Journal of Cachexia, Sarcopenia and Muscle最新文献

{"title":"Comment on 'Asian Reference Values for Handgrip Strength, Gait Speed, Five-Times-Sit-to-Stand Test, Muscle Mass and Calf Circumference' by Grgic et al.","authors":"Wee-Shiong Lim, Prasert Assantachai, Reshma Merchant, Chang Won Won, Jean Woo, Liang-Kung Chen, Hidenori Arai","doi":"10.1002/jcsm.70317","DOIUrl":"10.1002/jcsm.70317","url":null,"abstract":"","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 3","pages":"e70317"},"PeriodicalIF":9.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13273395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148262193","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":"MyoRep: A Novel Reporter System to Detect Early Muscle Atrophy In Vitro and In Vivo.","authors":"Andrea D Re Cecconi, Nicoletta Rizzi, Mara Barone, Federica Palo, Martina Lunardi, Mara Forti, Adriana Maggi, Paolo Ciana, Giulia Terribile, Michela Chiappa, Lorena Zentilin, Rosanna Piccirillo","doi":"10.1002/jcsm.70296","DOIUrl":"10.1002/jcsm.70296","url":null,"abstract":"<p><strong>Background: </strong>Muscle atrophy occurs during physiological (i.e., fasting) and pathological conditions (i.e., cancer) and anticipates death. Since not all patients will undergo muscle wasting, it would be highly useful to identify them soon to intervene early. We aim to generate a reporter system to follow only pathological, but not physiological, muscle wasting through in vivo imaging.</p><p><strong>Methods: </strong>Comparing the upstream non-coding regions of a subset of atrophy-related genes or atrogenes, using the MuRF1 promoter as a backbone, we cloned various promoters upstream of Firefly Luciferase. The best hits selected in vitro were further compared in in vivo imaging if able to sense early atrophy induced by MCG101 sarcoma or sciatic nerve resection through plasmid electroporation or AAV9 injections. The best promoter was used to generate the reporter mouse MyoRep, expressing the cassette in all skeletal and cardiac muscles using the loxP system.</p><p><strong>Results: </strong>Luciferase assays showed that only the newly generated promoters of MuRF1, one containing glucocorticoid-responsive elements or GRE (TWIST) (p ≤ 0.01, 1.7 FC) and a GRE-less promoter (GREDEL) (p ≤ 0.0001, 1.6 FC), discriminated the supernatants from cachectic tumoural cells (C26) from non-cachectic ones (4T1). Comparing both reporters electroporated in leg muscles, we found that GREDEL, but not TWIST, anticipated atrophy by 6 days in MCG101 carriers (p ≤ 0.05) and by 8 days upon denervation (p ≤ 0.05), recapitulating MuRF1 inductions. TWIST, but not GREDEL, drove an undesirable bioluminescent signal in vitro to dexamethasone (p ≤ 0.001, 1.5 FC) and in vivo upon fasting (p = 0.0553, 3 FC). GREDEL-carrying AAV9 injected in the legs of Apc^Min/+ mice unraveled sex-different cachexia and anticipated body emaciation by 1 week (p ≤ 0.001, 3.7 FC). GREDEL was then used to generate the MyoRep mouse. Dorsal view of bioluminescent signal of MCG101-carrying MyoRep mice increased already 6 days from tumour injection (p ≤ 0.01, 1.7 FC) when tumour is still unpalpable. Denervated MyoRep mice emitted a signal already 1 day after surgery (p ≤ 0.05, 1.4 FC), anticipating atrophy. Male Apc^Min/+ mice display less musclin in their muscles (p ≤ 0.05, 0.4 FC) and plasma (p ≤ 0.01, 0.6 FC). Such mice, when expressing MyoRep in their muscle legs, were given the anti-catabolic myokine musclin. The emitted signal was decreased by 30% 3 weeks after musclin-AAV9 administration (p ≤ 0.05), supporting MyoRep useful to test anti-atrophic drugs.</p><p><strong>Conclusions: </strong>Since MyoRep detects only pathological atrophy anticipating wasting, it represents an unprecedented tool to predict it early in diseases with local or systemic atrophy. It could also be useful to identify early biomarkers of atrophy and new drugs at once.