Sean Y. Ng, Andrew I. Mikhail, Stephanie R. Mattina, Magda A. Lesinski, Irena A. Rebalka, Sophie I. Hamstra, Donald Xhuti, Val A. Fajardo, Mark A. Tarnopolsky, Joshua P. Nederveen, Gregory R. Steinberg, Thomas J. Hawke, Vladimir Ljubicic
Duchenne muscular dystrophy (DMD) is a severe, life-limiting neuromuscular disorder (NMD) characterized by progressive muscle wasting and mitochondrial dysfunction. Although gene therapies offer promise, even those already approved by regulatory agencies, their use remains constrained by mutation specificity, delivery challenges and durability. Pharmacologically targeting AMPK has shown potential to ameliorate dystrophic pathology, but prior strategies have been hindered by inadequate efficacy and off-target effects.
{"title":"Direct AMPK Activation Confers Mutation-Independent Therapeutic Benefit in Duchenne Muscular Dystrophy","authors":"Sean Y. Ng, Andrew I. Mikhail, Stephanie R. Mattina, Magda A. Lesinski, Irena A. Rebalka, Sophie I. Hamstra, Donald Xhuti, Val A. Fajardo, Mark A. Tarnopolsky, Joshua P. Nederveen, Gregory R. Steinberg, Thomas J. Hawke, Vladimir Ljubicic","doi":"10.1002/jcsm.70200","DOIUrl":"https://doi.org/10.1002/jcsm.70200","url":null,"abstract":"Duchenne muscular dystrophy (DMD) is a severe, life-limiting neuromuscular disorder (NMD) characterized by progressive muscle wasting and mitochondrial dysfunction. Although gene therapies offer promise, even those already approved by regulatory agencies, their use remains constrained by mutation specificity, delivery challenges and durability. Pharmacologically targeting AMPK has shown potential to ameliorate dystrophic pathology, but prior strategies have been hindered by inadequate efficacy and off-target effects.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"53 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146115767","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}
Anna Stephan, Flavia A. Graca, Suresh Poudel, Yingxue Fu, Yong-Dong Wang, Myriam Labelle, Fabio Demontis
Skeletal muscle wasting and weakness are prominent disease features. Originally considered to arise from common transcriptional changes, recent analyses demonstrated that different stimuli induce muscle wasting via largely distinct mRNA and protein changes.
{"title":"Largely Distinct Post-Translational Modifications Differentiate Skeletal Muscle Wasting Caused by Cancer, Dexamethasone and Aging","authors":"Anna Stephan, Flavia A. Graca, Suresh Poudel, Yingxue Fu, Yong-Dong Wang, Myriam Labelle, Fabio Demontis","doi":"10.1002/jcsm.70220","DOIUrl":"https://doi.org/10.1002/jcsm.70220","url":null,"abstract":"Skeletal muscle wasting and weakness are prominent disease features. Originally considered to arise from common transcriptional changes, recent analyses demonstrated that different stimuli induce muscle wasting via largely distinct mRNA and protein changes.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"108 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146116164","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}
Joshua M. J. Price, Michael Macleod, Thomas Nicholson, Caitlin M. Ditchfield, Bethy Airstone, Natalie Lachlan-Jiraskova, Edward T. Davis, Kostas Tsintzas, Simon W. Jones
Sarcopenic obesity, where excess body fat coexists with reduced muscle mass and function, is becoming increasingly common in ageing populations and contributes to poor physical and metabolic health. Although adipose tissue–secreted factors are implicated in muscle decline, the specific mechanisms remain unclear. Extracellular vesicles (EVs), which carry regulatory cargo such as microRNAs (miRNAs) between cells, may play a key role in this adipose–muscle communication.
{"title":"Obesity Reprogrammes Adipose Extracellular Vesicles to Induce Muscle Atrophy via miR-150-5p-Mediated Transcriptional Silencing","authors":"Joshua M. J. Price, Michael Macleod, Thomas Nicholson, Caitlin M. Ditchfield, Bethy Airstone, Natalie Lachlan-Jiraskova, Edward T. Davis, Kostas Tsintzas, Simon W. Jones","doi":"10.1002/jcsm.70204","DOIUrl":"https://doi.org/10.1002/jcsm.70204","url":null,"abstract":"Sarcopenic obesity, where excess body fat coexists with reduced muscle mass and function, is becoming increasingly common in ageing populations and contributes to poor physical and metabolic health. Although adipose tissue–secreted factors are implicated in muscle decline, the specific mechanisms remain unclear. Extracellular vesicles (EVs), which carry regulatory cargo such as microRNAs (miRNAs) between cells, may play a key role in this adipose–muscle communication.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"9 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109888","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}
Emese Kasznár, Barbara Csendes, Dorottya Gergő, Péter Hegyi, Réka Tóth, András Fogarasi, Miklós Garami, Klementina Ocskay, Andrea Párniczky, Mahmoud Obeidat, Katalin Eszter Müller
Background Patients with inflammatory bowel disease (IBD) are often less active physically and experience impaired bone mineral density (BMD) as well as sarcopenia, which are associated with a higher risk of poor disease outcomes. Physical exercise can improve BMD and sarcopenia and may also play a role in controlling inflammation via anti‐inflammatory myokines. This study aimed to evaluate the effects of structured physical exercise on the disease activity and quality of life of patients with IBD by conducting a before‐and‐after analysis. Methods We conducted a systematic search on 16 November 2023. Studies with structured exercise interventions in patients with IBD focusing on quality of life, disease activity, body composition, muscle strength, inflammatory markers, aerobic fitness and sedentary time were included. The mean difference (MD) or the standardized MD (SMD) of the differences between the before and after values was used to measure the effect size with a 95% confidence interval (CI). Risk of bias was assessed using the MINORS tool. Results Twenty‐one studies involving 498 patients with IBD were included. Quality of life improved significantly: SMD 0.55 (CI, 0.30–0.80), particularly in the systemic subscale. Disease activity scores showed a non‐significant improvement: SMD −0.20 (CI, −0.47 to 0.07) in Crohn's disease and SMD −0.23 (CI, −0.46 to 0.00) in ulcerative colitis. Numbers of inflammatory markers and faecal calprotectin levels also improved, but not significantly. Muscle strength and aerobic fitness improved, with a significant increase in VO 2 max: SMD 1.88 (CI, 1.34–2.43). Due to the lack of available data, we were unable to conduct a statistical analysis of body composition parameters and sedentary time. Conclusion Regular physical activity improves quality of life and physical fitness of IBD patients, with potential benefits for disease activity and sarcopenia.
