Leo Delaire, Aymeric Courtay-Breuil, Joannès Humblot, Hubert Vidal, Marc Bonnefoy, Emmanuelle Meugnier
<div> <section> <h3> Background</h3> <p>Resistance training (RT) is the first-line treatment to improve sarcopenia features. However, increasing muscle mass with RT remains challenging and displays inconsistent results. Manipulating training variables may present a novel approach to improve muscle mass gain in sarcopenic individuals. The present study aimed to measure the effectiveness of RT alone on muscle mass outcomes in older adults with sarcopenia and determine the influence of RT variables on muscle mass improvement.</p> </section> <section> <h3> Method</h3> <p>We conducted a systematic review according to PRISMA standards to gather studies that conducted a supervised RT without nutritional intervention in sarcopenia-diagnosed older adults with a muscle mass outcome versus a control group. A search strategy was performed on PubMed, Medline, Cochrane and Google Scholar in the last 14 years, from the publication of the first agreement on the diagnosis (EWGSOP, 2010). Along with sample characteristics, we extracted and analysed the following training variables: frequency (number of sessions per week), intensity (in rating perceived effort and in % of the one repetition maximal load), duration (weeks), volume (number of sets per week), periodization (yes/no) and muscle failure (yes/no). First, we standardized the outcome with Hedge's <i>g</i> and pooled the effect size (ES) of each study in a univariate meta-analysis adjusted for risk of bias. Then, we performed training composition comparisons between ‘effective interventions’ and ‘ineffective interventions’, which were previously classified based on the 95% confidence interval (CI) effect size. Finally, relevant variables were regressed as moderators of the weighted ES in a mixed-effects model.</p> </section> <section> <h3> Results</h3> <p>A total of 14 studies representing 528 individuals (73.1 ± 6.6 years, 385 women [73%] and 143 men [27%]) were included for analysis. A significant effect of RT to improve muscle mass was found with a small weighted ES estimate (<i>g</i> = 0.38 [0.18; 0.58] 95% CI, <i>p</i> ≤ 0.001). There was no publication bias across studies (<i>p</i> = 0.7). ‘Ineffective interventions’ included significantly older individuals (<i>p</i> ≤ 0.01). Training composition was homogenous between the groups. The final model showed that age was the only significant moderator of the ES (estimate = −0.06 [−0.08; −0.03] 95% CI, <i>p</i> ≤ 0.001).</p> </section> <section> <h3> Conclusion</h3> <p>In sarcopenic older adults, designing an evidence-based RT induces significant gains in musc
{"title":"Influence of Resistance Training Variables to Improve Muscle Mass Outcomes in Sarcopenia: A Systematic Review With Meta-Regressions","authors":"Leo Delaire, Aymeric Courtay-Breuil, Joannès Humblot, Hubert Vidal, Marc Bonnefoy, Emmanuelle Meugnier","doi":"10.1002/jcsm.70162","DOIUrl":"10.1002/jcsm.70162","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Resistance training (RT) is the first-line treatment to improve sarcopenia features. However, increasing muscle mass with RT remains challenging and displays inconsistent results. Manipulating training variables may present a novel approach to improve muscle mass gain in sarcopenic individuals. The present study aimed to measure the effectiveness of RT alone on muscle mass outcomes in older adults with sarcopenia and determine the influence of RT variables on muscle mass improvement.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>We conducted a systematic review according to PRISMA standards to gather studies that conducted a supervised RT without nutritional intervention in sarcopenia-diagnosed older adults with a muscle mass outcome versus a control group. A search strategy was performed on PubMed, Medline, Cochrane and Google Scholar in the last 14 years, from the publication of the first agreement on the diagnosis (EWGSOP, 2010). Along with sample characteristics, we extracted and analysed the following training variables: frequency (number of sessions per week), intensity (in rating perceived effort and in % of the one repetition maximal load), duration (weeks), volume (number of sets per week), periodization (yes/no) and muscle failure (yes/no). First, we standardized the outcome with Hedge's <i>g</i> and pooled the effect size (ES) of each study in a univariate meta-analysis adjusted for risk of bias. Then, we performed training composition comparisons between ‘effective interventions’ and ‘ineffective interventions’, which were previously classified based on the 95% confidence interval (CI) effect size. Finally, relevant variables were regressed as moderators of the weighted ES in a mixed-effects model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 14 studies representing 528 individuals (73.1 ± 6.6 years, 385 women [73%] and 143 men [27%]) were included for analysis. A significant effect of RT to improve muscle mass was found with a small weighted ES estimate (<i>g</i> = 0.38 [0.18; 0.58] 95% CI, <i>p</i> ≤ 0.001). There was no publication bias across studies (<i>p</i> = 0.7). ‘Ineffective interventions’ included significantly older individuals (<i>p</i> ≤ 0.01). Training composition was homogenous between the groups. The final model showed that age was the only significant moderator of the ES (estimate = −0.06 [−0.08; −0.03] 95% CI, <i>p</i> ≤ 0.001).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In sarcopenic older adults, designing an evidence-based RT induces significant gains in musc","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70162","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710802","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}
Caroline Lauwers, Wouter Vankrunkelsven, Sarah Derde, Sarah Vander Perre, Inge Derese, Lies Pauwels, Ilse Vanhorebeek, Louis Libbrecht, Pieter Vermeersch, Jan Gunst, Greet Van den Berghe, Michael P. Casaer, Lies Langouche