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 3","pages":"e70296"},"PeriodicalIF":9.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13167697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147925052","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":"Combined Bisoprolol and Megestrol Acetate Improves Survival and Preserves Cardiac Performance in a Rat Model of Cancer Cachexia.","authors":"Zihao Chen, Siqi Wang, Sandra Palus, Stefan D Anker, Wolfram Doehner, Jochen Springer","doi":"10.1002/jcsm.70313","DOIUrl":"10.1002/jcsm.70313","url":null,"abstract":"<p><strong>Background: </strong>Cancer cachexia is associated with rapid body wasting and cardiac dysfunction. Bisoprolol (BIS) and megestrol acetate (MA) improve selected cachexia phenotypes in the Yoshida AH-130 model, but their combined effects are not defined. We tested reduced-dose combined treatment of BIS and MA (COMB) on survival and organ-specific outcomes.</p><p><strong>Methods: </strong>Male Wistar Han rats (approx. 200 g) received intraperitoneal Yoshida AH-130 hepatoma cells and were treated with placebo (PL, n = 49), BIS (5 mg/kg/day, n = 23), MA (100 mg/kg/day, n = 10) or COMB (BIS 3.75 mg/kg/day + MA 75 mg/kg/day, n = 16). Outcomes included survival, echocardiography (baseline and Day 11), body composition (EchoMRI), terminal tissue weights, food intake and spontaneous locomotor activity.</p><p><strong>Results: </strong>COMB reduced mortality versus placebo (HR = 0.21, p < 0.0001) and had the lowest HR among treatment groups. BIS also reduced mortality versus PL (HR = 0.32, p = 0.0007), whereas MA did not reach statistical significance (HR = 0.49, p = 0.082). COMB did not differ significantly from BIS (HR for COMB vs. BIS = 0.48, p = 0.28) or MA (HR for COMB vs. MA = 0.23, p = 0.06). On Day 11, COMB showed higher LVEF than PL (64.1% ± 9.7% vs. 50.5% ± 12.8%, p < 0.01), higher LV stroke volume (186 ± 49 μL vs. 112 ± 55 μL, p < 0.001) and higher LV mass (515 ± 95 mg vs. 429 ± 65 mg, p < 0.01); changes from baseline were smaller in COMB than PL for LVEF (Δ -12.0% ± 8.9% vs. -24.3% ± 16.2%, p < 0.05) and LV mass (Δ -57 ± 93 mg vs. -137 ± 79 mg, p < 0.05). Body weight, fat mass and lean mass decreased in all groups; COMB showed smaller reductions than PL (p < 0.05) but did not differ from BIS or MA (p > 0.05). BAT weight was higher in COMB than PL (p < 0.001) and higher than BIS (p < 0.001). Food intake on Day 11 was higher than PL in all active groups, and locomotor activity was higher than PL in MA and COMB.</p><p><strong>Conclusions: </strong>COMB reduced mortality versus placebo and showed the lowest HR among treatment groups, accompanied by preserved cardiac performance and a distinct BAT response. Differences versus monotherapy were not statistically significant. Future studies should test optimized dosing and include exposure assessment and tissue profiling to determine benefit over monotherapy and to clarify the basis of the cardiac and BAT phenotypes.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 3","pages":"e70313"},"PeriodicalIF":9.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13240587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148004010","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":"Gut Microbiota-Linked Benefits of Low-Intensity Pulsed Ultrasound Rejuvenate the Ageing Muscle.","authors":"Jia-Hua Jhuang,Kuo-Cheng Lan,Ting-Yu Chang,Ding-Cheng Chan,Shing-Hwa Liu","doi":"10.1002/jcsm.70291","DOIUrl":"https://doi.org/10.1002/jcsm.70291","url":null,"abstract":"BACKGROUNDAgeing is an inevitable biological process that contributes to increased prevalence of age-associated diseases, including sarcopenia, defined by progressive loss of muscle mass, functional decline