Journal of Cachexia, Sarcopenia and Muscle最新文献

{"title":"Early Identification and Prognostic Stratification of Cancer Cachexia Using Explainable Machine Learning: A Multicentre Cohort Study","authors":"Wei Huang, Kan Pan, Mingjian Zhao, Tingting Zhao, Nuo Xu, Hanping Shi","doi":"10.1002/jcsm.70370","DOIUrl":"https://doi.org/10.1002/jcsm.70370","url":null,"abstract":"Background Cancer cachexia is a heterogeneous syndrome that remains frequently underrecognized in routine oncology care, especially before overt wasting develops. We aimed to develop and externally validate an explainable two‐stage machine learning framework for early cachexia identification and prognostic stratification using routinely available clinical data. Methods In this multicentre real‐world study based on the INSCOC registry, 10 796 hospitalized adults with cancer were analysed, including 3995 patients with cachexia and 6801 without cachexia. First‐stage machine learning models were trained separately in high‐ and low‐prevalence settings to identify cachexia. Second‐stage survival models were developed in 1711 cachexia patients with follow‐up data from a 5172‐patient follow‐up cohort. A total of 586 deaths were observed in the cachexia follow‐up cohort. External validation used an independent Fujian cohort of 886 patients. Results Cachexia prevalence was 37.0% (3995/10 796). Compared with non‐cachexia patients, cachexia patients had lower median BMI (21.0 vs. 23.4 kg/m2), albumin (37.9 vs. 39.7 g/L), triceps skinfold thickness (13.0 vs. 16.0 mm), calf circumference (33.0 vs. 35.0 cm) and higher CRP (5.9 vs. 3.9 mg/L); all <jats:italic>p</jats:italic> &lt; 0.001. For cachexia identification, XGBoost achieved the best discrimination, with an AUC of 0.867 (95% CI: 0.857–0.878), sensitivity 0.706 and specificity 0.846 in the high‐prevalence group, and an AUC of 0.870 (95% CI: 0.861–0.880), sensitivity 0.817 and specificity 0.756 in the low‐prevalence group. In external validation, the AUCs were 0.744 in the high‐prevalence subgroup and 0.694 in the low‐prevalence subgroup. Among cachexia patients with follow‐up, the 1‐year mortality rate was 20.8% (95% CI: 19.0%–22.9%). For prognostic stratification, the random survival forest model showed the most favourable overall performance, with a C‐index of 0.680 and time‐dependent AUCs of 0.800, 0.777, 0.741 and 0.716 at 3, 6, 9 and 12 months, respectively. Advanced TNM stage and higher CRP were associated with worse survival, whereas higher albumin, prealbumin and HDL were associated with better survival. Conclusions This explainable two‐stage framework enables accurate cachexia identification across different prevalence settings and clinically meaningful prognostic stratification in patients with established cachexia. Using routine variables and independent external validation, it provides a practical basis for earlier recognition, risk‐adapted supportive care and precision management in oncology practice.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148768566","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":"Cachexia vs. Obesity: A Persisting Imbalance Between Clinical Need and Research Effort","authors":"Carolyn Blair, Alexander P. Maxwell, Adrian Slee, Clare McKeaveney, Marion Carson, Faizan Awan, Malcolm Brown, Marissa Burgermaster, Andrew Davenport, Damian Fogarty, Denis Fouque, Oonagh Gooding, Kamyar Kalantar‐Zadeh, Karen Magee, Robert Mullan, Helen Noble, Sam Porter, David S. Seres, Joanne Shields, Ian Swaine, Miles Witham, Joanne Reid","doi":"10.1002/jcsm.70372","DOIUrl":"https://doi.org/10.1002/jcsm.70372","url":null,"abstract":"","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"67 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148768511","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":"Blood Biomarkers of Alzheimer's Disease and Gait Speed Trajectories in Community‐Dwelling Older Adults: A Cohort Study","authors":"Javier Leal‐Martín, Giulia Grande, Caterina Gregorio, Amaia Calderón‐Larrañaga, Alice Margherita Ornago, Laura Fratiglioni, Martina Valletta, Claudia Fredolini, Anna‐Karin Welmer, Bengt Winblad, Davide Liborio Vetrano","doi":"10.1002/jcsm.70365","DOIUrl":"https://doi.org/10.1002/jcsm.70365","url":null,"abstract":"Background Gait speed (GS) has been suggested as a predictor of incident dementia in old age. However, the mechanisms underlying this body–mind connection remain unclear, and it is still