<div> <section> <h3> Background</h3> <p>Suppression of the peroxisome proliferator-activated receptor alpha (PPARα) has been related to poor outcomes in sepsis and may compromise ketogenesis during critical illness. Infusion of 3-hydroxybutyrate (3HB) was shown to attenuate muscle weakness in septic mice. We hypothesise that endogenous ketogenesis induced by pharmacological PPARα activation, either alone or combined with ketogenic nutrition, is safe and can also mitigate muscle weakness in septic mice.</p> </section> <section> <h3> Methods</h3> <p>In a fluid-resuscitated, antibiotic-treated mouse model of prolonged sepsis, we first (Study 1) assessed the safety and effectiveness (impact on ketosis and muscle weakness) of the PPARα agonist pemafibrate (1 mg/kg/d, <i>n</i> = 16), versus placebo (<i>n</i> = 15) combined with standard balanced parenteral nutrition (PN), composed of glucose, amino acids and long-chain triglycerides (LCT) (balanced-TPN). We subsequently (Study 2) evaluated the impact of pemafibrate combined with four types of PN on ketosis and muscle weakness: balanced-TPN (<i>n</i> = 18), TPN with extra LCTs (TPN + LCT, n = 18), low-dose pure LCT emulsion (Low-LCT, <i>n</i> = 16) and high-dose pure LCT emulsion (High-LCT <i>n</i> = 18). Carbohydrates and amino acids were omitted in the pure LCT groups. Healthy control mice (HC, <i>n</i> = 19) served as controls. Ex vivo muscle force was measured as the primary outcome. Metabolic, inflammatory and microstructural parameters were assessed on plasma and in muscle and liver tissue by targeted metabolomics, gene expression analysis, biochemical and metabolite assays and histological assessment.</p> </section> <section> <h3> Results</h3> <p>Pemafibrate treatment with balanced-TPN upregulated hepatic gene expression of PPARα (<i>Ppara</i>) and its downstream genes (<i>Cd36</i>, <i>Cpt1a</i>, <i>Atgl</i>, <i>Acadl, Hadha, Acox1,</i> and <i>Hmgcs2</i>) (<i>p</i> < 0.0001) and was well tolerated. However, pemafibrate treatment with the use of balanced-TPN administration did not induce detectable ketosis or improve muscle weakness. In combination with pemafibrate, TPN + LCT also did not induce ketosis, nor did it affect muscle weakness. In contrast, 3-hydroxybutyrate plasma concentrations increased with High-LCT (95-fold) and Low-LCT (10-fold) (<i>p</i> < 0.0001) in combination with pemafibrate, yet muscle force declined further (High-LCT 25.0%, Low-LCT 10.7% of HC, <i>p</i> < 0.0001). Blood glucose was lowered with pure High-LCT and Low-LCT (High-LCT 86.9%, Low-LCT 55.1% of TPN, <i>p</i> < 0.05), while plasma lipids and LC-carnitines were increased (<i>p</i> < 0.0001). Markers of h
背景：过氧化物酶体增殖物激活受体α (PPARα)的抑制与脓毒症的不良预后有关，并可能损害危重疾病期间的生酮作用。3-羟基丁酸（3HB）输注可减轻脓毒症小鼠的肌肉无力。我们假设通过药理激活PPARα诱导的内源性生酮，无论是单独还是联合生酮营养，都是安全的，并且还可以减轻脓毒症小鼠的肌肉无力。方法在液体复苏、抗生素治疗的长期脓毒症小鼠模型中，我们首先（研究1）评估了PPARα受体拮抗剂pemafibrate （1mg /kg/d, n = 16）与安慰剂（n = 15）联合由葡萄糖、氨基酸和长链甘油三酯（LCT）组成的标准平衡肠外营养（PN）的安全性和有效性（对酮症和肌肉无力的影响）。我们随后（研究2）评估了培马菲特联合四种类型的PN对酮症和肌肉无力的影响：平衡型TPN (n = 18)， TPN加额外LCT (TPN + LCT, n = 18)，低剂量纯LCT乳剂（Low-LCT, n = 16）和高剂量纯LCT乳剂（High-LCT, n = 18）。纯LCT组不含碳水化合物和氨基酸。健康小鼠（HC, n = 19）作为对照组。体外肌肉力作为主要观察指标。通过靶向代谢组学、基因表达分析、生化和代谢物分析以及组织学评估，评估血浆、肌肉和肝组织的代谢、炎症和显微结构参数。结果经平衡tpn治疗后，Ppara α (Ppara)及其下游基因（Cd36、Cpt1a、Atgl、Acadl、Hadha、Acox1、Hmgcs2）的肝脏基因表达上调（p < 0.0001），且耐受性良好。然而，使用平衡tpn给药的压脉颤动治疗并没有诱导可检测到的酮症或改善肌肉无力。TPN + LCT与培纤颤联合使用，也不会引起酮症，也不会影响肌肉无力。相比之下，3-羟基丁酸盐血浆浓度随着高lct组（95倍）和低lct组（10倍）联合帕玛菲特组（p < 0.0001）而增加，但肌肉力量进一步下降（高lct组25.0%，低lct组10.7%,p < 0.0001）。纯高lct和低lct组血糖降低（高lct占TPN的86.9%，低lct占55.1%,p < 0.05），血脂和lc -肉毒碱升高（p < 0.0001）。高lct和低lct组肝脏蛋白质分解代谢标志物上调（p < 0.007），而肌肉糖酵解中间体（p < 0.0001）和ATP水平（p < 0.0001）减少。结论在脓毒症小鼠中，pembrofiate联合平衡型TPN或富脂型TPN可诱导PPARα活化，但不会导致酮症，也不会影响肌肉无力。pemafbrate联合纯LCTs诱导脓毒症酮症，但加重肌肉无力，可能由肌肉生物能量衰竭解释。
{"title":"Ketogenic Nutrition in Combination With PPARα Activation Induced Metabolic Failure and Exacerbated Muscle Weakness in Septic Mice","authors":"Caroline Lauwers, Wouter Vankrunkelsven, Sarah Derde, Sarah Vander Perre, Inge Derese, Lies Pauwels, Ilse Vanhorebeek, Louis Libbrecht, Pieter Vermeersch, Jan Gunst, Greet Van den Berghe, Michael P. Casaer, Lies Langouche","doi":"10.1002/jcsm.70156","DOIUrl":"10.1002/jcsm.70156","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Suppression of the peroxisome proliferator-activated receptor alpha (PPARα) has been related to poor outcomes in sepsis and may compromise ketogenesis during critical illness. Infusion of 3-hydroxybutyrate (3HB) was shown to attenuate muscle weakness in septic mice. We hypothesise that endogenous ketogenesis induced by pharmacological PPARα activation, either alone or combined with ketogenic nutrition, is safe and can also mitigate muscle weakness in septic mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In a fluid-resuscitated, antibiotic-treated mouse model of prolonged sepsis, we first (Study 1) assessed the safety and effectiveness (impact on ketosis and muscle weakness) of the PPARα agonist pemafibrate (1 mg/kg/d, <i>n</i> = 16), versus placebo (<i>n</i> = 15) combined with standard balanced parenteral nutrition (PN), composed of glucose, amino acids and long-chain triglycerides (LCT) (balanced-TPN). We subsequently (Study 2) evaluated the impact of pemafibrate combined with four types of PN on ketosis and muscle weakness: balanced-TPN (<i>n</i> = 18), TPN with extra LCTs (TPN + LCT, n = 18), low-dose pure LCT emulsion (Low-LCT, <i>n</i> = 16) and high-dose pure LCT emulsion (High-LCT <i>n</i> = 18). Carbohydrates and amino acids were omitted in the pure LCT groups. Healthy control mice (HC, <i>n</i> = 19) served as controls. Ex vivo muscle force was measured as the primary outcome. Metabolic, inflammatory and microstructural parameters were assessed on plasma and in muscle and liver tissue by targeted metabolomics, gene expression analysis, biochemical and metabolite assays and histological assessment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Pemafibrate treatment with balanced-TPN upregulated hepatic gene expression of PPARα (<i>Ppara</i>) and its downstream genes (<i>Cd36</i>, <i>Cpt1a</i>, <i>Atgl</i>, <i>Acadl, Hadha, Acox1,</i> and <i>Hmgcs2</i>) (<i>p</i> < 0.0001) and was well tolerated. However, pemafibrate treatment with the use of balanced-TPN administration did not induce detectable ketosis or improve muscle weakness. In combination with pemafibrate, TPN + LCT also did not induce ketosis, nor did it affect muscle weakness. In contrast, 3-hydroxybutyrate plasma concentrations increased with High-LCT (95-fold) and Low-LCT (10-fold) (<i>p</i> < 0.0001) in combination with pemafibrate, yet muscle force declined further (High-LCT 25.0%, Low-LCT 10.7% of HC, <i>p</i> < 0.0001). Blood glucose was lowered with pure High-LCT and Low-LCT (High-LCT 86.9%, Low-LCT 55.1% of TPN, <i>p</i> < 0.05), while plasma lipids and LC-carnitines were increased (<i>p</i> < 0.0001). Markers of h","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70156","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710804","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}