and a heightened risk of injury. Developing effective interventions remains a critical clinical priority. This study employed a natural ageing mouse model to investigate whether noninvasive low-intensity pulsed ultrasound (LIPUS), a therapeutic ultrasound, delivered to the abdomen, could alleviate age-related muscle deterioration and whether its effects were linked to gut microbiota modulation.METHODSC57BL/6 mice were maintained until 92 weeks of age, after which abdominal LIPUS stimulation was administered for 8 weeks. At 100 weeks, both forelimb and hind limb grip strength were assessed prior to euthanasia. Faecal samples from the distal colon were collected for microbiota profiling, and gastrocnemius muscles were harvested for downstream analyses.RESULTSNaturally aged mice exhibited sarcopenia-like characteristics, including impaired muscle performance, reduced myofiber diameter and decreased muscle weight (n = 6, p < 0.01, p < 0.001). Age-related renal impairment promoted the accumulation of advanced glycation end products (AGEs) in skeletal muscle, triggering pro-inflammatory signalling cascades characterized by elevated COX-2, phosphorylated NF-κB, NLRP3, IL-1β and Caspase-1 (n = 5-6, p < 0.01). LIPUS treatment significantly improved muscle strength (forelimb and hind limb grip strength, n = 6, p < 0.001, p < 0.01) and muscle mass (n = 6, p < 0.01), while suppressing inflammatory mediators (n = 5-6, p < 0.05). Gut microbiota analysis showed that LIPUS increased microbial diversity (n = 5-6, p < 0.05) and altered taxonomic composition, enriching anti-inflammatory taxa such as Lactobacillus, Bifidobacterium, Faecalibaculum and Coriobacteriaceae_UCG_002 (n = 6, p < 0.05). Correlation analysis indicated that these LIPUS-enriched taxa were positively associated with enhanced muscle performance. These data suggest that LIPUS mitigates sarcopenia in naturally aged mice by restoring muscle integrity and attenuating inflammation, possibly via gut microbiota regulation.CONCLUSIONSThis study shows that natural ageing in mice induces sarcopenia-like features with inflammatory activation and gut microbiota alterations. Abdominal LIPUS treatment alleviated muscle loss, reduced inflammation and promoted beneficial microbes, rejuvenating the ageing muscle. These findings highlight LIPUS as a safe, noninvasive and potentially translatable strategy for sarcopenia, warranting further investigation of its microbiota-muscle interactions.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"73 1","pages":"e70291"},"PeriodicalIF":8.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147725947","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":"Triglyceride-Glucose-Waist-to-Weight Index: Novel Biomarker for Mild Cognitive Impairment in Older People With Sarcopenic Obesity.","authors":"Yue Xing, Qian Liu, Xiangfeng He, Lin Ma, Yanping Song, Nan Chen PhD","doi":"10.1002/jcsm.70307","DOIUrl":"10.1002/jcsm.70307","url":null,"abstract":"<p><strong>Background: </strong>Sarcopenic obesity (SO) is closely associated with mild cognitive impairment (MCI). However, traditional body composition-based diagnostic criteria for SO fail to adequately incorporate insulin resistance, a key pathophysiological mechanism. This study aimed to investigate the association between SO, defined using multiple diagnostic criteria including novel insulin resistance indices, and MCI and to identify the optimal SO criterion for MCI identification.</p><p><strong>Methods: </strong>This study analysed data from the 2025 Chongming Older People Screening Project, CHARLS (2015-2020) and ELSA (2012-2017). We used multivariable logistic regression to assess the link between SO and MCI. The optimal obesity indicator for identifying MCI in sarcopenia was identified using ROC analysis and then incorporated into an XGBoost model to detect MCI risk. Subgroup analyses were performed to assess the association between SO and decline in multiple cognitive domains.