unknown whether trajectories of GS decline differ according to levels of blood biomarkers related to Alzheimer's disease ( <jats:sc>AD</jats:sc> ). This study aims to investigate the association between levels of seven blood biomarkers related to AD and long‐term GS changes in dementia‐free older adults living in the community. Methods The present study included 1665 community‐dwelling adults ≥ 60 years, followed for 15 years, drawn from the Swedish National study on Aging and Care in Kungsholmen (SNAC‐K). GS (m·s <jats:sup>−1</jats:sup> ) was assessed at baseline and at five subsequent follow‐up time points. Blood biomarkers, including serum amyloid‐ <jats:italic>β</jats:italic> 42 to amyloid‐ <jats:italic>β</jats:italic> 40 ratio (A <jats:italic>β</jats:italic> 42/40), phosphorylated Tau181 ( <jats:italic>p</jats:italic> ‐Tau181) and Tau217 ( <jats:italic>p</jats:italic> ‐Tau217), total Tau ( <jats:italic>t</jats:italic> ‐Tau), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), were collected from peripheral venous blood samples at baseline. Linear mixed‐effects models were implemented to investigate the association between blood biomarkers and GS changes over time. Results After adjusting for potential confounders, participants in the highest quartile of <jats:italic>p</jats:italic> ‐Tau181 (Model I; 4th quartile <jats:italic>β</jats:italic> : −0.008, 95% CI: −0.013; −0.003), <jats:italic>p</jats:italic> ‐Tau217 (Model I; 4th quartile <jats:italic>β</jats:italic> : −0.010, 95% CI: −0.015; −0.005), NfL (Model I; 4th quartile <jats:italic>β</jats:italic> : −0.013, 95% CI: −0.019; −0.006) and GFAP (Model I; 4th quartile <jats:italic>β</jats:italic> : −0.007, 95% CI: −0.013; −0.002) exhibited a steeper decline in GS over time, as compared with those in the lowest quartile. Notably, participants in these highest quartiles developed mobility limitations (GS &lt; 0.8 m·s <jats:sup>−1</jats:sup> ), on average, 2.3 to 6.0 years earlier. Of note, only the association between NfL and GS changes over time persisted after further adjusting for time‐varying global cognition. Conclusions Higher blood biomarker levels of AD are associated with accelerated trajectories of GS decline and earlier onset of mobility limitations. Consequently, a faster decline in GS may reflect underlying neurodegeneration and indicate changes in brain health.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"70 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148768800","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":"Intermuscular Adipose Tissue as a Multimodality Quantitative Imaging Biomarker: Evidence Across Metabolic, Cardiovascular and Oncologic Diseases","authors":"Feier Ding, Atsushi Nakamoto, Xiaohan Zheng, Toru Honda, Gongzheng Wang, Yuwei Liu, Hideyuki Fukui, Takashi Ota, Masahiro Yanagawa, Noriyuki Tomiyama","doi":"10.1002/jcsm.70366","DOIUrl":"https://doi.org/10.1002/jcsm.70366","url":null,"abstract":"Intermuscular adipose tissue (IMAT) refers to adipose tissue located between muscle groups or beneath the muscle fascia, and its accumulation is closely linked to impaired muscle quality, reduced contractile function, and adverse metabolic profiles, establishing it as a core component of myosteatosis. Unlike subcutaneous and visceral adipose tissue, which reside outside the muscle architecture, IMAT expands within the muscle environment, where local metabolic and mechanical interactions may affect muscle integrity and performance. Elevated IMAT has been associated with diminished strength, impaired mobility, frailty, insulin resistance, and adverse cardiometabolic profiles, underscoring its clinical relevance beyond a passive fat depot. However, IMAT evidence remains dispersed across imaging techniques, anatomical regions, and disease‐specific literatures, limiting a unified understanding of its clinical utility. This review synthesizes current evidence on IMAT biology, imaging‐based quantification, disease‐specific distribution and clinical implications, with emphasis on its value as a risk‐stratification biomarker. Recent advances in medical imaging, including computed tomography (CT), magnetic resonance imaging (MRI), ultrasound and positron emission tomography (PET), have enabled noninvasive and reproducible IMAT quantification. These modalities provide complementary measures of muscle fat infiltration, including CT‐derived area, volume and attenuation; MRI‐based