomics). Differentially expressed genes (p < 0.05, fold-change > 1.5) were identified via Qlucore and DESeq2, and pathway analysis performed using Ingenuity (Qiagen). The impact of physiological concentrations of candidate cytokines (IL-1α, GDF-15 and HGF) on myotube thickness, differentiation and mitochondrial function was assessed by immunofluorescence microscopy, RT-qPCR and metabolic flux assays.RESULTSIn ESLD muscle, 387 and 225 genes were significantly up- and downregulated compared to HC, respectively, with cellular senescence identified as a top dysregulated function. Upstream regulator analysis predicted activation of hepatocyte growth factor (HGF) and interleukin-1 signalling. Subgroup analysis revealed distinct transcriptomic profiles based on disease aetiology. Serum profiling identified 15 cytokines significantly elevated (p < 0.05) and five reduced (p < 0.05) in ESLD, including increased HGF and reduced interleukin-1 receptor antagonist. Stratified analysis also revealed aetiology specific cytokine profiles, with only GDF-15 significantly (p < 0.0001) elevated in all groupsTwenty-four-hour ESLD plasma treatment induced 423 differentially expressed genes in human myotubes, which were again associated with significant activation of senescence pathways, with IL-1 identified as a key upstream driver. In vitro, IL-1α, GDF-15, and HGF significantly reduced myotube thickness, nuclear fusion index and perturbed metabolism (increased glycolysis, impaired oxidative phosphorylation).CONCLUSIONSCollectively, these findings suggest that sarcopenia in ESLD is driven by aetiology-specific mechanisms, highlighting the potential for targeted therapies to improve muscle mass and function.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"250 1","pages":"e70294"},"PeriodicalIF":8.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147751343","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-Adipose Aging Dynamics and Inflammaging Patterns Across Ethnically Diverse Populations: Exploring Potential Roles of Lipolysis.","authors":"Fei-Yuan Hsiao, Jamie Chi-Yun Wu, I-Tzu Chen, Yu-Ting Lin, Lin-Chieh Meng, Liang-Kung Chen","doi":"10.1002/jcsm.70316","DOIUrl":"10.1002/jcsm.70316","url":null,"abstract":"<p><strong>Background: </strong>Muscle-adipose aging reflects interactions between body composition changes and chronic inflammatory processes, but age-related patterns in these measures across ethnically diverse populations remain incompletely described. Understanding population-specific patterns is crucial for developing tailored prevention and intervention strategies. We aimed to characterize age- and sex-specific patterns of muscle-related measures, adiposity, inflammatory markers and lipolysis-related biomarkers within large cohorts from the United Kingdom, the United States and Taiwan, and to examine how these observed patterns varied across cohorts.</p><p><strong>Methods: </strong>In this cross-cohort comparative study, we analysed data from UK Biobank (n = 35 436), US NHANES (n = 9157) and Taiwan NAHSIT (n = 4959). We examined age-related trajectories of muscle mass, adiposity, muscle-to-fat ratio, and biomarkers of inflammation and lipolysis. Inflammaging was assessed using C-reactive protein (CRP) and insulin-like growth factor-1 (IGF-1) decline profiles. Lipolytic activity was evaluated using circulating ketone bodies (β-hydroxybutyrate, acetoacetate, acetone) in the UK cohort. Age-specific patterns were described across populations, with particular attention to masking effects of body mass index (BMI) adjustment and late-life metabolic selection.