<div> <section> <h3> Background</h3> <p>Chronic obstructive pulmonary disease (COPD) is frequently associated with cachexia, leading to poor prognoses and reduced quality of life. However, the mechanisms underlying adipose tissue atrophy, its pathological significance and its interaction with skeletal muscle remain poorly understood. We hypothesised that adipose tissue atrophy precedes muscle wasting in COPD-associated cachexia, and muscle atrophy progresses through adipose–muscle crosstalk.</p> </section> <section> <h3> Methods</h3> <p>We analysed chest computed tomography scans of 185 patients with COPD to quantify the cross-sectional areas of the pectoralis muscle (PM), subcutaneous adipose tissue (SAT) and epicardial adipose tissue (EAT), and the percentage of low attenuation area (LAA%) as an index of emphysema. To elucidate the pathophysiological mechanisms underlying cachexia in COPD, we performed histological and molecular analyses of the lung, muscle and adipose tissues over time in a cigarette smoke–induced emphysema mouse model. Further, we used an in vitro culture system of differentiated adipocytes (3T3-L1) and myotubes (C2C12) to study the effects of cigarette smoke extract (CSE) on adipose–muscle interaction.</p> </section> <section> <h3> Results</h3> <p>In patients with COPD, the areas of PM, SAT and EAT all demonstrated significant negative correlations with LAA%; notably, PM and EAT were independently associated with the extent of emphysematous changes. In the smoke-exposed murine model, adipose tissue atrophy was observed after 1 month of exposure, accompanied by increased expressions of IL-6 and IL-1β, macrophage infiltration and the upregulation of the lipolytic enzymes ATGL and HSL. The adipose atrophy had further progressed after 3 months of exposure, and the high expression of UCP1 was sustained, which suggested the browning of adipose tissue. Conversely, muscle atrophy was not evident at 1 month but became apparent after 3 months, coinciding with emphysema development. This was associated with the downregulation of the myogenic markers MyoD and Myogenin and the upregulation of the muscle degradation marker Atrogin-1. In vitro experiments revealed that CSE exposure reduced lipid droplet content and induced IL-6 and IL-1β expressions in adipocytes. Conditioned media from CSE-treated adipocytes triggered myotube atrophy and downregulated MyoD and Myogenin but upregulated Atrogin-1.</p> </section> <section> <h3> Conclusions</h3> <p>Our findings indicate that cigarette smoke-induced adipose tissue atrophy precedes muscle wasting
{"title":"Adipose–Muscle Crosstalk in COPD Cachexia: Early Adipose Atrophy Drives Subsequent Muscle Wasting","authors":"Takashi Shimada, Shotaro Chubachi, Keisuke Nishikawa, Tetsuya Arai, Hideto Iizuka, Shiro Otake, Kaori Sakurai, Junko Hamamoto, Mamoru Sasaki, Tomoki Maetani, Naoya Tanabe, Katsunori Masaki, Hiroki Kabata, Jun Miyata, Yoshitake Yamada, Masahiro Jinzaki, Hidetoshi Nakamura, Koichiro Asano, Koichi Fukunaga","doi":"10.1002/jcsm.70154","DOIUrl":"10.1002/jcsm.70154","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Chronic obstructive pulmonary disease (COPD) is frequently associated with cachexia, leading to poor prognoses and reduced quality of life. However, the mechanisms underlying adipose tissue atrophy, its pathological significance and its interaction with skeletal muscle remain poorly understood. We hypothesised that adipose tissue atrophy precedes muscle wasting in COPD-associated cachexia, and muscle atrophy progresses through adipose–muscle crosstalk.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analysed chest computed tomography scans of 185 patients with COPD to quantify the cross-sectional areas of the pectoralis muscle (PM), subcutaneous adipose tissue (SAT) and epicardial adipose tissue (EAT), and the percentage of low attenuation area (LAA%) as an index of emphysema. To elucidate the pathophysiological mechanisms underlying cachexia in COPD, we performed histological and molecular analyses of the lung, muscle and adipose tissues over time in a cigarette smoke–induced emphysema mouse model. Further, we used an in vitro culture system of differentiated adipocytes (3T3-L1) and myotubes (C2C12) to study the effects of cigarette smoke extract (CSE) on adipose–muscle interaction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In patients with COPD, the areas of PM, SAT and EAT all demonstrated significant negative correlations with LAA%; notably, PM and EAT were independently associated with the extent of emphysematous changes. In the smoke-exposed murine model, adipose tissue atrophy was observed after 1 month of exposure, accompanied by increased expressions of IL-6 and IL-1β, macrophage infiltration and the upregulation of the lipolytic enzymes ATGL and HSL. The adipose atrophy had further progressed after 3 months of exposure, and the high expression of UCP1 was sustained, which suggested the browning of adipose tissue. Conversely, muscle atrophy was not evident at 1 month but became apparent after 3 months, coinciding with emphysema development. This was associated with the downregulation of the myogenic markers MyoD and Myogenin and the upregulation of the muscle degradation marker Atrogin-1. In vitro experiments revealed that CSE exposure reduced lipid droplet content and induced IL-6 and IL-1β expressions in adipocytes. Conditioned media from CSE-treated adipocytes triggered myotube atrophy and downregulated MyoD and Myogenin but upregulated Atrogin-1.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings indicate that cigarette smoke-induced adipose tissue atrophy precedes muscle wasting","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70154","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710801","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}
Stephan von Haehling, Ryosuke Sato, Henning Langer, Muhammad Shahzeb Khan, Andrew J. S. Coats, William Evans, Steven Heymsfield, Stefan D. Anker
The Society on Cachexia and Wasting Disorders (SCWD) convened a Regulatory and Trial Update Workshop in Washington, D.C., in December 2024, assembling experts from academic institutions, the pharmaceutical industry and the US Food and Drug Administration (FDA) for focused discussions. This article summarizes the latter half of the meeting, which primarily focused on novel anti-obesity therapies based on incretin pathway alteration. Discussions highlighted the impact of glucagon-like peptide-1 (GLP-1) receptor agonists or GLP-1/glucose-dependent insulinotropic polypeptide (i.e., GLP-1/GIP) agonists on body composition and muscle health; the challenges of distinguishing ‘true’ skeletal muscle from fat-free tissue; the impact of treatment discontinuation and weight regain; advances in imaging and quantitative assessment of lean body mass; as well as insights from emerging muscle-preserving therapies (e.g., bimagrumab, pemvidutide and enobosarm). There are significant challenges in defining meaningful structural, functional and patient-reported endpoints for the use of muscle-‘protective’ drug therapies in the context of weight loss therapies. These also involve significant regulatory considerations for future drug development and approval pathways, for instance related to the very large number of individuals that may be considered for these therapeutic approaches as well as from the potential long (or life-long) duration of therapy considered with these drugs. Together, these discussions highlight the growing importance of integrating body composition and functional assessments in future clinical trials.