{"title":"Physical Activity Improves Quality of Life in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta‐Analysis","authors":"Emese Kasznár, Barbara Csendes, Dorottya Gergő, Péter Hegyi, Réka Tóth, András Fogarasi, Miklós Garami, Klementina Ocskay, Andrea Párniczky, Mahmoud Obeidat, Katalin Eszter Müller","doi":"10.1002/jcsm.70206","DOIUrl":"https://doi.org/10.1002/jcsm.70206","url":null,"abstract":"Background Patients with inflammatory bowel disease (IBD) are often less active physically and experience impaired bone mineral density (BMD) as well as sarcopenia, which are associated with a higher risk of poor disease outcomes. Physical exercise can improve BMD and sarcopenia and may also play a role in controlling inflammation via anti‐inflammatory myokines. This study aimed to evaluate the effects of structured physical exercise on the disease activity and quality of life of patients with IBD by conducting a before‐and‐after analysis. Methods We conducted a systematic search on 16 November 2023. Studies with structured exercise interventions in patients with IBD focusing on quality of life, disease activity, body composition, muscle strength, inflammatory markers, aerobic fitness and sedentary time were included. The mean difference (MD) or the standardized MD (SMD) of the differences between the before and after values was used to measure the effect size with a 95% confidence interval (CI). Risk of bias was assessed using the MINORS tool. Results Twenty‐one studies involving 498 patients with IBD were included. Quality of life improved significantly: SMD 0.55 (CI, 0.30–0.80), particularly in the systemic subscale. Disease activity scores showed a non‐significant improvement: SMD −0.20 (CI, −0.47 to 0.07) in Crohn's disease and SMD −0.23 (CI, −0.46 to 0.00) in ulcerative colitis. Numbers of inflammatory markers and faecal calprotectin levels also improved, but not significantly. Muscle strength and aerobic fitness improved, with a significant increase in VO <jats:sub>2</jats:sub> max: SMD 1.88 (CI, 1.34–2.43). Due to the lack of available data, we were unable to conduct a statistical analysis of body composition parameters and sedentary time. Conclusion Regular physical activity improves quality of life and physical fitness of IBD patients, with potential benefits for disease activity and sarcopenia.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"80 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097907","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}
Background The purpose of this study was to explore the associations of the triglyceride‐glucose (TyG) index and its clinically relevant derivatives with handgrip strength asymmetry (HGS‐A) in a nationally representative cohort of older adults in China. Methods Here, we used the data of participants aged between 45 and 80 years who were from wave 2015 of the China Health and Retirement Longitudinal Study (CHARLS). HGS asymmetry was defined as the ratio of nondominant to dominant HGS, categorized into the following four groups: 0.9–1.1 (nonasymmetry), 0.80 ≤ ratio < 0.90 or 1.10 < ratio ≤ 1.20 (mild asymmetry), 0.70 ≤ ratio < 0.80 or 1.20 < ratio ≤ 1.30 (moderate asymmetry) and ratio < 0.70 or ratio > 1.30 (severe asymmetry). Multivariable logistic regression was adopted to assess the association of TyG, TyG‐body mass index (TyG‐BMI) and TyG‐waist‐to‐height ratio (TyG‐WHtR) with HGS asymmetry. Results A total of 3521 middle‐aged and elderly individuals (mean age: 59.74 years; 47.9% male) were included, with the mean TyG of 8.733 ± 0.660, mean TyG‐BMI of 243.559 ± 31.120, mean TyG‐WHtR of 4.702 ± 0.733. The mean HGS ratio was 0.97 ± 0.16, and participants were classified into the following four groups: nonasymmetry ( n = 2174), mild asymmetry ( n = 972), moderate asymmetry ( n = 237) and severe asymmetry ( n = 138). Overall, the prevalence of HGS asymmetry was 38.26%. The prevalence of severe asymmetry increased across TyG quartiles from 3.7% to 4.5% (Q1–Q4, p = 0.018). TyG‐WHtR showed increasing prevalence of severe asymmetry from 4.9% to 5.1% across quartiles ( p = 0.042). For TyG‐BMI, it exhibited an inverse relationship with severe asymmetry prevalence decreasing from 5.3% to 2.4%. Multivariable‐adjusted models confirmed that TyG‐WHtR demonstrated the strongest effect size with Q2 and Q3 associated with significantly increased odds of asymmetry (OR = 1.507 and 1.437, respectively). TyG‐BMI showed a protective effect with higher quartiles associated with reduced odds (Q2–Q4 OR range: 0.973–0.984). Conclusions Higher levels of TyG‐WHtR and lower levels of TyG‐BMI are both associated with a higher prevalence and severity of HGS asymmetry in middle‐aged and older Chinese adults.