</p><p><strong>Results: </strong>Muscle-adipose aging patterns differed substantially across populations. Taiwanese men, despite having lower absolute appendicular lean mass, showed steeper cross-sectional differences while maintaining higher muscle-to-fat ratios than other cohorts. Inflammaging patterns were consistent across cohorts, with CRP increasing by up to 90% and IGF-1 declining by 20.3%-23.8% from ages 45 to 79, consistent with a potential link between chronic inflammation and anabolic resistance. BMI-adjusted muscle mass showed greater deterioration with age compared with height-adjusted measures, suggesting conventional assessments may mask sarcopenic progression. Adiposity trajectories peaked earlier in Western populations (55-59 years) than in Taiwanese adults (60-64 years), followed by late-life declines of 10.3%-23.5%, indicative of differential lipolytic activation. In the UK cohort, ketone body concentrations increased with age, suggesting higher fat oxidation in older age groups. Among adults aged 80 years or older, reversals in the muscle-to-fat ratio suggested metabolic selection effects across all populations.</p><p><strong>Conclusions: </strong>Muscle-adipose aging reflects population-specific patterns of inflammatory and lipolytic reprogramming, with metabolic efficiency-rather than absolute tissue quantity-emerging as a key determinant of healthy aging. Establishing ethnically tailored reference standards may improve the precision of aging-related risk stratification and interventions across diverse populations.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 3","pages":"e70316"},"PeriodicalIF":9.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13581085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154303","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":"Heme Metabolism-Derived Carbon Monoxide Regulates Skeletal Muscle Function.","authors":"Rodrigo W Alves de Souza, Hyo In Kim, Paula Ketilly Nascimento Alves, Ailma Oliveira da Paixão, Ashlee Rasmussen, Sidharth Shankar, James Harbison, Vanessa Azevedo Voltarelli, Leo E Otterbein","doi":"10.1002/jcsm.70309","DOIUrl":"10.1002/jcsm.70309","url":null,"abstract":"<p><strong>Background: </strong>Heme oxygenases, HO-1 (Hmox1) and HO-2 (Hmox2), regulate skeletal muscle homeostasis by degrading heme and generating carbon monoxide (CO), a bioactive signalling molecule. Although HO-1 is known to influence muscle fibre composition and mitochondrial function, the role of HO-2 in activity-dependent neuromuscular plasticity remains poorly understood. This study aimed to define the distinct contributions of each isoform and test whether CO could restore muscle function in HO-deficient states.</p><p><strong>Methods: </strong>We generated Hmox1/2 double-knockout mice (Hmox1/2^-/-) and compared their skeletal muscle phenotype with that of single HO-1 or HO-2 knockouts and wild-type (WT) controls under sedentary and exercised conditions. We evaluated endurance capacity using treadmill running (n = 8-12 per group), assessed fibre-type distribution and neuromuscular junction (NMJ) morphology via immunohistochemistry and measured mitochondrial function using high-resolution respirometry. Primary neuronal cultures were analysed using multielectrode array recordings to assess firing dynamics. Inhaled CO was administered to test its capacity to rescue muscle phenotype and performance.</p><p><strong>Results: </strong>HO-1 deficiency led to a significant reduction in oxidative fibres (Type I and IIa), decreased mitochondrial respiratory capacity (reduced by ~30%, p < 0.01) and diminished treadmill endurance (-40% running time vs. WT, p < 0.001). Hmox2 deficiency was associated with NMJ remodelling, increased acetylcholine receptor expression, reduced Sox2 transcription and heightened burst firing. The double deletion of HO-1/HO-2 produced an additive phenotype characterized by severe mitochondrial dysfunction, increased glycolytic fibre content and NMJ remodelling. We identify CO, a by-product of HO-1, as a crucial modulator of skeletal muscle adaptation, capable of compensating for HO deficiency. Treatment with CO in Hmox1/2^-/- mice restored fibre-type distribution toward oxidative fibres (increased by 25%, p < 0.01), improved mitochondrial respiratory parameters and doubled endurance performance (p < 0.001). CO also normalized mitochondrial protein expression and modulated key metabolic pathways, including nucleotide metabolism, the TCA cycle and redox balance.