{"title":"Muscle Loss in Obesity Therapy as a Therapeutic Target: Trial Design and Endpoints for Regulatory Discussions","authors":"Stephan von Haehling, Ryosuke Sato, Henning Langer, Muhammad Shahzeb Khan, Andrew J. S. Coats, William Evans, Steven Heymsfield, Stefan D. Anker","doi":"10.1002/jcsm.70147","DOIUrl":"10.1002/jcsm.70147","url":null,"abstract":"<p>The Society on Cachexia and Wasting Disorders (SCWD) convened a Regulatory and Trial Update Workshop in Washington, D.C., in December 2024, assembling experts from academic institutions, the pharmaceutical industry and the US Food and Drug Administration (FDA) for focused discussions. This article summarizes the latter half of the meeting, which primarily focused on novel anti-obesity therapies based on incretin pathway alteration. Discussions highlighted the impact of glucagon-like peptide-1 (GLP-1) receptor agonists or GLP-1/glucose-dependent insulinotropic polypeptide (i.e., GLP-1/GIP) agonists on body composition and muscle health; the challenges of distinguishing ‘true’ skeletal muscle from fat-free tissue; the impact of treatment discontinuation and weight regain; advances in imaging and quantitative assessment of lean body mass; as well as insights from emerging muscle-preserving therapies (e.g., bimagrumab, pemvidutide and enobosarm). There are significant challenges in defining meaningful structural, functional and patient-reported endpoints for the use of muscle-‘protective’ drug therapies in the context of weight loss therapies. These also involve significant regulatory considerations for future drug development and approval pathways, for instance related to the very large number of individuals that may be considered for these therapeutic approaches as well as from the potential long (or life-long) duration of therapy considered with these drugs. Together, these discussions highlight the growing importance of integrating body composition and functional assessments in future clinical trials.</p>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70147","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704149","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}
<p>Every era of medicine faces unique challenges. Today, aging is at the forefront, with the global population over 65 years expected to rise from 9% in 2019 to 17% in 2050. With this demographic shift, we must address the specific limitations of older adults, particularly frailty [<span>1</span>].</p><p>Frailty lacks a universal definition but broadly reflects a progressive decline in physiological and psychosocial reserves, resulting in vulnerability to stressors. The same insult—such as chemotherapy, infection or acute cardiopulmonary disease—may have very different outcomes in robust versus frail individuals [<span>2-5</span>]. Reported prevalence varies widely due to inconsistent definitions, but studies suggest 11%–53% of elderly people are frail; the prevalence is higher in institutionalized elderly [<span>2</span>]. Cancer is also largely a disease of older adults: About 30% of new diagnoses occur in those aged 65–74 and 25% in those over 75 [<span>6</span>]. Some years ago, diagnosis of advanced cancer generally labelled patients with incurable disease; thus, work-up beyond malignancy was considered irrelevant. However, over time, effective therapies emerged that transformed many types of cancer into chronic diseases. These therapies are not without side effects which are tolerated differently depending on the patient's general condition. We should avoid futile treatments in fragile patients where adverse effects are likely to outweigh potential benefits. With a lack of guidelines or expert consensus, these decisions are largely based on ad hoc individual clinical judgement.</p><p>Within this new framework of cancer management, comorbidities affecting the quality of life and physical performance are relevant [<span>7, 8</span>]. Physical performance and nutritional status-related assessments are gaining traction while frailty still remains underrecognized. The standard tools like ‘Fried frailty phenotype’ (FFP) and ‘Comprehensive Geriatric Assessment’ (CGA) are time-consuming and poorly suited to routine oncology practice.</p><p>Regarding open considerations about frailty in cancer patients, the work by Weinländer et al. [<span>9</span>] in the recent issue of the Journal is spot on. The authors meticulously evaluated the concordance of the considered gold standard but more time-consuming tool FFP and clinically more convenient ‘Simple Frail Questionnaire’ (SFQ) [<span>10, 11</span>]. FFP assesses five criteria (low physical activity, poor endurance, unintentional weight loss, weakness and slowness), categorizing patients as robust, prefrail or frail [<span>10</span>]. SFQ uses a similar three-level classification but is quick, requires no special training and can be administered remotely. Weinländer et al. found a strong correlation between both scores (<i>r</i>s = 0.65, <i>p</i> < 0.001) with good internal consistency (Cronbach's alpha coefficient 0.80). Evaluation by SFQ and FFP revealed that 41% and 31% of advanced cancer patients
医学的每个时代都面临着独特的挑战。如今，老龄化是最重要的问题，全球65岁以上人口预计将从2019年的9%上升到2050年的17%。随着人口结构的变化，我们必须解决老年人的具体限制，特别是体弱多病。虚弱缺乏一个普遍的定义，但大致反映了生理和社会心理储备的逐渐下降，导致对压力源的脆弱性。同样的侮辱——如化疗、感染或急性心肺疾病——在健壮和虚弱的个体中可能会产生截然不同的结果[2-5]。由于定义不一致，报告的患病率差异很大，但研究表明，11%-53%的老年人体弱；在机构老年人中患病率更高。癌症在很大程度上也是老年人的疾病：大约30%的新诊断发生在65-74岁的人群中，25%发生在75岁以上的人群中。几年前，晚期癌症的诊断通常将患者标记为不治之症；因此，恶性肿瘤以外的检查被认为是无关紧要的。然而，随着时间的推移，出现了有效的治疗方法，将许多类型的癌症转化为慢性疾病。这些疗法并非没有副作用，根据患者的一般情况，这些副作用的耐受性不同。我们应该避免对身体虚弱的病人进行无效的治疗，因为他们的副作用可能超过潜在的益处。由于缺乏指导方针或专家共识，这些决定主要基于临时的个人临床判断。在这种新的癌症管理框架中，影响生活质量和身体表现的合并症是相关的[7,8]。身体表现和营养状况相关的评估正在获得关注，而虚弱仍然没有得到充分认识。像“Fried脆弱表型”（FFP）和“综合老年评估”（CGA）这样的标准工具耗时且不适合常规肿瘤学实践。关于癌症患者虚弱的公开考虑，Weinländer等人在最近一期的《杂志》上的工作是正确的。作者仔细评估了被认为是金标准但更耗时的工具FFP和临床更方便的“简单虚弱问卷”（SFQ）的一致性[10,11]。FFP评估五项标准（低体力活动、耐力差、无意体重减轻、虚弱和行动迟缓），将患者分为强壮、体弱或体弱[10]。SFQ使用类似的三级分类，但速度很快，不需要特殊培训，可以远程管理。Weinländer等人发现两个分数之间存在很强的相关性（rs = 0.65, p < 0.001），且具有良好的内部一致性（Cronbach's alpha系数0.80）。SFQ和FFP的评估显示，41%和31%的晚期癌症患者是虚弱的，而13%和17%的患者是虚弱的。与已发表的癌症患者虚弱的荟萃分析相比，他们发现了相似的患病率，而虚弱的患病率较低（分别为43%和42%）。两种工具在多变量分析中预测死亡率。这些结果表明SFQ不逊于FFP，并为其临床应用提供了强有力的依据。Weinländer等人填补了一个重要的空白，证明SFQ在识别虚弱或降低死亡风险方面并不亚于FFP。这些发现应该指导临床实践，以促进虚弱评估，这应该改善我们对可能对虚弱患者造成弊大于利的治疗的决策。虚弱本身并不是癌症的危险因素，但它会显著影响治疗的可行性和结果。虚弱的诊断应该促使临床医生寻找致病因素，使用虚弱进行风险分层，并将虚弱纳入治疗决策。对所有癌症患者进行普遍筛查似乎不现实，而对那些开始治疗或表现出残疾的患者进行有针对性的评估应该是可行的。虚弱筛查的要素——如营养和功能评估——已经是常规的，当发现异常时应该触发干预。除了具体的治疗方式外，还应鼓励推广健康的生活方式措施，如果确定了具体的目标，还应鼓励其他干预措施（例如，铁缺乏症中的铁和倾向于摔倒的患者的平衡训练）。约21%-79%的晚期癌症患者出现呼吸困难，通常由呼吸肌肉丧失引起，呼吸物理治疗可能对患者有益。目前，对虚弱的癌症患者进行全身治疗的决定很大程度上依赖于临床判断，没有正式的指导方针。医生严重依赖患者报告的活动水平，这可能是不可靠的。新技术——可穿戴传感器和移动应用——提供了客观的监测，而新兴的生物标志物(如： （3-甲基组氨酸，白细胞介素和微量营养素）可以支持评估bb0。虚弱筛查的价值超出了风险分层：它确定了干预的目标，并将支持性护理纳入肿瘤学。癌症患者管理的一个新概念正在出现，表明衰老，作为生物年龄的评估，可以代表一个全面的，可治疗的和敏感的恢复力差的标志，包括虚弱，营养不良和恶病质bb10的概念。在此背景下，Weinländer等人提供了令人信服的证据，证明SFQ是癌症患者虚弱评估的有效实用工具。在几分钟内，它产生临床相关的信息，应该指导治疗决策和支持干预。将虚弱评估纳入肿瘤学实践将有助于避免对脆弱患者的有害治疗，定制支持性策略并最终改善结果。由斯洛文尼亚研究与创新署(批准号：3 - 456)。作者声明无利益冲突。