{"title":"Association of Triglyceride‐Glucose Index and Its Related Parameters With Handgrip Strength Asymmetry","authors":"Yuan Zhang, Yali Jing","doi":"10.1002/jcsm.70165","DOIUrl":"https://doi.org/10.1002/jcsm.70165","url":null,"abstract":"Background The purpose of this study was to explore the associations of the triglyceride‐glucose (TyG) index and its clinically relevant derivatives with handgrip strength asymmetry (HGS‐A) in a nationally representative cohort of older adults in China. Methods Here, we used the data of participants aged between 45 and 80 years who were from wave 2015 of the China Health and Retirement Longitudinal Study (CHARLS). HGS asymmetry was defined as the ratio of nondominant to dominant HGS, categorized into the following four groups: 0.9–1.1 (nonasymmetry), 0.80 ≤ ratio < 0.90 or 1.10 < ratio ≤ 1.20 (mild asymmetry), 0.70 ≤ ratio < 0.80 or 1.20 < ratio ≤ 1.30 (moderate asymmetry) and ratio < 0.70 or ratio > 1.30 (severe asymmetry). Multivariable logistic regression was adopted to assess the association of TyG, TyG‐body mass index (TyG‐BMI) and TyG‐waist‐to‐height ratio (TyG‐WHtR) with HGS asymmetry. Results A total of 3521 middle‐aged and elderly individuals (mean age: 59.74 years; 47.9% male) were included, with the mean TyG of 8.733 ± 0.660, mean TyG‐BMI of 243.559 ± 31.120, mean TyG‐WHtR of 4.702 ± 0.733. The mean HGS ratio was 0.97 ± 0.16, and participants were classified into the following four groups: nonasymmetry ( <jats:italic>n</jats:italic> = 2174), mild asymmetry ( <jats:italic>n</jats:italic> = 972), moderate asymmetry ( <jats:italic>n</jats:italic> = 237) and severe asymmetry ( <jats:italic>n</jats:italic> = 138). Overall, the prevalence of HGS asymmetry was 38.26%. The prevalence of severe asymmetry increased across TyG quartiles from 3.7% to 4.5% (Q1–Q4, <jats:italic>p</jats:italic> = 0.018). TyG‐WHtR showed increasing prevalence of severe asymmetry from 4.9% to 5.1% across quartiles ( <jats:italic>p</jats:italic> = 0.042). For TyG‐BMI, it exhibited an inverse relationship with severe asymmetry prevalence decreasing from 5.3% to 2.4%. Multivariable‐adjusted models confirmed that TyG‐WHtR demonstrated the strongest effect size with Q2 and Q3 associated with significantly increased odds of asymmetry (OR = 1.507 and 1.437, respectively). TyG‐BMI showed a protective effect with higher quartiles associated with reduced odds (Q2–Q4 OR range: 0.973–0.984). Conclusions Higher levels of TyG‐WHtR and lower levels of TyG‐BMI are both associated with a higher prevalence and severity of HGS asymmetry in middle‐aged and older Chinese adults.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"80 1","pages":""},"PeriodicalIF":8.9,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097906","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}
Mia Y Kawaida, Abigail L Tice, Samuel Alvarez, Jacob A Lackey, Benjamin Izaguirre, Qingping Yang, Lan Wei-LaPierre, Russell T Hepple, Terence E Ryan
Background: L-Kynurenine (L-Kyn), a product of tryptophan catabolism, increases with age and has been associated with reduced physical function and increased frailty in humans. Robustly expressed in skeletal muscle, kynurenine aminotransferases (KATs) degrade L-Kyn into kynurenic acid and are regulated by the transcriptional co-regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α).
Methods: The study investigated (1) if elevating L-Kyn levels via a diet intervention exacerbates an age-related decline in physical, muscle and mitochondrial functions and (2) if transgenic expression of PGC1α in skeletal muscle (MCK-PGC1α) protects against age-dependent L-Kyn associated pathology in a cohort of aging MCK-PGC1α transgenic mice and their wildtype littermates of both sexes (n = 262). Physical function was assessed longitudinally from 16 to 24 months of age using treadmill endurance capacity, grip strength, walking speed and daily physical activity. Muscle function was assessed in situ using nerve-mediated contraction of the soleus muscle. Mitochondrial energetics were assessed using high resolution respirometry and fluorescence spectroscopy.
Results: MCK-PGC1α transgenic mice had significantly higher KAT expression ~2-5-fold compared with wildtype littermates (p < 0.0001 for all isoforms). A main effect of L-Kyn diet was observed for decreasing treadmill endurance capacity and daily physical activity in male mice (p ≦ 0.002). A main effect of L-Kyn diet for decreasing maximal walking speed only was found in female mice (p = 0.037). Correspondingly, L-Kyn increased frailty prevalence in male (+17%) and female (+26%) wildtype mice (p = 0.025 and 0.0001 respectively), which was mitigated by MCK-PGC1α in both sexes. Soleus muscle strength and power were not impacted by diet or genotype in either sex (p > 0.5). Mitochondrial oxidative phosphorylation function in male and female MCK-PGC1α mice was greater than wild type mice regardless of diet (p < 0.04), which is likely driven by upregulated expression of mitochondrial biogenesis related genes.
Conclusions: We conclude that PGC1α overexpression in skeletal muscle mitigates the exacerbation of physical frailty induced by elevated circulating L-Kyn in aging mice, in part through increased skeletal muscle capacity for L-Kyn metabolism due to PGC1α-induced increase in muscle KAT expression.