</p><p><strong>Results: </strong>This study included 2326 individuals from the 2025 Chongming Older People Screening Project, 3392 from CHARLS and 1825 from ELSA. The mean age was 72.62 ± 5.56 years in the cross-sectional study, 66.70 ± 5.39 years in CHARLS and 67.99 ± 5.55 years in ELSA. The proportion of female participants was 55.93% in the cross-sectional study, 57.59% in ELSA and 40.60% in CHARLS. MCI was consistently identified across all assessment tools in three independent cohorts using the metabolically oriented definition integrating sarcopenia with an elevated triglyceride-glucose-waist-to-weight index (TyG-WWI) (Chongming: OR = 3.04, 95% CI: 1.83-5.07, p < 0.001; CHARLS: HR = 1.57, 95% CI: 1.01-2.42, p = 0.043; and ELSA: HR = 1.87, 95% CI: 1.01-3.46, p = 0.047). TyG-WWI was identified as the optimal obesity indicator to identify MCI (AUC = 0.71, 95% CI: 0.63-0.78). The machine learning model based on TyG-WWI demonstrated strong discriminative performance in the cross-sectional study (AUC = 0.93, 95% CI: 0.90-0.97) and maintained robust discriminative ability in external validation (CHARLS: AUC = 0.86, 95% CI: 0.80-0.92; ELSA: AUC = 0.84, 95% CI: 0.73-0.95). Subgroup analyses revealed that SO was associated with decline in multiple cognitive domains, particularly executive function and memory.</p><p><strong>Conclusions: </strong>This study demonstrates that a metabolically oriented SO definition integrating sarcopenia with elevated TyG-WWI is a more effective tool for identifying MCI among community-dwelling older people compared with traditional body composition-based criteria.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 3","pages":"e70307"},"PeriodicalIF":9.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13161463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147872520","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":"Prevalence and Prognostic Impact of the Coexistence of Cachexia and Sarcopenia in Patients With Chronic Liver Diseases.","authors":"Takatsugu Tanaka, Goki Suda, Masatsugu Ohara, Daisuke Yokoyama, Shoichi Kitano, Osamu Maehara, Tomoka Yoda, Qingjie Fu, Zijian Yang, Naohiro Yasuura, Akimitsu Meno, Takashi Sasaki, Risako Kohya, Takashi Kitagataya, Naoki Kawagishi, Masato Nakai, Takuya Sho, Shunsuke Ohnishi, Naoya Sakamoto","doi":"10.1002/jcsm.70305","DOIUrl":"10.1002/jcsm.70305","url":null,"abstract":"<p><strong>Background: </strong>Cachexia and sarcopenia are prevalent, inflammation-linked syndromes in chronic liver disease that worsen outcomes. To our knowledge, their coexistence in a single chronic liver disease cohort has not been systematically examined. In this study, we evaluated the prevalence, clinical features and prognostic impact of cachexia and sarcopenia-alone and combined-in chronic liver disease.</p><p><strong>Methods: </strong>We retrospectively screened 776 patients with liver cirrhosis (LC) and/or hepatocellular carcinoma (HCC) at Hokkaido University Hospital (August 2014-May 2025). The inclusion criteria were grip strength, CT-based muscle mass and complete clinical data, yielding 307 patients; 469 did not meet one of the inclusion criteria. Cachexia was determined following the Asian Working Group for Cachexia criteria, and sarcopenia was determined following Japan Society of Hepatology guidelines. Patients were grouped as no cachexia/sarcopenia, cachexia only, sarcopenia only or cachexia+sarcopenia. The outcomes were overall survival, time to liver-related events and time to readmission (Kaplan-Meier and Cox-proportional models).