{"title":"Frailty in Cancer: Why Bother and Ways Forward","authors":"Luka Cavka, Alessandro Laviano, Mitja Lainscak","doi":"10.1002/jcsm.70139","DOIUrl":"10.1002/jcsm.70139","url":null,"abstract":"<p>Every era of medicine faces unique challenges. Today, aging is at the forefront, with the global population over 65 years expected to rise from 9% in 2019 to 17% in 2050. With this demographic shift, we must address the specific limitations of older adults, particularly frailty [<span>1</span>].</p><p>Frailty lacks a universal definition but broadly reflects a progressive decline in physiological and psychosocial reserves, resulting in vulnerability to stressors. The same insult—such as chemotherapy, infection or acute cardiopulmonary disease—may have very different outcomes in robust versus frail individuals [<span>2-5</span>]. Reported prevalence varies widely due to inconsistent definitions, but studies suggest 11%–53% of elderly people are frail; the prevalence is higher in institutionalized elderly [<span>2</span>]. Cancer is also largely a disease of older adults: About 30% of new diagnoses occur in those aged 65–74 and 25% in those over 75 [<span>6</span>]. Some years ago, diagnosis of advanced cancer generally labelled patients with incurable disease; thus, work-up beyond malignancy was considered irrelevant. However, over time, effective therapies emerged that transformed many types of cancer into chronic diseases. These therapies are not without side effects which are tolerated differently depending on the patient's general condition. We should avoid futile treatments in fragile patients where adverse effects are likely to outweigh potential benefits. With a lack of guidelines or expert consensus, these decisions are largely based on ad hoc individual clinical judgement.</p><p>Within this new framework of cancer management, comorbidities affecting the quality of life and physical performance are relevant [<span>7, 8</span>]. Physical performance and nutritional status-related assessments are gaining traction while frailty still remains underrecognized. The standard tools like ‘Fried frailty phenotype’ (FFP) and ‘Comprehensive Geriatric Assessment’ (CGA) are time-consuming and poorly suited to routine oncology practice.</p><p>Regarding open considerations about frailty in cancer patients, the work by Weinländer et al. [<span>9</span>] in the recent issue of the Journal is spot on. The authors meticulously evaluated the concordance of the considered gold standard but more time-consuming tool FFP and clinically more convenient ‘Simple Frail Questionnaire’ (SFQ) [<span>10, 11</span>]. FFP assesses five criteria (low physical activity, poor endurance, unintentional weight loss, weakness and slowness), categorizing patients as robust, prefrail or frail [<span>10</span>]. SFQ uses a similar three-level classification but is quick, requires no special training and can be administered remotely. Weinländer et al. found a strong correlation between both scores (<i>r</i>s = 0.65, <i>p</i> < 0.001) with good internal consistency (Cronbach's alpha coefficient 0.80). Evaluation by SFQ and FFP revealed that 41% and 31% of advanced cancer patients","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70139","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704150","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}
Jacob D. Steffen, Seth Garton, Ravi Ashwath, Jennifer R. Maldonado, Krista Young, Colleen Lancial, Osamah Aldoss, Prashob Porayette
<div> <section> <h3> Background</h3> <p>The growing population of adults with congenital heart disease (ACHD) faces lifelong morbidities despite advancements in medical and surgical care. Sarcopenia, characterized by loss of muscle mass and strength, is linked to increased disability, poor quality of life and mortality. This study examines sex-specific thoracic skeletal muscle characteristics in ACHD patients using advanced imaging techniques, comparing them with healthy reference values and investigating their association with exercise capacity.</p> </section> <section> <h3> Material and Methods</h3> <p>In this single-centre retrospective study, ACHD patients (age 18–50 years) who underwent both cardiopulmonary exercise tests and thoracic CT/MRI within a year were included. Skeletal muscle area (SMA) was manually measured and compared with healthy reference data.</p> </section> <section> <h3> Results</h3> <p>Among 60 ACHD patients (mean age 28.3 ± 8.3 years; 48% females), males exhibited significantly lower SMA (T10: 116.8 ± 24.6 cm<sup>2</sup>, <i>p</i> < 0.0001; T11: 114.4 ± 24.7 cm<sup>2</sup>, <i>p</i> = 0.0002) and skeletal muscle index (SMI) (T10: 37.2 ± 8 cm<sup>2</sup>/m<sup>2</sup>, <i>p</i> = 0.005; T11: 36.4 ± 8.1 cm<sup>2</sup>/m<sup>2</sup>, <i>p</i> = 0.0014) at T10 and T11 vertebral level, whereas females showed a reduction in SMA at T10 (79.7 ± 14.9 cm<sup>2</sup>, <i>p</i> = 0.0242) and T12 (74.2 ± 10.7 cm<sup>2</sup>, <i>p</i> = 0.0015) compared with healthy individuals. Females had significantly lower skeletal muscle radiation attenuation (SMRA) at T10 (16.3 ± 14.6 HU, <i>p</i> < 0.001), T11 (17.1 ± 10.3 HU, <i>p</i> < 0.001) and T12 (25 ± 10.7 HU, <i>p</i> < 0.001) levels, suggesting increased muscle fat content. Peak O<sub>2</sub> pulse correlated with SMA at T10 (<i>r</i> = 0.57, <i>R</i><sup>2</sup> = 0.32, <i>p</i> ≤ 0.0001), T11 (<i>r</i> = 0.61, <i>R</i><sup>2</sup> = 0.38, <i>p</i> < 0.0001) and T12 (<i>r</i> = 0.73, <i>R</i><sup>2</sup> = 0.53, <i>p</i> = 0.001) levels. Similar correlations were observed between peak O<sub>2</sub> pulse and SMI, whereas peak VO<sub>2</sub> correlated with SMA at T10 (<i>r</i> = 0.27, <i>R</i><sup>2</sup> = 0.07, <i>p</i> = 0.0394) and T11 (<i>r</i> = 0.34, <i>R</i><sup>2</sup> = 0.11, <i>p</i> = 0.02) and SMRA across all levels (T10: <i>r</i> = 0.64, <i>R</i><sup>2</sup> = 0.41, <i>p</i> = 0.0076; T11: <i>r</i> = 0.85, <i>R</i><sup>2</sup> = 0.72, <i>p</i> = 0.0003; T12: <i>r</i> = 0.62, <i>R</i><sup>2</sup> = 0.38, <i>p</i> = 0.0327). SMA at T11 had a negative correlation with VE/VCO<sub>2</sub> (<i>r</i> = −0.36, <i>R</i><sup>2</sup> = 0.13, <i>p</i> = 0.01). There was
背景：尽管医学和外科治疗取得了进步，但患有先天性心脏病（ACHD）的成人人数不断增加，面临终身发病率。肌肉减少症的特点是肌肉质量和力量的减少，与残疾增加、生活质量差和死亡率有关。本研究使用先进的成像技术检查了ACHD患者的性别特异性胸椎骨骼肌特征，将其与健康参考值进行比较，并调查其与运动能力的关系。材料和方法在这项单中心回顾性研究中，纳入了在一年内接受心肺运动试验和胸部CT/MRI检查的ACHD患者（18-50岁）。人工测量骨骼肌面积（SMA），并与健康参考数据进行比较。RESULTSAmong 60 ACHD患者(平均年龄28.3±8.3年,48%的女性),男性表现出显著降低SMA (T10: 116.8±24.6厘米2,p < 0.0001; T11: 114.4±24.7厘米2,p = 0.0002)和骨骼肌指数(SMI) (T10: 37.2±8厘米2 / m2, p = 0.005; T11: 36.4±8.1厘米2 / m2, p = 0.0014)在T10和T11椎水平,而雌性显示减少SMA在T10(79.7±14.9厘米2,p = 0.0242)和病人(74.2±10.7厘米2,p = 0.0015)与健康人相比。女性在T10（16.3±14.6 HU, p < 0.001）、T11（17.1±10.3 HU, p < 0.001）和T12（25±10.7 HU, p < 0.001）水平时骨骼肌辐射衰减（SMRA）显著降低，提示肌肉脂肪含量增加。在T10 O2脉冲峰值与SMA (r = 0.57, R2 = 0.32, p≤0.0001),T11 (r = 0.61, R2 = 0.38, p < 0.0001),病人(r = 0.73, R2 = 0.53, p = 0.001)的水平。T10 （r = 0.27, R2 = 0.07, p = 0.0394）和T11 （r = 0.34, R2 = 0.11, p = 0.02）和SMRA （T10: r = 0.64, R2 = 0.41, p = 0.0076; T11: r = 0.85, R2 = 0.72, p = 0.0003; T12: r = 0.62, R2 = 0.38, p = 0.0327）的峰值VO2与SMA和SMRA的相关性相似。T11时SMA与VE/VCO2呈负相关（r = -0.36, R2 = 0.13, p = 0.01）。胸骨切开术次数与运动参数无相关性。与未安装起搏器的ACHD患者相比，安装起搏器的受试者VO2峰值（p = 0.04）和合成代谢阈值（p = 0.03）显著降低。结论ACHD患者胸椎横断成像骨骼肌参数异常与运动能力下降有关。对胸椎骨骼肌特征的评估可能有助于早期发现肌肉损失，为了解导致该人群运动受限的复杂因素提供有价值的见解。