{"title":"Elevating Circulating L-Kynurenine Promotes Frailty in Aging Mice.","authors":"Mia Y Kawaida, Abigail L Tice, Samuel Alvarez, Jacob A Lackey, Benjamin Izaguirre, Qingping Yang, Lan Wei-LaPierre, Russell T Hepple, Terence E Ryan","doi":"10.1002/jcsm.70214","DOIUrl":"10.1002/jcsm.70214","url":null,"abstract":"<p><strong>Background: </strong>L-Kynurenine (L-Kyn), a product of tryptophan catabolism, increases with age and has been associated with reduced physical function and increased frailty in humans. Robustly expressed in skeletal muscle, kynurenine aminotransferases (KATs) degrade L-Kyn into kynurenic acid and are regulated by the transcriptional co-regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α).</p><p><strong>Methods: </strong>The study investigated (1) if elevating L-Kyn levels via a diet intervention exacerbates an age-related decline in physical, muscle and mitochondrial functions and (2) if transgenic expression of PGC1α in skeletal muscle (MCK-PGC1α) protects against age-dependent L-Kyn associated pathology in a cohort of aging MCK-PGC1α transgenic mice and their wildtype littermates of both sexes (n = 262). Physical function was assessed longitudinally from 16 to 24 months of age using treadmill endurance capacity, grip strength, walking speed and daily physical activity. Muscle function was assessed in situ using nerve-mediated contraction of the soleus muscle. Mitochondrial energetics were assessed using high resolution respirometry and fluorescence spectroscopy.</p><p><strong>Results: </strong>MCK-PGC1α transgenic mice had significantly higher KAT expression ~2-5-fold compared with wildtype littermates (p < 0.0001 for all isoforms). A main effect of L-Kyn diet was observed for decreasing treadmill endurance capacity and daily physical activity in male mice (p ≦ 0.002). A main effect of L-Kyn diet for decreasing maximal walking speed only was found in female mice (p = 0.037). Correspondingly, L-Kyn increased frailty prevalence in male (+17%) and female (+26%) wildtype mice (p = 0.025 and 0.0001 respectively), which was mitigated by MCK-PGC1α in both sexes. Soleus muscle strength and power were not impacted by diet or genotype in either sex (p > 0.5). Mitochondrial oxidative phosphorylation function in male and female MCK-PGC1α mice was greater than wild type mice regardless of diet (p < 0.04), which is likely driven by upregulated expression of mitochondrial biogenesis related genes.</p><p><strong>Conclusions: </strong>We conclude that PGC1α overexpression in skeletal muscle mitigates the exacerbation of physical frailty induced by elevated circulating L-Kyn in aging mice, in part through increased skeletal muscle capacity for L-Kyn metabolism due to PGC1α-induced increase in muscle KAT expression.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"17 1","pages":"e70214"},"PeriodicalIF":9.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12862278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099611","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}
BACKGROUNDCachexia, characterized by severe weight loss and muscle atrophy, frequently occurs in chronic conditions such as sepsis, cancer and chemotherapy, with limited effective treatments. Despite similar clinical manifestations, the underlying mechanisms across different disease contexts remain unclear. Identifying common pathways could lead to novel therapies. This study examines the role of Toll-like receptor 4 (TLR4), which is upregulated in various cachexia models, and assesses the therapeutic potential of the TLR4-inhibiting peptide OH-CATH30 in mitigating muscle atrophy.METHODSIn vivo models using 8-week-old mice treated with lipopolysaccharide (LPS), 4T1 tumour cells and cisplatin were used to investigate common pathways in cachexia. In vitro models were established by treating C2C12 myotubes with TNF-α, 4T1 culture supernatants and cisplatin. OH-CATH30's effects on muscle atrophy were assessed by measuring myotube diameter, grip strength, muscle weight and muscle fibre cross-sectional area (CSA) via H&E staining. RNA-seq, qPCR, ELISA and Western blotting were performed to explore pathways in cachexia-induced muscle atrophy and OH-CATH30's action mechanism.RESULTSTranscriptomic analysis showed significant enrichment of inflammation and protein degradation pathways in skeletal muscle in LPS-induced sepsis, 4T1 tumour-induced cancer cachexia and cisplatin-induced cachexia models, with upregulated expression of TLR4 pathway genes such as Cd14, Tlr4 and Irak4 (p < 0.05). In myotube atrophy models induced by TNF-α, 4T1 and cisplatin, OH-CATH30 significantly increased MyHC protein levels (p < 0.05) and myotube diameter (p < 0.05). In mouse cachexia models induced by LPS, 4T1 and cisplatin, OH-CATH30 treatment significantly increased body weight (p < 0.05), muscle weight (p < 0.001), CSA (p < 0.05) and improved grip strength (p < 0.05). Transcriptomic analysis further revealed that OH-CATH30 treatment downregulated expression of inflammation and protein degradation-related genes across all cachexia models. In 4T1-treated mice, qPCR confirmed OH-CATH30 reduced mRNA levels of Il6 (p = 0.05), Mstn (p < 0.0001) and protein degradation genes such as Trim63, Fbxo32, Bnip3, Gabarapl1 and Ulk1 (p < 0.05). ELISA showed reduced serum IL-6 levels, and Western blot confirmed downregulation of atrogin1 (p < 0.05) and autophagy marker LC3II (p < 0.05) with OH-CATH30 treatment. Pharmacological inhibition of TLR4 using TAK-242 recapitulated the protective effects of OH-CATH30, with no additive benefit observed (p > 0.05).CONCLUSIONSOur findings underscore the critical role of TLR4 signalling in cachexia-associated muscle wasting across different disease contexts and demonstrate the efficacy of OH-CATH30, a TLR4 inhibitor, in alleviating muscle atrophy in various cachexia models.