segmentation and proton density fat fraction; ultrasound echo intensity; and PET‐derived metabolic activity. Deep learning–based segmentation methods have improved large‐scale IMAT quantification and reproducibility across anatomical regions. Mechanistically, IMAT is associated with chronic low‐grade inflammation and impaired glucose homeostasis, promoting progressive fat infiltration and muscle degeneration. Human studies indicate that IMAT exhibits an inflammatory secretory profile linked to insulin resistance and metabolic dysfunction. Quantitative imaging shows anatomically heterogeneous IMAT distribution, with frequent involvement of the lower extremities, paraspinal muscles and trunk. Across disease settings, IMAT appears to provide complementary information beyond muscle mass alone by capturing muscle quality and systemic vulnerability. Evidence is strongest in oncology, where elevated IMAT or IMAT‐based ratios have repeatedly been associated with poorer survival, recurrence, treatment toxicity, and reduced treatment tolerance. In metabolic and musculoskeletal disorders, IMAT is consistently related to insulin resistance, reduced strength, impaired mobility, and frailty, whereas cardiovascular evidence suggests prognostic relevance but remains less standardized and more heterogeneous. Clinically, IMAT imaging may help identify patients whose preserved muscle size or body mass index masks poor muscle quality, thereby refining prognostic assessment, perioperative risk evaluation","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"21 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148754448","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 Reserves and Survival: Protective in Prefrail but Ineffective in Frail Oldest‐Old","authors":"Jin Yan, Ming Zhao, Cheng Qin, Zhihui Zhu, Ning Di, Bingjie Lu, Cunmei Yang, Qiuli Xu, Zheng Liu, Li Fan, Yixin Hu","doi":"10.1002/jcsm.70358","DOIUrl":"https://doi.org/10.1002/jcsm.70358","url":null,"abstract":"Background and Aim Among the oldest‐old, the impact of body composition on survival outcomes exhibits pronounced heterogeneity. Although the obesity paradox has been widely discussed, clear evidence is still lacking regarding whether the biological effects of adipose reserves are modulated by functional status. Therefore, this study aims to investigate the association between adipose reserve indicators and long‐term all‐cause mortality risk in the oldest‐old and to elucidate the regulatory role of frailty, thereby providing an evidence‐based foundation for precision clinical health management. Methods This prospective cohort study included 529 community‐dwelling oldest‐old individuals. Participants were categorized into prefrailty and frailty groups at baseline using the Fried frailty phenotype. Bioelectrical impedance analysis was utilized to measure body composition. Stratified multivariate Cox proportional hazards regression models were employed to evaluate the relationship between adipose indicators and all‐cause mortality. Additionally, restricted cubic splines (RCS) and Kaplan–Meier curves were used to analyse survival heterogeneity. Results During a median follow‐up of 3.84 years, 88 deaths (16.6%) occurred. In the prefrail oldest‐old, adipose reserves exhibited significant protective effects on survival: The fully adjusted model showed that PBF (HR = 0.92, 95% CI: 0.87–0.98, <jats:italic>p</jats:italic> = 0.006), VFA (HR = 0.99, 95% CI: 0.97–0.99, <jats:italic>p</jats:italic> = 0.013) and WHR (HR = 0.91, 95% CI: 0.86–0.95, <jats:italic>p</jats:italic> &lt; 0.001) were all inversely associated with mortality risk. In contrast, these protective effects vanished in the frail oldest‐old (all <jats:italic>p</jats:italic> &gt; 0.05), suggesting that the benefits of adipose tissue are contingent upon the individual's basal functional reserve. RCS analysis revealed a linear dose–response relationship between adipose indicators and mortality risk (all <jats:italic>p</jats:italic> for non‐linearity &gt; 0.05), with no significant threshold effect observed. Interaction analyses confirmed that frailty status significantly modulated the prognostic value of adipose metrics ( <jats:italic>p</jats:italic> &lt; 0.05), with protective effects restricted exclusively to prefrail individuals. Kaplan–Meier curves confirmed that individuals in the prefrailty stage with higher adipose reserves achieved the highest survival rates (all Log‐rank <jats:italic>p</jats:italic> &lt; 0.001). Conclusion These findings suggest that the protective effect of adipose reserves is frailty‐dependent in the oldest‐old, and that weight management strategies should consider baseline functional status.