</p><p><strong>Results: </strong>Among 776 patients, 307 were included in the final-analysis. Of 307 patients, 206 (67.1%) were male, the median age was 70 years (range, 19-90 years), 262 patients (85.3%) had LC and 188 patients (61.2%) had HCC. The patients were grouped as no cachexia/sarcopenia (213; 69.4%), cachexia only (54; 17.6%), sarcopenia only (17; 5.5%) and cachexia+sarcopenia (23; 7.5%). The combined group compared with the others had the lowest body mass index, psoas-muscle-index and grip strength (all p < 0.001). Overall survival (OS), liver-related events, LC progression and readmissions were compared between 246 patients with and without cachexia or sarcopenia, after excluding those who visited the hospital on or after July 2023 and had ≤ 3 months of follow-up. OS was shorter in the cachexia only (median 61.8 [95% CI 40.90-not reached (NR)] months, p = 0.046) and cachexia+sarcopenia (median 59.6 [95% CI 14.26-NR] months, p = 0.027) groups than in the no cachexia/sarcopenia group. Multivariable analysis showed that cachexia+sarcopenia (hazard ratio 2.48, p = 0.010), HCC (hazard ratio 3.40, p < 0.001) and diabetes mellitus (hazard ratio 1.80, p = 0.013) independently predicted mortality. The combined group compared with the other groups had a shorter time to liver-related events and readmission.</p><p><strong>Conclusions: </strong>The coexistence of cachexia and sarcopenia-rather than either alone-can be used as an indicator for identifying patients with chronic liver disease at the highest risk of poor outcomes. Concurrent assessment and early, targeted interventions may improve outcomes in this population.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 3","pages":"e70305"},"PeriodicalIF":9.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831496","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":"Deletion of Tgf-β1 From CD206⁺ M2 Macrophages Ameliorates Obesity-Induced Suppression of Myogenesis and AMPK Phosphorylation in Skeletal Muscle.","authors":"Muhammad Bilal, Le Duc Anh, Nguyen Quynh Phuong, Sana Khalid, Allah Nawaz, Memoona, Muhammad Rahil Aslam, Tomonobu Kado, Yoshiyuki Watanabe, Ayumi Nishimura, Yoshiko Igarashi, Aamir Sharif, Yasuhiro Onogi, Tsutomu Wada, Ryuji Hayashi, Kenichi Hirabayashi, Seiji Yamamoto, Takashi Nakagawa, Hisashi Mori, Isao Usui, Masaru Kato, Shiho Fujisaka, Kazuyuki Tobe","doi":"10.1002/jcsm.70322","DOIUrl":"10.1002/jcsm.70322","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Backgrounds: &lt;/strong&gt;Obesity and diabetes impair the ability of the muscle to regenerate, repair and remodel, resulting in a gradual decrease in muscle mass and function. However, the underlying mechanisms and effective therapeutic strategies remain poorly understood. M2 macrophages within skeletal muscle play an important role in tissue recovery following injury. This study aims to investigate the role of M2 macrophages derived transforming growth factor-beta 1 (Tgf-β1) in regulation of skeletal muscle function under diet-induced obese conditions.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;An CD206&lt;sup&gt;+&lt;/sup&gt; M2 macrophage-specific Tgf-β1 gene knockout (Tgf-β1 KO) mouse model was generated by crossing CD206-CreER&lt;sup&gt;T2&lt;/sup&gt; mice with Tgf-β1&lt;sup&gt;f/f&lt;/sup&gt; mice, followed by tamoxifen administration to induce Tgf-β1 gene deletion. Mice were then placed on a high-fat diet (HFD) for 12 weeks to develop obesity-induced skeletal muscle dysfunction. The study used multiple physiological and molecular analyses, including exercise tolerance, hanging time, grip strength, glucose and insulin tolerance tests, western blotting, RT-qPCR and others.