{"title":"Peptide OH-CATH30 Mitigates Cachexia-Induced Muscle Atrophy via Modulation of TLR4-Associated Inflammation.","authors":"Qiquan Wang,Jian Li,Mengqi Yang,Caifen Guo,Ming Zhang,Chunping Huang,Xiang Wang,Dongqin Zhang,Lin Zeng,Hao Ke,Yunling Wen,Shengan Li,Wenhui Lee,Limin Zhao,Xinqiang Lan,Yang Xiang","doi":"10.1002/jcsm.70195","DOIUrl":"https://doi.org/10.1002/jcsm.70195","url":null,"abstract":"BACKGROUNDCachexia, characterized by severe weight loss and muscle atrophy, frequently occurs in chronic conditions such as sepsis, cancer and chemotherapy, with limited effective treatments. Despite similar clinical manifestations, the underlying mechanisms across different disease contexts remain unclear. Identifying common pathways could lead to novel therapies. This study examines the role of Toll-like receptor 4 (TLR4), which is upregulated in various cachexia models, and assesses the therapeutic potential of the TLR4-inhibiting peptide OH-CATH30 in mitigating muscle atrophy.METHODSIn vivo models using 8-week-old mice treated with lipopolysaccharide (LPS), 4T1 tumour cells and cisplatin were used to investigate common pathways in cachexia. In vitro models were established by treating C2C12 myotubes with TNF-α, 4T1 culture supernatants and cisplatin. OH-CATH30's effects on muscle atrophy were assessed by measuring myotube diameter, grip strength, muscle weight and muscle fibre cross-sectional area (CSA) via H&E staining. RNA-seq, qPCR, ELISA and Western blotting were performed to explore pathways in cachexia-induced muscle atrophy and OH-CATH30's action mechanism.RESULTSTranscriptomic analysis showed significant enrichment of inflammation and protein degradation pathways in skeletal muscle in LPS-induced sepsis, 4T1 tumour-induced cancer cachexia and cisplatin-induced cachexia models, with upregulated expression of TLR4 pathway genes such as Cd14, Tlr4 and Irak4 (p < 0.05). In myotube atrophy models induced by TNF-α, 4T1 and cisplatin, OH-CATH30 significantly increased MyHC protein levels (p < 0.05) and myotube diameter (p < 0.05). In mouse cachexia models induced by LPS, 4T1 and cisplatin, OH-CATH30 treatment significantly increased body weight (p < 0.05), muscle weight (p < 0.001), CSA (p < 0.05) and improved grip strength (p < 0.05). Transcriptomic analysis further revealed that OH-CATH30 treatment downregulated expression of inflammation and protein degradation-related genes across all cachexia models. In 4T1-treated mice, qPCR confirmed OH-CATH30 reduced mRNA levels of Il6 (p = 0.05), Mstn (p < 0.0001) and protein degradation genes such as Trim63, Fbxo32, Bnip3, Gabarapl1 and Ulk1 (p < 0.05). ELISA showed reduced serum IL-6 levels, and Western blot confirmed downregulation of atrogin1 (p < 0.05) and autophagy marker LC3II (p < 0.05) with OH-CATH30 treatment. Pharmacological inhibition of TLR4 using TAK-242 recapitulated the protective effects of OH-CATH30, with no additive benefit observed (p > 0.05).CONCLUSIONSOur findings underscore the critical role of TLR4 signalling in cachexia-associated muscle wasting across different disease contexts and demonstrate the efficacy of OH-CATH30, a TLR4 inhibitor, in alleviating muscle atrophy in various cachexia models.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"221 1","pages":"e70195"},"PeriodicalIF":8.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073070","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}
BACKGROUNDWhile the Global Leadership Initiative on Sarcopenia (GLIS) is promising to standardize sarcopenia diagnosis, its operational implementation remains largely undefined. This study aims to operationalize GLIS and evaluate its feasibility, diagnostic concordance and clinical relevance.METHODSThis three-stage, multicenter study enrolled 12 116 participants for cut-off development (mean age 58.7 years, 48.2% men) and 11 241 participants for outcome analysis (mean age 58.4 years, 49.4% men) from a national survey in China. Another 504 patients with chronic kidney disease were included for validation. We proposed the lower limb skeletal muscle mass to five-time chair stand test ratio (LFR) to assess muscle-specific strength (MSS). The GLIS conceptual framework was instantiated into six diagnostic criteria combinations using handgrip strength (HGS), appendicular skeletal muscle mass index (ASMI, estimated using a validated formula) and MSS: (1) all three criteria being low (HAM); (2) low HGS plus low ASMI (HA); (3) low MSS (M); (4) low HGS plus low ASMI, or low MSS (HA/M); (5) low HGS or low MSS (H/M); and (6) low ASMI or low MSS (A/M). Intercriteria concordance of these definitions, relevance with functional outcomes and their concordance with the Asian Working Group for Sarcopenia 2019 (AWGS) criteria were evaluated.RESULTSLow MSS cut-offs were established as < 0.74 for men and < 0.47 for women. Sarcopenia prevalence varied significantly across different definitions: 1055 (8.7%, AWGS), 405 (3.3%, HAM), 619 (5.1%, HA), 2409 (19.9%, M), 2623 (21.6%, HA/M), 3184 (26.3%, H/M) and 3868 (31.9%, A/M). The HA method showed the highest concordance with the AWGS (accuracy = 0.964, κ = 0.722, sensitivity = 1.000, specificity = 0.962). The H/M method demonstrated the strongest correlation with functional outcomes and optimal diagnostic performance (AUCs range from 0.566 to 0.729), with superior discrimination for impaired activities of daily living (ADL), other functional measures and global functional scores (p < 0.05). All methods independently predicted poor functional outcomes. External validation in CKD showed that the H/M method was either superior or comparable to other methods in identifying disabilities (e.g., predicting functional measures, AUC = 0.627, 95% CI = 0.582-0.672).CONCLUSIONSThis study establishes an operational framework for GLIS using nationally representative data from China and validates its effectiveness in a clinical setting. LFR proves to be a feasible method for assessing MSS. The H/M method effectively captures functional impairment, which may serve as a useful approach for diagnosing sarcopenia. These findings provide actionable benchmarks for sarcopenia research and clinical practice, potentially informing more refined prevention and intervention strategies.