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"56 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148729136","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":"Changes in Muscle Mass and Quality Mediate the Effect of High‐Calorie Intake on Clinical Outcomes","authors":"Yassir Aarab, Fabrice Raynaud, Mathieu Capdevila, Aurelien Flatres, Gérald Hugon, Céline Lauret, Nicolas Molinari, Celia Vidal, Kada Klouche, Samir Jaber, Stefan Matecki, Boris Jung","doi":"10.1002/jcsm.70355","DOIUrl":"https://doi.org/10.1002/jcsm.70355","url":null,"abstract":"Background Critically ill patients frequently experienced acquired muscle dysfunction, which adversely affects outcomes. The relationship between calorie intake, muscle dysfunction and outcomes remains unclear. This study aims to determine if early calorie intake affects patients' outcomes through changes in skeletal muscle mass or quality, and to explore changes in muscle structure and underlying molecular pathways using limb muscle biopsies in a piglet model. Methods This translational study combines data from a prospective observational study including critically ill patients and a 72‐h ventilated piglet model with early high calorie full enteral nutrition, both recording serial ultrasound measurements of limb muscle thickness and stiffness. Patients were classified into two trajectory groups based on thickness, stiffness and calorie intake. Adjusted mediation analysis quantified the effect of calorie intake on outcomes explained by muscle trajectories. The primary endpoint was ventilator‐free days at Day 28 (VFD28). In vivo limb muscle biopsies from piglets were analysed. Results Among 102 patients, 21% and 28% exhibited decreased thickness and stiffness by Day 7, respectively; 36% received high‐calorie intake at Day 7. Patients categorized into the ‘decreased trajectory group’ for both thickness and stiffness showed lower VFD28 ( <jats:italic>p</jats:italic> &lt; 0.01) and longer ICU stay ( <jats:italic>p</jats:italic> &lt; 0.01) compared to the ‘stable trajectory group’. High‐calorie intake was associated with significantly lower VFD28 (−8.7 days [−14.7 to −1.7]; <jats:italic>p</jats:italic> = 0.01), longer ICU stay ( <jats:italic>p</jats:italic> &lt; 0.01) and higher ICU mortality ( <jats:italic>p</jats:italic> &lt; 0.01). Decreased muscle trajectories mediated, respectively, 42% and 28% of the association between high‐calorie intake and VFD 28. The porcine model showed a limb muscle stiffness reduction associated with muscle fibre atrophy and increased intramuscular lipid content linked to decreased protein synthesis (IGF‐1 and myostatin downregulation), increased autophagy (ATG5, ATG7 and P62 increased activity) and impaired fatty acid metabolism (carnitine palmitoyltransferase 1B reduced expression). Conclusions This study demonstrates that early calorie intake in critically ill patients adversely affects muscle mass and quality, mediating negative outcomes. The porcine model helps elucidate underlying mechanisms, with early high‐calorie intake resulting in a metabolic oversupply state associated with metabolic disorders leading to muscle fibre atrophy and lipid accumulation. These results highlight the importance of targeted nutritional strategies to preserve muscle health in critically ill patients.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148717606","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":"Presurgical miR‐675‐5p Associates With the Inflammatory Response Following Surgery and Increases Inflammatory Gene Expression In Vitro","authors":"Narmin Akhundova, Richard Paul, Benjamin Fletcher, Martin Connolly, Mark J. Griffiths, Paul R. Kemp","doi":"10.1002/jcsm.70359","DOIUrl":"https://doi.org/10.1002/jcsm.70359","url":null,"abstract":"Background A loss of muscle mass and strength is a marker of poor outcomes following surgery. Changes in muscle gene expression following surgery are likely to contribute to postsurgical muscle loss, but the mechanisms controlling these changes are not known. We have previously shown that miRNAs associate with muscle loss in disease, including surgery, so may contribute to changes