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The present findings demonstrated improved exercise performance, as evidenced by increased running distance twice (p = 0.0008) in Tgf-β1 KO mice. Deletion of CD206&lt;sup&gt;+&lt;/sup&gt; M2 macrophage-specific Tgf-β1 stimulates fibro-adipogenic progenitors (FAPs), inducing Follistatin (Fst) expression by 1.70-fold (p = 0.04) and follistatin-like protein 1 (Fstl1) by 2.60-fold (p = 0.01) in tibialis anterior (TA), thus enhancing myogenesis. The Tgf-β1 KO mice showed increased muscle fibre type I (Myh7 by 2.40-fold, p = 0.005), muscle fibre type IIa (Myh2 by 1.50-fold, p = 0.003), type IIx (Myh1 by 2.35-fold, p = 0.002) in soleus and type II (Myh4 by 1.76-fold, p = 0.02) in TA. In Tgf-β1 KO mice, insulin-stimulated Akt phosphorylation was significantly increased in adipose tissue by 2.14-fold (p = 0.0003) and in the liver by 1.62-fold (p = 0.01). Besides, the Tgf-β1 KO mice showed increased circulating adiponectin by 1.23 fold (p = 0.003), thereby activating the AMPK/SIRT1/PGC-1α pathway with the phosphorylation level of AMPKα increased by 1.5-fold (p = 0.02), and PGC1α protein level increased by 2.2-fold (p = 0.02) via increased AdipoR1 mRNA expression by 1.8-fold in TA, p = 0.0001 and by 1.8-fold in soleus, p = 0.01 in skeletal muscle, leading to improved mitochondrial function in skeletal muscle.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;The CD206&lt;sup&gt;+&lt;/sup&gt; M2 macrophage-specific Tgf-β1 deletion ameliorates obesity-induced muscle dysfunction, potentially via two distinct mechanisms. Firstly, it enhances myogenesis by promoting FAP-mediated expression of Fst and Fstl1, thereby augmenting myogenesis-related gene expression in skeletal muscle. Secondly, it also induces adipocytes to produce and secrete adiponectin into the bloodstream, thereby enhancing mitochondrial function via the AMPK/SIRT1/PG","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 3","pages":"e70322"},"PeriodicalIF":9.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13280218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275128","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":"RIPK3 Inhibition Mitigates Denervated Muscle Atrophy via NOX4-Mediated Mitochondrial Restoration and Inflammation Suppression.","authors":"Yuntian Shen, Chen Zhang, Zihao Zhao, Jia Yi, Xinlei Yao, Bingqian Chen, Hualin Sun","doi":"10.1002/jcsm.70311","DOIUrl":"10.1002/jcsm.70311","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Peripheral nerve injury-induced muscle atrophy shares core pathophysiological features with systemic wasting disorders including cachexia and sarcopenia, yet early molecular triggers remain undefined. This study investigates the pathogenic role of receptor-interacting protein kinase 3 (RIPK3) in denervation atrophy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Sciatic denervation was induced in rats for initial time-course transcriptomics and in mice for genetic and pharmacological studies. Assessments in wild-type and RIPK3-knockout mice included transcriptomics (RNA-seq, qPCR), muscle morphology (wet weight ratio, cross-sectional area), histological inflammation (H&E, CD68 immunofluorescence), mitochondrial function (complex I/V activity, ultrastructure and biogenesis/fission regulators), STRING analysis to identify downstream effectors, validated key effectors NOX2 and NOX4 (qPCR/Western blotting) and associated redox status (DHE staining), and analysis of myofibrillar protein content and proteolytic markers (Western blotting). Confirmatory studies included RIPK3 overexpression in C2C12 myotubes and its pharmacological inhibition (GSK872) in mice.