{"title":"Operationalizing the Global Leadership Initiative in Sarcopenia: Muscle-Specific Strength, Optimal Criteria and Clinical Relevance.","authors":"Liangyu Yin,Yu Cao,Mengda Tang,Hanping Shi,Hua Jiang,Jinghong Zhao","doi":"10.1002/jcsm.70222","DOIUrl":"https://doi.org/10.1002/jcsm.70222","url":null,"abstract":"BACKGROUNDWhile the Global Leadership Initiative on Sarcopenia (GLIS) is promising to standardize sarcopenia diagnosis, its operational implementation remains largely undefined. This study aims to operationalize GLIS and evaluate its feasibility, diagnostic concordance and clinical relevance.METHODSThis three-stage, multicenter study enrolled 12 116 participants for cut-off development (mean age 58.7 years, 48.2% men) and 11 241 participants for outcome analysis (mean age 58.4 years, 49.4% men) from a national survey in China. Another 504 patients with chronic kidney disease were included for validation. We proposed the lower limb skeletal muscle mass to five-time chair stand test ratio (LFR) to assess muscle-specific strength (MSS). The GLIS conceptual framework was instantiated into six diagnostic criteria combinations using handgrip strength (HGS), appendicular skeletal muscle mass index (ASMI, estimated using a validated formula) and MSS: (1) all three criteria being low (HAM); (2) low HGS plus low ASMI (HA); (3) low MSS (M); (4) low HGS plus low ASMI, or low MSS (HA/M); (5) low HGS or low MSS (H/M); and (6) low ASMI or low MSS (A/M). Intercriteria concordance of these definitions, relevance with functional outcomes and their concordance with the Asian Working Group for Sarcopenia 2019 (AWGS) criteria were evaluated.RESULTSLow MSS cut-offs were established as < 0.74 for men and < 0.47 for women. Sarcopenia prevalence varied significantly across different definitions: 1055 (8.7%, AWGS), 405 (3.3%, HAM), 619 (5.1%, HA), 2409 (19.9%, M), 2623 (21.6%, HA/M), 3184 (26.3%, H/M) and 3868 (31.9%, A/M). The HA method showed the highest concordance with the AWGS (accuracy = 0.964, κ = 0.722, sensitivity = 1.000, specificity = 0.962). The H/M method demonstrated the strongest correlation with functional outcomes and optimal diagnostic performance (AUCs range from 0.566 to 0.729), with superior discrimination for impaired activities of daily living (ADL), other functional measures and global functional scores (p < 0.05). All methods independently predicted poor functional outcomes. External validation in CKD showed that the H/M method was either superior or comparable to other methods in identifying disabilities (e.g., predicting functional measures, AUC = 0.627, 95% CI = 0.582-0.672).CONCLUSIONSThis study establishes an operational framework for GLIS using nationally representative data from China and validates its effectiveness in a clinical setting. LFR proves to be a feasible method for assessing MSS. The H/M method effectively captures functional impairment, which may serve as a useful approach for diagnosing sarcopenia. These findings provide actionable benchmarks for sarcopenia research and clinical practice, potentially informing more refined prevention and intervention strategies.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"2 1","pages":"e70222"},"PeriodicalIF":8.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089025","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}
BACKGROUNDSarcopenia and delirium are two highly prevalent clinical syndromes among hospitalized elderly patients, both independently associated with adverse outcomes such as increased risk of falls, disability and mortality. Although a correlation between sarcopenia and delirium has been previously reported, past studies have often relied on less reliable surrogate markers for sarcopenia, leading to potential inaccuracies in diagnosis and assessment. This study aims to address these limitations by utilizing a more precise and reliable diagnostic tool for sarcopenia, specifically, muscle ultrasound (US) to measure the quadriceps femoris muscle and its pennation angle, to accurately evaluate the correlation between sarcopenia and delirium in acutely admitted geriatric patients.METHODSWe used muscle US to measure sarcopenia with reliable markers, specifically the Ultrasound Sarcopenia Index (USSI). This index evaluates the ratio between vastus lateralis thickness and fascicle length (L/f), offering a detailed view of muscle structure that is not affected by sex or body size.RESULTSIn 194 patients (mean age 86.5 years; 46.4% women; 81.4% with delirium), USSI correlated with MMSE (r = -0.619, p < 0.001), 4AT (r = 0.844, p < 0.001), ADL/IADL (r ≈ -0.32, p < 0.001), BMI, grip strength and muscle thickness (all p < 0.001). Women had higher USSI and worse cognitive/frailty scores; patterns were consistent across sexes.CONCLUSIONOur findings are expected to support the implementation of more targeted assessments and interventions, emphasizing the crucial role of accurate sarcopenia diagnosis in improving outcomes for elderly patients and highlighting its interconnectedness with delirium in comprehensive geriatric care.