in gene expression. We analysed the change in muscle gene expression following surgery and compared it to pre‐ and postsurgical miRNA expression. We then analysed the effect of one of these miRNAs (miR‐675‐5p) on gene expression in myoblasts in the presence and absence of an inflammatory stimulus. Methods Differential gene expression analysis was performed on RNAseq data from rectus femoris biopsies ( &lt;jats:italic&gt;n&lt;/jats:italic&gt; = 18 male patients) pre‐ and postsurgery. Gene expression was compared with miRNA expression in the same samples to identify patterns of mRNA expression associated with physiology and miRNA expression. The effect of miR‐675‐5p on gene expression in the presence and absence of TNF‐ &lt;jats:italic&gt;α&lt;/jats:italic&gt; was determined in LHCN myoblasts by RNAseq. Results Postsurgery muscle had increased expression of gene sets associated with TNF‐ &lt;jats:italic&gt;α&lt;/jats:italic&gt; signalling (2.7‐fold) and &lt;jats:italic&gt;MYC&lt;/jats:italic&gt; targets (2.7‐fold). Loss of muscle mass and strength associated with &lt;jats:italic&gt;MYC&lt;/jats:italic&gt; target gene sets, but inflammatory gene sets only associated with loss of strength. Comparing miRNA expression with postsurgery gene expression showed that presurgery miR‐675‐5p expression was most closely associated with postsurgical gene expression, indicating that the presurgery phenotype is important in determining the response to surgery. Presurgery miR‐675‐5p correlated with change in gene expression in response to surgery ( &lt;jats:italic&gt;β&lt;/jats:italic&gt; = 1.30, &lt;jats:italic&gt;p&lt;/jats:italic&gt; &lt; 0.001), such that individuals with the highest presurgery miR‐675‐5p had the largest change in gene expression in response to surgery. In LHCN myoblasts miR‐675‐5p increased CCL2 protein release approximately 1.5‐fold ( &lt;jats:italic&gt;p&lt;/jats:italic&gt; &lt; 0.001). RNAseq showed that, in the absence of TNF‐ &lt;jats:italic&gt;α&lt;/jats:italic&gt; , transfection with miR‐675‐5p increased the expression of 3422 genes with greatest enrichment of the hypoxia, myogenesis and TNF‐ &lt;jats:italic&gt;α&lt;/jats:italic&gt; signalling via NF‐κB gene sets. In the presence of TNF‐ &lt;jats:italic&gt;α&lt;/jats:italic&gt; , miR‐675‐5p increased the expression of 3403 genes, and the most enriched gene sets were the same suggesting that miR‐675‐5p increases the inflammatory response. miR‐675‐5p also increased the expression of MuRF1 in the presence and absence of TNF‐ &lt;jats:italic&gt;α&lt;/jats:italic&gt; . Conclusions Male patients with higher presurgical expression of miR‐675‐5p experienced a larger increase in inflammatory gene expression following surgery. MiR‐675‐5p increased inflammatory ","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"29 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148688072","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":"Early and Divergent Lipid Mediator Remodelling in Fast Versus Slow Skeletal Muscles of Female hSOD1 G93A Mice","authors":"Sebastiaan Dalle, Kaat Vanderbeke, Thibaut Burg, Moniek Schouten, Wout Lauriks, Nicole Hersmus, Ludo Van Den Bosch, Katrien Koppo","doi":"10.1002/jcsm.70357","DOIUrl":"https://doi.org/10.1002/jcsm.70357","url":null,"abstract":"Background Skeletal muscle atrophy in amyotrophic lateral sclerosis (ALS) drives loss of muscle strength, function and quality of life in ALS patients. The endocannabinoid system (ECS) regulates muscle homeostasis via regenerative and metabolic processes, and although ECS alterations have been reported in ALS neural tissues, ECS remodelling within ALS skeletal muscle has never been studied. This study investigated temporal and muscle type–specific ECS changes in ALS. Methods Female hSOD1 &lt;jats:sup&gt;G93A&lt;/jats:sup&gt; transgenic mice and nontransgenic littermates were studied at presymptomatic and symptomatic ages (56–138 days of age; &lt;jats:italic&gt;n&lt;/jats:italic&gt; = 7–8/group). Endocannabinoids, &lt;jats:italic&gt;N&lt;/jats:italic&gt; ‐acyl‐ethanolamine congeners and inflammatory lipid mediators were quantified using targeted LC–MS/MS in the tibialis anterior (TA) and soleus (SOL) muscles. ECS‐related enzymes and receptors were assessed by immunoblotting and integrated with transcriptomic analyses of skeletal muscle biopsies from ALS patients ( &lt;jats:italic&gt;n&lt;/jats:italic&gt; = 5/group; ~63 years). To evaluate