</p><p><strong>Conclusions: </strong>HO-1 and HO-2 have distinct roles in regulating muscle phenotype and metabolic adaptation. HO-1 modulates mitochondrial content and muscle plasticity, whereas Hmox2 regulates, in part, activity-dependent neuromuscular plasticity and responsiveness to exercise. Exogenous CO effectively restores mitochondrial and functional deficits in HO-deficient muscle, mimicking endurance exercise adaptations. These findings support the therapeutic potential of CO in conditions of muscle disuse, aging or disease where exercise is limited or not feasible.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 3","pages":"e70309"},"PeriodicalIF":9.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13176642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939714","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":"Elevated Circulating Ceramides 18:0 and 24:1 as a Risk Factor for Sarcopenia: In Vitro, Animal, and Clinical Evidence.","authors":"So Jeong Park, Ji Yeon Baek, Shibo Wei, Jin Young Lee, Yuna Lee, Sang-Hoon Lee, Il-Young Jang, Hyuk Sakong, Hyun Ju Yoo, Hee-Won Jung, Eunju Lee, Su Jung Kim, Yunju Jo, Kyunggon Kim, Dongryeol Ryu, Beom-Jun Kim","doi":"10.1002/jcsm.70310","DOIUrl":"10.1002/jcsm.70310","url":null,"abstract":"<p><strong>Background: </strong>Ceramides have garnered considerable attention as pro-aging bioactive lipids implicated in both metabolic dysfunction and musculoskeletal decline. Among these, C18:0 and C24:1 ceramides may play a role in the pathophysiology of sarcopenia, a key manifestation of age-related deterioration. However, their specific contributions to muscle degeneration remain poorly defined.</p><p><strong>Methods: </strong>C2C12 myoblasts and primary myoblasts were treated with C18:0 or C24:1 ceramides during differentiation to assess myotube formation, migration and intracellular reactive oxygen species (ROS) levels. Three-month-old C57BL/6 mice received daily intraperitoneal injections of C18:0 or C24:1 ceramides for 4 weeks to evaluate muscle morphology and function. In a human cohort of 165 community-dwelling older adults (≥ 65 years), serum ceramide levels were measured via LC-MS/MS and analysed in relation to sarcopenia parameters.</p><p><strong>Results: </strong>Both C18:0 and C24:1 ceramides significantly impaired myogenic differentiation in vitro, as evidenced by reduced myotube number, total myotube area, average area per myotube, nuclei count per myotube and fusion index, through ROS-mediated mechanisms (with up to an 8.6-fold increase in ROS production). Consistently, C18:0 and C24:1 ceramides markedly downregulated key myogenic markers and inhibited ITGB1-FAK-AKT signalling while promoting nuclear activation of FoxO-associated catabolic pathways. These deleterious effects were attenuated by treatment with the antioxidant N-acetylcysteine. In mice, systemic administration of either ceramide resulted in reduced muscle fibre cross-sectional area in the tibialis anterior (by 20.5% and 20.9% for C18:0 and C24:1, respectively) and soleus muscles (by 18.1% and 16.1%), accompanied by decreased grip strength, shorter grid hanging times and reduced latency to fall in the rotarod test. Clinically, in a cohort of 165 older adults (80.6% female; mean age 75.2 ± 5.2 years in controls and 79.7 ± 4.8 years in the sarcopenia group), serum levels of C18:0 and C24:1 ceramides were 27% and 14% higher, respectively, in individuals with sarcopenia compared to controls (p = 0.001 and 0.018). Furthermore, each standard deviation increase in serum C18:0 and C24:1 ceramide levels was associated with a 2.0- and 1.6-fold increased risk of sarcopenia, respectively (p = 0.003 and 0.040).</p><p><strong>Conclusions: </strong>Our findings reveal that circulating C18:0 and C24:1 ceramides are significantly associated with sarcopenia in older adults, while experimental models demonstrate they promote muscle atrophy through oxidative stress-induced impairment of myogenesis and muscle function. These ceramides may serve as minimally invasive biomarkers and potential therapeutic targets for age-related muscle decline. Interventions aimed at modulating ceramide metabolism could offer new avenues for sarcopenia prevention and treatment in aging populations.