{"title":"Thoracic Skeletal Muscle and Exercise Capacity in Adults With Congenital Heart Disease: A Cross-Sectional Imaging Analysis","authors":"Jacob D. Steffen, Seth Garton, Ravi Ashwath, Jennifer R. Maldonado, Krista Young, Colleen Lancial, Osamah Aldoss, Prashob Porayette","doi":"10.1002/jcsm.70157","DOIUrl":"10.1002/jcsm.70157","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The growing population of adults with congenital heart disease (ACHD) faces lifelong morbidities despite advancements in medical and surgical care. Sarcopenia, characterized by loss of muscle mass and strength, is linked to increased disability, poor quality of life and mortality. This study examines sex-specific thoracic skeletal muscle characteristics in ACHD patients using advanced imaging techniques, comparing them with healthy reference values and investigating their association with exercise capacity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Material and Methods</h3>\u0000 \u0000 <p>In this single-centre retrospective study, ACHD patients (age 18–50 years) who underwent both cardiopulmonary exercise tests and thoracic CT/MRI within a year were included. Skeletal muscle area (SMA) was manually measured and compared with healthy reference data.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among 60 ACHD patients (mean age 28.3 ± 8.3 years; 48% females), males exhibited significantly lower SMA (T10: 116.8 ± 24.6 cm<sup>2</sup>, <i>p</i> < 0.0001; T11: 114.4 ± 24.7 cm<sup>2</sup>, <i>p</i> = 0.0002) and skeletal muscle index (SMI) (T10: 37.2 ± 8 cm<sup>2</sup>/m<sup>2</sup>, <i>p</i> = 0.005; T11: 36.4 ± 8.1 cm<sup>2</sup>/m<sup>2</sup>, <i>p</i> = 0.0014) at T10 and T11 vertebral level, whereas females showed a reduction in SMA at T10 (79.7 ± 14.9 cm<sup>2</sup>, <i>p</i> = 0.0242) and T12 (74.2 ± 10.7 cm<sup>2</sup>, <i>p</i> = 0.0015) compared with healthy individuals. Females had significantly lower skeletal muscle radiation attenuation (SMRA) at T10 (16.3 ± 14.6 HU, <i>p</i> < 0.001), T11 (17.1 ± 10.3 HU, <i>p</i> < 0.001) and T12 (25 ± 10.7 HU, <i>p</i> < 0.001) levels, suggesting increased muscle fat content. Peak O<sub>2</sub> pulse correlated with SMA at T10 (<i>r</i> = 0.57, <i>R</i><sup>2</sup> = 0.32, <i>p</i> ≤ 0.0001), T11 (<i>r</i> = 0.61, <i>R</i><sup>2</sup> = 0.38, <i>p</i> < 0.0001) and T12 (<i>r</i> = 0.73, <i>R</i><sup>2</sup> = 0.53, <i>p</i> = 0.001) levels. Similar correlations were observed between peak O<sub>2</sub> pulse and SMI, whereas peak VO<sub>2</sub> correlated with SMA at T10 (<i>r</i> = 0.27, <i>R</i><sup>2</sup> = 0.07, <i>p</i> = 0.0394) and T11 (<i>r</i> = 0.34, <i>R</i><sup>2</sup> = 0.11, <i>p</i> = 0.02) and SMRA across all levels (T10: <i>r</i> = 0.64, <i>R</i><sup>2</sup> = 0.41, <i>p</i> = 0.0076; T11: <i>r</i> = 0.85, <i>R</i><sup>2</sup> = 0.72, <i>p</i> = 0.0003; T12: <i>r</i> = 0.62, <i>R</i><sup>2</sup> = 0.38, <i>p</i> = 0.0327). SMA at T11 had a negative correlation with VE/VCO<sub>2</sub> (<i>r</i> = −0.36, <i>R</i><sup>2</sup> = 0.13, <i>p</i> = 0.01). There was ","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70157","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696621","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}
Héctor Vázquez-Lorente, Indira Paz-Graniel, Hernando J. Margara-Escudero, Miguel Ángel Martínez-González, Dora Romaguera, D. Martinez Urbistondo, Ramon Estruch, Vicente Martín Sánchez, Josep Vidal, Montserrat Fitó, Nuria Goñi, Alice Chaplin, M. Angeles Zulet, Emilio Sacanella, José Antonio de Paz Fernández, Andreu Altés, Jesús F. García-Gavilán, Jadwiga Konieczna, J. Alfredo Martínez, Jordi Salas-Salvadó
<div> <section> <h3> Background</h3> <p>Sarcopenic obesity has been suggested as a potential risk factor for cognitive decline; however, few prospective studies have been conducted to test this hypothesis. We aimed to assess the relationship between baseline sarcopenic obesity and 6-year trajectories of cognitive performance and subtle cognitive impairment in older adults.</p> </section> <section> <h3> Methods</h3> <p>This longitudinal study comprised 1097 older adults aged 55–75 years (mean [SD] age, 65.3 [4.9] years; 506 females [46.1%] and 591 males [53.9%]) exhibiting baseline overweight/obesity and metabolic syndrome. Baseline lower-limb muscle strength was determined by the validated 30-s Chair Stand Test. Baseline total body weight, fat mass percentage and appendicular lean mass were obtained through dual-energy x-ray absorptiometry scans. Baseline sarcopenic obesity (<i>n</i> = 364 [33.2%]) was subsequently defined based on the new European Society for Clinical Nutrition and Metabolism and the European Association for the Study of Obesity consensus criteria. Cognitive performance was assessed at baseline, 2, 4 and 6 years of follow-up through five composite scores derived from a comprehensive battery of eight validated neuropsychological tests, encompassing global cognitive function, general cognitive function, executive function, attention and language. Subtle cognitive impairment was defined for those <i>z</i>-scores 0.5 standard deviations below the mean for each cognitive performance composite score at baseline. Linear and logistic two-level mixed models including lost to follow-up participants were fitted as main analyses. Complete case analyses were additionally performed.</p> </section> <section> <h3> Results</h3> <p>After adjusting for multiple covariates, main analyses showed that, compared to older adults without sarcopenic obesity, those with sarcopenic obesity showed a higher decline in global cognitive function (between-group difference, −1.0 [95% CI, −2.2 to 0.2] after 6 years; overall <i>p</i> = 0.048) and general cognitive function (between-group difference, −2.5 [95% CI, −4.4 to 0.5] after 6 years; overall <i>p</i> = 0.028) and had a higher risk of subtle global cognitive function impairment (between-group difference, 2.3 [95% CI, 0.9 to 5.6] after 6 years; overall <i>p</i> = 0.038) over 6 years of follow-up. Associations remained consistent in the complete case analysis and attenuated when comparing those participants with baseline sarcopenic obesity with those only presenting sarcopenia, obesity or overweight. Of note, participants with baseline sarcopenia or obesity, compared to the absence of these conditions, showed no