therapeutic relevance, ALS mice were treated with the fatty acid amide hydrolase (FAAH) inhibitor URB937 or vehicle ( &lt;jats:italic&gt;n&lt;/jats:italic&gt; = 10–11/group), and survival, body weight, welfare and motor function were assessed longitudinally. Results ALS caused severe atrophy in the predominantly fast‐twitch TA muscle (−76.5%; &lt;jats:italic&gt;p&lt;/jats:italic&gt; &lt; 0.01), while the slow‐twitch soleus was largely preserved (−14.4%; &lt;jats:italic&gt;p&lt;/jats:italic&gt; &lt; 0.01). Accordingly, the lipid perturbation due to ALS was more pronounced in the TA, reflected by extensive alterations in unsaturated fatty acids, hydroxy‐ and epoxy‐fatty acids (TA: 63% and SOL: 22% of lipid mediators different between ALS vs. NTG) and marked ECS remodelling, including elevated anandamide (+37.3%; &lt;jats:italic&gt;p&lt;/jats:italic&gt; = 0.03) and multiple &lt;jats:italic&gt;N&lt;/jats:italic&gt; ‐acyl‐ethanolamine congeners (+76–102%; &lt;jats:italic&gt;p&lt;/jats:italic&gt; &lt; 0.05), reduced 2‐arachidonoylglycerol (−28%; &lt;jats:italic&gt;p&lt;/jats:italic&gt; = 0.06), increased CB1 receptor expression (+93%; &lt;jats:italic&gt;p&lt;/jats:italic&gt; &lt; 0.01) and dynamic, age‐dependent regulation of FAAH (presymptomatic: −68%; &lt;jats:italic&gt;p&lt;/jats:italic&gt; = 0.04, symptomatic: +21%; &lt;jats:italic&gt;p&lt;/jats:italic&gt; = 0.02). In contrast, the SOL showed modest or opposite changes, consistent with its relative resistance to atrophy. Notably, ECS remodelling in the TA was already evident at presymptomatic age (e.g., CB1: +76%; &lt;jats:italic&gt;p&lt;/jats:italic&gt; = 0.01) and the same ECS enzymes were affected in human ALS skeletal muscle transcriptomes (e.g., twofold decrease in FAAH; &lt;jats:italic&gt;p&lt;/jats:italic&gt; &lt;jats:sub&gt;FDR&lt;/jats:sub&gt; = 0.010). Despite evidence for a therapeutic potential, chronic peripheral FAAH inhibition with URB937 did not improve weight loss, motor functions and survival of ALS mice (all &lt;jats:italic&gt;p&lt;/jats:italic&gt; &gt; 0.05","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"359 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148675054","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":"Imeglimin Attenuates Skeletal Muscle Atrophy in Mouse Models of Obesity and Ageing.","authors":"Yangli Ye, Diandian Qian, Ikumi Nomura, Naoki Kobayashi, Yukiko Shimizu, Tadashi Okamura, Motoharu Awazawa, Kohjiro Ueki","doi":"10.1002/jcsm.70354","DOIUrl":"10.1002/jcsm.70354","url":null,"abstract":"<p><strong>Background: </strong>Sarcopenia is a major contributor to frailty and mortality in ageing and obesity and is tightly linked to metabolic dysfunction. Imeglimin is a first-in-class oral hypoglycaemic agent targeting mitochondrial function; however, despite the central role of mitochondria in skeletal muscle homeostasis, its effects on skeletal muscle under sarcopenia-relevant conditions remain unclear.</p><p><strong>Methods: </strong>Imeglimin was administered to male C57BL/6 mice with high-fat diet (HFD)-induced obesity for 6 weeks and to naturally aged (18 months old) male mice for 12 weeks. Skeletal muscle fibre morphology and transcriptomic profiles were analysed in fast- and slow-twitch muscles. In parallel, C2C12 myotubes were exposed to palmitate with or without imeglimin, and inflammatory gene expression and reactive oxygen species (ROS) generation were assessed.</p><p><strong>Results: </strong>Imeglimin significantly increased the cross-sectional area (CSA) of Type II fibres in the extensor digitorum longus (EDL) muscle of HFD-fed mice (+66%, p < 0.01 vs. controls). Transcriptomic analyses revealed suppression of conserved molecular signatures of muscle atrophy, including activation of immediate-early genes and inflammatory pathways (-62% to -79%, p < 0.05 vs. HFD-fed mice). In palmitate-treated C2C12 myotubes, imeglimin attenuated lipotoxicity-induced inflammatory gene expression (-28% to -72%, p < 0.05 vs. controls) with reduced ROS generation, consistent with its cell-autonomous effect on myocytes. Notably, in naturally aged mice, 12-week imeglimin treatment preserved EDL muscle fibre size (+14%, p < 0.05 vs. controls) without altering systemic glucose tolerance, accompanied by transcriptomic changes overlapping with those observed in the HFD model (-27% to -82%, p < 0.05 vs. aged controls).