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 3","pages":"e70310"},"PeriodicalIF":9.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809017","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":"Exercise Modalities to Preserve Muscle Mass and Bone Health After Metabolic Bariatric Surgery.","authors":"Ariela Goldenshluger, Lior Friedman, Tamir Turjeman, Roi Yavetz, Asnat Raziel, David Goitein, Irit Markus, Hassan Kais, Ron Sternfeld, Estherina Trachtenberg, Gal Dubnov-Raz, Ilanit Mhaler, Ilan Youngster, David Peled, Roee Amedi, Andrei Keidar, Edward H Livingston, Nasser Sakran, Dror Dicker, Yftach Gepner","doi":"10.1002/jcsm.70289","DOIUrl":"10.1002/jcsm.70289","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Metabolic bariatric surgery (MBS) effectively reduces fat mass (FM), but how to best preserve muscle and bone mass after MBS is unknown.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;This study aimed to evaluate the effect of aerobic, resistance and combined exercise regimens on body composition, bone mineral density (BMD) and physical function in adults following MBS.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Patients were randomized into aerobic, resistance, combined and control groups after undergoing MBS. Exercise groups completed a 26-week supervised program (three sessions per week) with progressively increasing intensity. The primary outcome was the change in fat-free mass (FFM) measured by dual-energy X-ray absorptiometry (DXA). Secondary outcomes included FM, hip, femoral neck and lumbar spine BMD, serum collagen type I C-telopeptide (CTX) and physical function (e.g., 6-min walk test and handgrip strength). Between-group differences were assessed using Bayesian analysis of covariance (ANCOVA) adjusted for age, sex, surgery type and baseline body mass index, with credible differences inferred when the 95% credible interval of the standardized effect size excluded zero. Associations between outcomes were assessed using Pearson correlation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Of 443 eligible candidates, 58 participants (aged 18-65 years, 70% women, BMI 41.7 ± 4.4 kg/m&lt;sup&gt;2&lt;/sup&gt;) were randomized to aerobic (n = 15), resistance (n = 13), combined (n = 14) or control (n = 16) groups, and 91.3% were included in the analysis. The combined exercise group preserved more FFM (-5.1 ± 2.8 kg vs. -7.7 ± 2.8 kg; ES 0.60 [0.41, 0.77]) and reduced more FM (-11.9% ± 5.7% vs. -10.1% ± 4.9%, ES -0.64 [-0.85, -0.40]) than control. Aerobic training most attenuated total hip BMD loss (-0.037 ± 0.033 g/cm&lt;sup&gt;2&lt;/sup&gt;, -3.3%) compared with control (-0.058 ± 0.021 g/cm&lt;sup&gt;2&lt;/sup&gt;, -5.4%; ES 0.69 [0.42, 0.92]) and modestly attenuated femoral neck BMD loss (ES 0.30 [0.11, 0.48]), with no differences at the lumbar spine. The relative increase in serum CTX was smaller in the aerobic (157.8%; ES -0.44 [-0.65, -0.18]) and combined groups (161.8%; ES -0.42 [-0.63, -0.17]) compared with control (196.4%). Physical function improved modestly, with aerobic training showing a greater improvement in walking distance than control (80.0 ± 56.4 m vs. 65.6 ± 39.2 m; ES 0.33 [0.08, 0.54]). Walking distance improvement correlated with weight loss. Handgrip strength was best preserved in the resistance group (ES 0.77 [0.47, 1.04]) and was positively correlated with protein intake.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Following MBS, combined aerobic and resistance training improved body composition by preserving FFM and reducing FM, while aerobic training most attenuated bone loss. Exercise was associated with modest improvements in physical function, supporting individualized exercise strategies to promote metabolic, musculoskeletal and functional health after MBS. Trial Reg","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 3","pages":"e70289"},"PeriodicalIF":9.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13129681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147758270","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}