{"title":"Sarcopenic Obesity and Longitudinal Trajectories on Cognitive Performance and Subtle Cognitive Impairment Over 6 Years in Older Adults","authors":"Héctor Vázquez-Lorente, Indira Paz-Graniel, Hernando J. Margara-Escudero, Miguel Ángel Martínez-González, Dora Romaguera, D. Martinez Urbistondo, Ramon Estruch, Vicente Martín Sánchez, Josep Vidal, Montserrat Fitó, Nuria Goñi, Alice Chaplin, M. Angeles Zulet, Emilio Sacanella, José Antonio de Paz Fernández, Andreu Altés, Jesús F. García-Gavilán, Jadwiga Konieczna, J. Alfredo Martínez, Jordi Salas-Salvadó","doi":"10.1002/jcsm.70158","DOIUrl":"10.1002/jcsm.70158","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sarcopenic obesity has been suggested as a potential risk factor for cognitive decline; however, few prospective studies have been conducted to test this hypothesis. We aimed to assess the relationship between baseline sarcopenic obesity and 6-year trajectories of cognitive performance and subtle cognitive impairment in older adults.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This longitudinal study comprised 1097 older adults aged 55–75 years (mean [SD] age, 65.3 [4.9] years; 506 females [46.1%] and 591 males [53.9%]) exhibiting baseline overweight/obesity and metabolic syndrome. Baseline lower-limb muscle strength was determined by the validated 30-s Chair Stand Test. Baseline total body weight, fat mass percentage and appendicular lean mass were obtained through dual-energy x-ray absorptiometry scans. Baseline sarcopenic obesity (<i>n</i> = 364 [33.2%]) was subsequently defined based on the new European Society for Clinical Nutrition and Metabolism and the European Association for the Study of Obesity consensus criteria. Cognitive performance was assessed at baseline, 2, 4 and 6 years of follow-up through five composite scores derived from a comprehensive battery of eight validated neuropsychological tests, encompassing global cognitive function, general cognitive function, executive function, attention and language. Subtle cognitive impairment was defined for those <i>z</i>-scores 0.5 standard deviations below the mean for each cognitive performance composite score at baseline. Linear and logistic two-level mixed models including lost to follow-up participants were fitted as main analyses. Complete case analyses were additionally performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>After adjusting for multiple covariates, main analyses showed that, compared to older adults without sarcopenic obesity, those with sarcopenic obesity showed a higher decline in global cognitive function (between-group difference, −1.0 [95% CI, −2.2 to 0.2] after 6 years; overall <i>p</i> = 0.048) and general cognitive function (between-group difference, −2.5 [95% CI, −4.4 to 0.5] after 6 years; overall <i>p</i> = 0.028) and had a higher risk of subtle global cognitive function impairment (between-group difference, 2.3 [95% CI, 0.9 to 5.6] after 6 years; overall <i>p</i> = 0.038) over 6 years of follow-up. Associations remained consistent in the complete case analysis and attenuated when comparing those participants with baseline sarcopenic obesity with those only presenting sarcopenia, obesity or overweight. Of note, participants with baseline sarcopenia or obesity, compared to the absence of these conditions, showed no","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70158","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704148","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}
<div> <section> <h3> Background</h3> <p>Ultrasound is a promising tool for diagnosing sarcopenia, yet standardized cut-off points and criteria are currently lacking. This study aimed to identify the optimal muscle sites and reference values for diagnosing low muscle mass in older Chinese adults using ultrasound, with dual-energy X-ray absorptiometry (DXA) as the reference standard, and to compare its diagnostic performance with bioelectrical impedance analysis (BIA).</p> </section> <section> <h3> Methods</h3> <p>We included 1011 participants aged over 60 years. Fat thickness (FT), muscle thickness (MT) and muscle cross-section area (CSA) at various sites, including biceps brachii, rectus abdominis, rectus femoris, vastus intermedius, vastus lateralis, vastus medialis and tibialis anterior, were assessed for participants. DXA measurements were used as the standard for defining low muscle mass. Receiver operating characteristic (ROC) curve analysis and 10-fold cross-validation were conducted to evaluate the prediction performance of ultrasound parameters for low muscle mass. The Youden index was employed to determine optimal cut-offs, while sensitivity, specificity and accuracy were calculated to assess diagnostic performance. Intra-class correlation coefficients (ICC) were used to evaluate inter-rater reliability between two examiners.</p> </section> <section> <h3> Results</h3> <p>In males, the biceps brachii CSA (AUC = 0.832, 95% CI: 0.793–0.870) and in females, the tibialis anterior MT (0.833, 95% CI: 0.789–0.877) demonstrated superior predictive power for low muscle mass compared with other ultrasound parameters. A biceps brachii CSA < 7.1 cm<sup>2</sup> in males and tibialis anterior MT < 2.3 cm in females were identified as effective indicators for diagnosing low muscle mass, with good sensitivities (73.9% in males, 73.6% in females), specificities (78.6% in males, 76.8% in females) and accuracies (75.7% in males, 75.8% in females). These values were comparable with those obtained using BIA (sensitivity: 62.6%, specificity: 80.2% and accuracy: 71.5%). Low muscle mass as defined by ultrasound was significantly associated with poor performance on the Short Physical Performance Battery, Activities of Daily Living and frailty indices, with effect sizes higher than DXA or BIA defined low muscle mass. The inter-rater reliability was excellent for biceps brachii CSA (ICC = 0.869, 95% CI: 0.650–0.937) and good for tibialis anterior MT (ICC = 0.730, 95% CI: 0.622–0.810).</p> </section> <section> <h3> Conclusions</h3> <p>Muscle ultrasound demonstra
{"title":"Determination of Ultrasound Reference Values for Diagnosing Low Muscle Mass in Older Chinese Adults","authors":"Shumin Li, Keying Xu, Ange Wang, Chenfan Qin, Nan Hua, Xinrui Ling, Liqian Xu, Caihong He, Shixian Zhou, Jing Chen, Qin Zhang, Yunmei Yang","doi":"10.1002/jcsm.70155","DOIUrl":"10.1002/jcsm.70155","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Ultrasound is a promising tool for diagnosing sarcopenia, yet standardized cut-off points and criteria are currently lacking. This study aimed to identify the optimal muscle sites and reference values for diagnosing low muscle mass in older Chinese adults using ultrasound, with dual-energy X-ray absorptiometry (DXA) as the reference standard, and to compare its diagnostic performance with bioelectrical impedance analysis (BIA).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We included 1011 participants aged over 60 years. Fat thickness (FT), muscle thickness (MT) and muscle cross-section area (CSA) at various sites, including biceps brachii, rectus abdominis, rectus femoris, vastus intermedius, vastus lateralis, vastus medialis and tibialis anterior, were assessed for participants. DXA measurements were used as the standard for defining low muscle mass. Receiver operating characteristic (ROC) curve analysis and 10-fold cross-validation were conducted to evaluate the prediction performance of ultrasound parameters for low muscle mass. The Youden index was employed to determine optimal cut-offs, while sensitivity, specificity and accuracy were calculated to assess diagnostic performance. Intra-class correlation coefficients (ICC) were used to evaluate inter-rater reliability between two examiners.