</p><p><strong>Conclusions: </strong>Imeglimin attenuates skeletal muscle atrophy in obesity and ageing, accompanied by coordinated suppression of stress- and inflammation-associated transcriptional programmes. These findings indicate that pharmacological regulation of mitochondrial stress responses influences skeletal muscle vulnerability under chronic metabolic stress and identify skeletal muscle as a previously underappreciated target of imeglimin action.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 4","pages":"e70354"},"PeriodicalIF":9.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13416397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148596959","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":"Supervised Exercise Intervention Restores Physical Activity and MultiOMIC-Derived Frailty Biomarkers in Older Adults.","authors":"Diego Marcos-Perez, Sara Cruces-Salguero, Morelva Saeteros, Rafael Garcia Molina, Ruben Alcantud-Córcoles, Cristina Alonso-Bouzon, Itziar Vergara, Sergio J Sanabria, Leocadio Rodriguez-Mañas, Pedro Abizanda, Ander Matheu","doi":"10.1002/jcsm.70362","DOIUrl":"10.1002/jcsm.70362","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The molecular mechanisms underlying frailty are under intense investigation. Independent observational studies revealed various biological processes and biomarkers differentially expressed in frail individuals and after interventions. Recently, several transcriptomic approaches have described molecular patterns associated with frailty status. However, the effects of physical exercise interventions remain unexplored. Two studies (FRAILOMIC and BIOFRAIL) identified molecular signatures associated with frailty. The objective of the study was to analyse the expression of the FRAILOMIC and BIOFRAIL biomarkers following a multicomponent personalized exercise intervention in older adults.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A multi-centre study included a control (n = 24, with 14 women and 10 men, median age 80 ± 5) and an exercise intervention group (n = 44, with 38 women and 6 men, median age 79 ± 4). The latter underwent a 16-week multicomponent presential physical exercise programme; clinical, functional and frailty assessments were performed before and after the intervention in both groups. Latent class analysis identified 'responders' and 'non-responders' to the intervention. Data in a testosterone-suppressed control cohort of older men with prostatic cancer receiving androgen deprivation therapy (n = 21) were included. Molecular biomarkers were measured via qRT-PCR and ELISA.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The exercise group presented improvements in functional capacity, as shown by Short Physical Performance Battery (SPPB) (post- 10.1 vs. 9.1 in pre-intervention), grip strength (18.3 vs. 16.9 kg), gait speed (0.85 vs. 0.78 m/s), sarcopenia (2.1 vs. 3.0) and frailty status by Fried Frailty Phenotype (1.6 vs 2.1 criteria) (all ≤ 0.004). ANCOVA revealed significant improvements in SPPB (p = 0.04) and grip strength (p &lt; 0.005) with exercise. Four of the six FRAILOMIC biomarkers (miR125b, miR194, RAGE and Troponin) and six of seven BIOFRAIL biomarkers (EGR1, CXCL8, GOS2, NSF, DDX11L1 and miR454) reversed significantly their expression after exercise training (p ≤ 0.05 for FRAIOLMIC and ≤ 0.01 for BIOFRAIL respectively). In contrast, these changes were not observed in testosterone-suppressed controls, who experienced muscle loss. Latent class analysis revealed 36 'responders' (with 32 cases from intervention group) and 29 'non-responders'. Logistic regression showed that miR454, EGR1, DDX11L1 and Troponin displayed the strongest predictive value in distinguishing responders from non-responders.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Exercise intervention improved functional status and reversed biological frailty, as evidenced by changes in multiple MultiOMIC frailty biomarkers. Among these, the BIOFRAIL trio-miR454, EGR1 and DDX11L1-showed the strongest predictive power for intervention response with AUC of 0.83. This study provides proof-of-concept for the utility of OMIC-derived frailty biomarkers as outcome measures after ","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 4","pages":"e70362"},"PeriodicalIF":9.1,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13453334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700283","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}