背景：骨骼肌减少症和谵妄是住院老年患者中两种非常普遍的临床综合征，两者均与不良结局（如跌倒、残疾和死亡风险增加）独立相关。虽然以前有报道过肌少症和谵妄之间的相关性，但过去的研究往往依赖于不太可靠的肌少症替代标志物，导致诊断和评估的潜在不准确性。本研究旨在通过使用更精确可靠的肌少症诊断工具来解决这些局限性，特别是肌肉超声（US）测量股四头肌及其夹角，以准确评估急性入院老年患者肌少症与谵妄之间的相关性。方法我们使用肌肉US测量肌少症，并使用可靠的标记物，特别是超声肌少症指数（USSI）。该指数评估股外侧肌厚度与肌束长度之间的比率（L/f），提供不受性别或体型影响的肌肉结构的详细视图。结果194例患者（平均年龄86.5岁，女性占46.4%，谵妄占81.4%），USSI与MMSE （r = -0.619, p < 0.001）、4AT （r = 0.844, p < 0.001）、ADL/IADL （r≈-0.32,p < 0.001）、BMI、握力、肌厚相关（均p < 0.001）。女性的USSI较高，认知/虚弱得分较差；这种模式在两性之间是一致的。结论：我们的研究结果有望支持实施更有针对性的评估和干预措施，强调准确的肌肉减少症诊断在改善老年患者预后方面的关键作用，并强调其与谵妄在老年综合护理中的相互联系。
{"title":"The Clinical Impact of Sarcopenia and Delirium in Hospitalized Elderly Patients: An Analysis Using Muscle Ultrasound.","authors":"Thomas Fraccalini,Laura Santos Ribeiro,Andrea Trogolo,Beatrice Tarozzo,Valerio Piras,Julia Michelin Vecchini,Rouslan Senkeev,Oksana Sukhova,Luciano Cardinale,Giuseppe Maina,Salvatore Di Gioia,Davide Minniti,Truce Massimiliano,Binello Elisa,Finiguerra Ivana,Roberta Vacchelli,Fustamante Elda,Romano Gianfranco,Turja Reald,Valerio Ricci,Alessandro Maraschi,Thomas Roberts,Giovanni Volpicelli","doi":"10.1002/jcsm.70202","DOIUrl":"https://doi.org/10.1002/jcsm.70202","url":null,"abstract":"BACKGROUNDSarcopenia and delirium are two highly prevalent clinical syndromes among hospitalized elderly patients, both independently associated with adverse outcomes such as increased risk of falls, disability and mortality. Although a correlation between sarcopenia and delirium has been previously reported, past studies have often relied on less reliable surrogate markers for sarcopenia, leading to potential inaccuracies in diagnosis and assessment. This study aims to address these limitations by utilizing a more precise and reliable diagnostic tool for sarcopenia, specifically, muscle ultrasound (US) to measure the quadriceps femoris muscle and its pennation angle, to accurately evaluate the correlation between sarcopenia and delirium in acutely admitted geriatric patients.METHODSWe used muscle US to measure sarcopenia with reliable markers, specifically the Ultrasound Sarcopenia Index (USSI). This index evaluates the ratio between vastus lateralis thickness and fascicle length (L/f), offering a detailed view of muscle structure that is not affected by sex or body size.RESULTSIn 194 patients (mean age 86.5 years; 46.4% women; 81.4% with delirium), USSI correlated with MMSE (r = -0.619, p < 0.001), 4AT (r = 0.844, p < 0.001), ADL/IADL (r ≈ -0.32, p < 0.001), BMI, grip strength and muscle thickness (all p < 0.001). Women had higher USSI and worse cognitive/frailty scores; patterns were consistent across sexes.CONCLUSIONOur findings are expected to support the implementation of more targeted assessments and interventions, emphasizing the crucial role of accurate sarcopenia diagnosis in improving outcomes for elderly patients and highlighting its interconnectedness with delirium in comprehensive geriatric care.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"43 1","pages":"e70202"},"PeriodicalIF":8.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069959","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}
Woo Yong Park,Beomsu Kim,Gahee Song,Sang Hee Kim,Jin-Hyung Kim,Ja Yeon Park,Se Jin Jung,Wenjun Jiao,Jisoo Han,Taekyoung Kong,Kwang Seok Ahn,Hyun Jeong Kwak,Jae-Young Um
BACKGROUNDCancer cachexia is a syndrome characterized by significant weight loss, particularly of adipose tissue, which negatively impacts patient survival. Pharmacological approaches to prevent this abnormal fat reduction remain poorly defined. This study investigated the potential of ellagic acid (EA) to mitigate cancer-induced fat loss.METHODSIn vitro, 3T3-L1 adipocytes were exposed to 50% conditioned medium (CM) from CT26 colon cancer cells to mimic cachectic conditions. The effects of EA on lipid accumulation and adipogenesis-related markers (PPARγ and RXRβ) were analysed. The mechanism was validated using molecular docking and siRNA-mediated gene silencing. In vivo, a cachexia mouse model was established by subcutaneous injection of CT26 cells into BALB/c mice. Mice were orally administered EA at dose of 10, 20 and 40 mg/kg, respectively (n = 7 per group) for 14 days to evaluate its protective effects.RESULTSIn 3T3-L1 cells, the 50% CM-treatment reduced lipid accumulation by 14% (p < 0.05) and downregulated PPARγ (p < 0.05) and RXRβ (p < 0.01) expression. The EA treatment restored diminished lipid levels and rescued downregulated the expression of PPARγ (p < 0.05) and RXRβ (p < 0.01). This pro-adipogenic effect was abolished by siRNA-mediated inhibition of RXRβ. In the cachexia mouse model, EA treatment significantly improved physical performance and body composition. Specifically, EA enhanced grip strength by 1.32-fold (10 mg/kg, p < 0.0001) and 1.24-fold (20 mg/kg, p < 0.001), increased the inguinal white adipose tissue (iWAT) mass by 59.8% (10 mg/kg, p < 0.01), and 56.1% (20 mg/kg, p < 0.05), and was accompanied by a significant increase in the tumour-free body weight of 6.4% (10 mg/kg, p < 0.05), and 5.6% (20 mg/kg, p < 0.01) compared to cachectic mice. EA treatment did not affect tumour growth. It increased the adipogenesis-related protein expression of C/EBPα (2.1-fold, p < 0.05), PPARγ (1.5-fold, p < 0.05) and SREBP1 (1.5-fold, p < 0.05) in the iWAT. The EA treatment enhanced the nuclear localization index of RXRβ in the iWAT by 0.51 (10 mg/kg, 1.9-fold, p < 0.05) and 0.46 (20 mg/kg, 1.7-fold, p < 0.05) compared to cachectic mice.CONCLUSIONSEA mitigates cancer cachexia-induced fat loss by the activation of the RXRβ-PPARγ pathway. These findings present EA as a potential pharmacological agent to improve the abnormal fat reduction and muscle dysfunction associated with cachexia.