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;RIPK3 emerged from transcriptomic analysis as an early upregulated mediator in denervated muscle, with protein levels increasing approximately threefold at 36 h post-injury. Genetic ablation of RIPK3 attenuated muscle atrophy, as shown by improved gastrocnemius wet weight ratio (p = 0.0110). This protective effect was directly evidenced by a 40.7% increase in cross-sectional area (p = 0.04). The morphological preservation was accompanied by markedly suppressed expression of key atrophy markers, including MAFbx, MuRF1 and FoxO3a (all p &lt; 0.01), and preserved MHC levels (p = 0.0278). Mechanistically, RIPK3 knockout reduced inflammation, enhanced oxidative phosphorylation (GSEA FDR &lt; 0.001) and partially restored mitochondrial function, evidenced by significantly increased complex I (p = 0.0438) and complex V (p &lt; 0.001) activity, preserved ultrastructure, upregulated PGC-1α and NRF2 (both p &lt; 0.05) and downregulated mitochondrial fission proteins (p-DRP1, MFF, FIS1; all p &lt; 0.01). STRING analysis predicted NOX4 as a key downstream effector, validated by reduced NOX4 protein (-46.6%, p = 0.0366) and a consequent 52.2% decrease in ROS accumulation (p &lt; 0.001). Consistently, RIPK3 overexpression in C2C12 myotubes elevated NOX4 (p = 0.0046) and atrophy markers, whereas pharmacological inhibition of RIPK3 in mice replicated the protective phenotype, increasing muscle wet weight ratio (p = 0.0277) and suppressing NOX4 (p = 0.0398) and proteolytic markers.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Denervation activates RIPK3 as a master regulator that drives muscle atrophy via NOX4/ROS-induced mitochondrial dysfunction, sustained inflammation and ubiquitin-proteasome activation. Targeting RIPK3 preserves muscle mass and may offer a novel therapeutic strategy for ne","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 3","pages":"e70311"},"PeriodicalIF":9.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809171","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":"Sema4A Protects Against Muscle Atrophy and Promotes Repair by Regulating Intracellular Metabolic Signalling.","authors":"Caiyun Wang, Honghong Chen, Lingjie Shen, Shenhan Xu, Jie Xu, Qiuyuan Huang, Weiheng Zhang, Chengshou Lin, Jun Chang, Xinhua Liu, Wugui Chen","doi":"10.1002/jcsm.70315","DOIUrl":"10.1002/jcsm.70315","url":null,"abstract":"<p><strong>Background: </strong>Skeletal muscle atrophy is a debilitating condition associated with diverse diseases and clinical interventions. Although triggers such as glucocorticoid excess or direct muscle injury disrupt the balance between protein homeostasis and tissue repair, the upstream molecular signals that actively preserve muscle integrity remain largely unknown. Semaphorin 4A (Sema4A) is a Class IV transmembrane semaphorin traditionally recognized for its roles in neural development and immune regulation; however, its function in skeletal muscle maintenance has not been explored.</p><p><strong>Methods: </strong>We first examined Sema4A expression in established models of muscle catabolism. Subsequently, adeno-associated virus (AAV)-mediated Sema4A restoration was employed to evaluate its therapeutic potential in both dexamethasone-induced atrophy and acute injury mouse models. Mechanistic studies were performed in C2C12 myotubes using gain- and loss-of-function approaches.</p><p><strong>Results: </strong>Sema4A expression was significantly downregulated under atrophic conditions (p < 0.05). Restoration of Sema4A effectively attenuated dexamethasone-induced muscle loss (4.766 vs. 5.075 mg/g B.W., p = 0.0414) and accelerated functional recovery (6.219 × 10^-2 vs. 7.124 × 10^-2 N/g B.W., p = 0.0422). We identified Plexin B2 (Plxnb2) as the functional receptor mediating these effects. At the molecular level, Sema4A signalling suppressed FoxO3a nuclear translocation (FoxO3a positive cells: vector-Dex 27.99% vs. OE-Sema4A-Dex 12.49%, p < 0.05), thereby inhibiting the expression of key atrogenes, while simultaneously reactivating the PI3K-AKT-mTOR anabolic pathway. This reprogramming of intracellular metabolic signalling was further associated with the establishment of a reparative immune microenvironment, a process potentially modulated by muscle-derived factors such as Gdf15.