癌症恶病质是一种以显著的体重减轻为特征的综合征，尤其是脂肪组织的体重减轻，这对患者的生存产生了负面影响。预防这种异常脂肪减少的药理学方法仍然不明确。这项研究调查了鞣花酸（EA）减轻癌症引起的脂肪减少的潜力。方法体外将3T3-L1脂肪细胞暴露于CT26结肠癌细胞50%条件培养基（CM）中，模拟恶病质条件。分析了EA对脂质积累和脂肪生成相关标志物（PPARγ和RXRβ）的影响。通过分子对接和sirna介导的基因沉默验证了其机制。在体内，通过皮下注射CT26细胞建立BALB/c小鼠恶病质模型。小鼠分别以10、20、40 mg/kg的剂量（每组7只）口服EA，观察其对小鼠的保护作用。结果在3T3-L1细胞中，50% cm处理可使脂质积累减少14% (p < 0.05)，下调PPARγ (p < 0.05)和RXRβ (p < 0.01)的表达。EA治疗恢复了降低的脂质水平，挽救了下调的PPARγ和RXRβ的表达（p < 0.05）。这种促脂肪作用被sirna介导的RXRβ抑制所消除。在恶病质小鼠模型中，EA治疗显著改善了身体性能和身体成分。其中，EA可使小鼠握力分别提高1.32倍（10 mg/kg, p < 0.0001）和1.24倍（20 mg/kg, p < 0.001），使腹股沟白色脂肪组织（iWAT）质量分别提高59.8% （10 mg/kg, p < 0.01）和56.1% (20 mg/kg, p < 0.05)，使小鼠无瘤体重分别显著增加6.4% （10 mg/kg, p < 0.05）和5.6% （20 mg/kg, p < 0.01）。EA治疗不影响肿瘤生长。增加了脂肪相关蛋白C/EBPα（2.1倍，p < 0.05）、PPARγ（1.5倍，p < 0.05）和SREBP1（1.5倍，p < 0.05）在iWAT中的表达。EA处理可使iWAT中RXRβ的核定位指数分别提高0.51 （10 mg/kg， 1.9倍，p < 0.05）和0.46 （20 mg/kg， 1.7倍，p < 0.05）。结论sea通过激活RXRβ-PPARγ通路减轻癌症恶病质诱导的脂肪损失。这些发现表明EA是一种潜在的药物，可以改善与恶病质相关的异常脂肪减少和肌肉功能障碍。
{"title":"Ellagic Acid Alleviates Abnormal Fat Reduction by Activating the RXRβ-PPARγ Pathways in a CT26 Tumour-Induced Cachexia Mouse Model.","authors":"Woo Yong Park,Beomsu Kim,Gahee Song,Sang Hee Kim,Jin-Hyung Kim,Ja Yeon Park,Se Jin Jung,Wenjun Jiao,Jisoo Han,Taekyoung Kong,Kwang Seok Ahn,Hyun Jeong Kwak,Jae-Young Um","doi":"10.1002/jcsm.70176","DOIUrl":"https://doi.org/10.1002/jcsm.70176","url":null,"abstract":"BACKGROUNDCancer cachexia is a syndrome characterized by significant weight loss, particularly of adipose tissue, which negatively impacts patient survival. Pharmacological approaches to prevent this abnormal fat reduction remain poorly defined. This study investigated the potential of ellagic acid (EA) to mitigate cancer-induced fat loss.METHODSIn vitro, 3T3-L1 adipocytes were exposed to 50% conditioned medium (CM) from CT26 colon cancer cells to mimic cachectic conditions. The effects of EA on lipid accumulation and adipogenesis-related markers (PPARγ and RXRβ) were analysed. The mechanism was validated using molecular docking and siRNA-mediated gene silencing. In vivo, a cachexia mouse model was established by subcutaneous injection of CT26 cells into BALB/c mice. Mice were orally administered EA at dose of 10, 20 and 40 mg/kg, respectively (n = 7 per group) for 14 days to evaluate its protective effects.RESULTSIn 3T3-L1 cells, the 50% CM-treatment reduced lipid accumulation by 14% (p < 0.05) and downregulated PPARγ (p < 0.05) and RXRβ (p < 0.01) expression. The EA treatment restored diminished lipid levels and rescued downregulated the expression of PPARγ (p < 0.05) and RXRβ (p < 0.01). This pro-adipogenic effect was abolished by siRNA-mediated inhibition of RXRβ. In the cachexia mouse model, EA treatment significantly improved physical performance and body composition. Specifically, EA enhanced grip strength by 1.32-fold (10 mg/kg, p < 0.0001) and 1.24-fold (20 mg/kg, p < 0.001), increased the inguinal white adipose tissue (iWAT) mass by 59.8% (10 mg/kg, p < 0.01), and 56.1% (20 mg/kg, p < 0.05), and was accompanied by a significant increase in the tumour-free body weight of 6.4% (10 mg/kg, p < 0.05), and 5.6% (20 mg/kg, p < 0.01) compared to cachectic mice. EA treatment did not affect tumour growth. It increased the adipogenesis-related protein expression of C/EBPα (2.1-fold, p < 0.05), PPARγ (1.5-fold, p < 0.05) and SREBP1 (1.5-fold, p < 0.05) in the iWAT. The EA treatment enhanced the nuclear localization index of RXRβ in the iWAT by 0.51 (10 mg/kg, 1.9-fold, p < 0.05) and 0.46 (20 mg/kg, 1.7-fold, p < 0.05) compared to cachectic mice.CONCLUSIONSEA mitigates cancer cachexia-induced fat loss by the activation of the RXRβ-PPARγ pathway. These findings present EA as a potential pharmacological agent to improve the abnormal fat reduction and muscle dysfunction associated with cachexia.","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"7 1","pages":"e70176"},"PeriodicalIF":8.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056816","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}
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