</p><p><strong>Conclusions: </strong>Our study identifies Sema4A as a novel protective regulator that mitigates muscle atrophy and enhances regeneration through a dual mechanism: restoring intracellular anabolic signalling and fostering a proregenerative immune niche. These findings highlight Sema4A as a promising therapeutic target for the treatment of muscle-wasting disorders.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 3","pages":"e70315"},"PeriodicalIF":9.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13240067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148051578","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":"Deubiquitinase YOD1 Inhibition Suppresses DEX- and Denervation-Induced Muscle Atrophy Through MAFbx Destabilization.","authors":"Jongbeom Chae,Seon Min Woo,Seung Un Seo,Simmyung Yook,Hyo Je Cho,Jung Yeol Lee,Kyoung Jin Min,Junhyeon Park,Dongryeol Ryu,Taeg Kyu Kwon","doi":"10.1002/jcsm.70300","DOIUrl":"https://doi.org/10.1002/jcsm.70300","url":null,"abstract":"BACKGROUNDSMuscle atrophy, characterized by progressive loss of muscle mass and function, is driven by muscle-specific E3 ligases MAFbx and MuRF1. While transcriptional regulation of E3 ligases is documented, the mechanism of their regulation by the ubiquitin-proteasome system remains unclear. This study aims to identify a deubiquitinase (DUB) regulating these E3 ligases and reveal the mechanisms underlying the mitigation of muscle atrophy through inhibition of the discovered DUB.METHODSDifferentiated C2C12 myotubes were screened using siRNAs to identify DUB genes that can regulate muscle atrophy. Muscle fibre cross-sectional area (CSA), grip strength and gene expression (MAFbx, MyoD, etc.) were evaluated in muscle atrophy-induced mouse model. Human translational relevance was analysed using GTEx skeletal muscle data.RESULTSWe identified that OTU DUBs family genes are increased (log2 FC > 1, p < 0.05) in DEX-induced muscle atrophy. Pharmacological (ubiquitin isopeptidase inhibitor I, G5) and genetic inhibition of YOD1 alleviated DEX- and denervation-induced muscle atrophy by MAFbx destabilization. The UBX domain of YOD1 was found to interact with the LZ domain of MAFbx, and YOD1 stabilized the MAFbx protein by removing polyubiquitin chains at lysine 48 in MAFbx. In in vivo mouse models, G5 treatment effectively ameliorated DEX- or NTX-induced muscle atrophy. Specifically, G5 increased grip strength by 37.64% (DEX, p < 0.0001) and 36.37% (NTX, p < 0.01), while muscle fibre size was improved by 35.85% (DEX, p < 0.01) and 30.76% (NTX, p < 0.0001). These improvements were accompanied by the restoration of MyoD and eIF3-f expression. Consistently, GTEx-based analysis revealed that high YOD1 expression in human skeletal muscles is significantly associated with an increased proportion of smaller fibres (< 2000 μm2), correlating with enriched proteostasis (NES = 1.51)-related and muscle development (NES = -1.44)-related transcriptional signatures.CONCLUSIONSOur study indicates that YOD1 inhibition destabilizes MAFbx protein levels, leading to protection against DEX- and denervation-induced muscle atrophy. Integration of human GTEx data further supports the translational relevance of YOD1 as a regulator of muscle fibre homeostasis. This study provides new insights into the post-translational regulation of muscle-specific E3 ligases and presents evidence showing that targeting YOD1 is a promising therapeutic approach for the prevention and treatment of muscle atrophy.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"6 1","pages":"e70300"},"PeriodicalIF":8.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147754870","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}