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In males, the biceps brachii CSA (AUC = 0.832, 95% CI: 0.793–0.870) and in females, the tibialis anterior MT (0.833, 95% CI: 0.789–0.877) demonstrated superior predictive power for low muscle mass compared with other ultrasound parameters. A biceps brachii CSA < 7.1 cm<sup>2</sup> in males and tibialis anterior MT < 2.3 cm in females were identified as effective indicators for diagnosing low muscle mass, with good sensitivities (73.9% in males, 73.6% in females), specificities (78.6% in males, 76.8% in females) and accuracies (75.7% in males, 75.8% in females). These values were comparable with those obtained using BIA (sensitivity: 62.6%, specificity: 80.2% and accuracy: 71.5%). Low muscle mass as defined by ultrasound was significantly associated with poor performance on the Short Physical Performance Battery, Activities of Daily Living and frailty indices, with effect sizes higher than DXA or BIA defined low muscle mass. The inter-rater reliability was excellent for biceps brachii CSA (ICC = 0.869, 95% CI: 0.650–0.937) and good for tibialis anterior MT (ICC = 0.730, 95% CI: 0.622–0.810).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Muscle ultrasound demonstra","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70155","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704146","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}
Yonghui Wang, Xinrun Ma, Yang Chen, Chao Xia, Xue Lei, Junran Liu, Yunyi Jiang, Rang Xu, Yanhong Gao
<div> <section> <h3> Background</h3> <p>Previous research has shown that the conditional knockout of Slo1 in muscle leads to a reduction in muscle strength and inhibits myogenic differentiation. Exosomes are emerging as necessary mediators of the crosstalk between muscle and bones. The present study focused on the communication between muscle and bone to investigate the effects and mechanisms of skeletal muscle-specific knockout of Slo1 on bone mass and bone metabolism.</p> </section> <section> <h3> Methods</h3> <p>Myf5-Cre mice were mated with Slo1<sup>flox/flox</sup> mice to construct skeletal muscle-specific Slo1 knockout mice (CKO mice). The legs of the Slo1 CKO mice were isolated, and a series of examinations were conducted to monitor bone mineral density (BMD) and bone microstructure. Exosomes were extracted from C2C12-shNC and C2C12-shSlo1 cells and subjected to transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blotting (WB). The osteogenic effect of EXO-shSlo1 was examined in vitro and in vivo by Alkaline phosphatase (ALP) staining, q-PCR, WB and microCT. RNA sequencing (RNA-seq) analysis of EXO-shNC and EXO-shSlo1 was used to identify differentially expressed microRNAs. Mimics and inhibitors of miR-222-3p were transfected into MC3T3-E1 cells to induce differentiation. The predicted targets of miR-222-3p were examined with Luciferase, qPCR, and WB.</p> </section> <section> <h3> Results</h3> <p>In Slo1 CKO mice, the bone mass decreased, and the microstructure was disrupted. TEM, NTA and WB assays showed that Slo1-silenced C2C12 cells secreted exosomes and localized to MC3T3-E1 cells and bone tissue through the circulation. EXO-shSlo1 inhibited osteogenesis both in vivo and in vitro, as demonstrated by the decreased ALP activity (~40%, <i>p</i> < 0.05), osteogenic marker expression (~30%, <i>p</i> < 0.05), mineral deposition in osteoblasts and BMD. qPCR was performed to confirm the exosome RNA-seq results, which indicated that miR-222-3p was increased by three times in the EXO-shSlo1 group compared with the EXO-shNC group. Transfection of mimics or inhibitors of miR-222-3p in MC3T3-E1 cells inhibited or improved osteogenic differentiation. Luciferase reporter assays revealed that miR-222-3p targets STAT3. The mRNA and protein level of STAT3 was affected by miR-222-3p. Through inhibiting miR-222-3p or upregulating STAT3, the EXO-shSlo1-mediated osteogenic inhibition of MC3T3-E1 cells was ameliorated, as indicated by increased ALP activity and osteogenic marker expression.</p> </section> <section> <h3> Conclusion</h3>
{"title":"Slo1 Deficient Myoblast Exosomes-Derived miR-222-3p Inhibits Osteogenic Differentiation via Targeting of STAT3","authors":"Yonghui Wang, Xinrun Ma, Yang Chen, Chao Xia, Xue Lei, Junran Liu, Yunyi Jiang, Rang Xu, Yanhong Gao","doi":"10.1002/jcsm.70115","DOIUrl":"10.1002/jcsm.70115","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Previous research has shown that the conditional knockout of Slo1 in muscle leads to a reduction in muscle strength and inhibits myogenic differentiation. Exosomes are emerging as necessary mediators of the crosstalk between muscle and bones. The present study focused on the communication between muscle and bone to investigate the effects and mechanisms of skeletal muscle-specific knockout of Slo1 on bone mass and bone metabolism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Myf5-Cre mice were mated with Slo1<sup>flox/flox</sup> mice to construct skeletal muscle-specific Slo1 knockout mice (CKO mice). The legs of the Slo1 CKO mice were isolated, and a series of examinations were conducted to monitor bone mineral density (BMD) and bone microstructure. Exosomes were extracted from C2C12-shNC and C2C12-shSlo1 cells and subjected to transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blotting (WB). The osteogenic effect of EXO-shSlo1 was examined in vitro and in vivo by Alkaline phosphatase (ALP) staining, q-PCR, WB and microCT. RNA sequencing (RNA-seq) analysis of EXO-shNC and EXO-shSlo1 was used to identify differentially expressed microRNAs. Mimics and inhibitors of miR-222-3p were transfected into MC3T3-E1 cells to induce differentiation. The predicted targets of miR-222-3p were examined with Luciferase, qPCR, and WB.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In Slo1 CKO mice, the bone mass decreased, and the microstructure was disrupted. TEM, NTA and WB assays showed that Slo1-silenced C2C12 cells secreted exosomes and localized to MC3T3-E1 cells and bone tissue through the circulation. EXO-shSlo1 inhibited osteogenesis both in vivo and in vitro, as demonstrated by the decreased ALP activity (~40%, <i>p</i> < 0.05), osteogenic marker expression (~30%, <i>p</i> < 0.05), mineral deposition in osteoblasts and BMD. qPCR was performed to confirm the exosome RNA-seq results, which indicated that miR-222-3p was increased by three times in the EXO-shSlo1 group compared with the EXO-shNC group. Transfection of mimics or inhibitors of miR-222-3p in MC3T3-E1 cells inhibited or improved osteogenic differentiation. Luciferase reporter assays revealed that miR-222-3p targets STAT3. The mRNA and protein level of STAT3 was affected by miR-222-3p. Through inhibiting miR-222-3p or upregulating STAT3, the EXO-shSlo1-mediated osteogenic inhibition of MC3T3-E1 cells was ameliorated, as indicated by increased ALP activity and osteogenic marker expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 ","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70115","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704147","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}
Laura Pérez-Guàrdia, Roberto Silva-Rojas, Jocelyn Laporte, Johann Böhm
<div> <section> <h3> Background</h3> <p>Ageing is an irreversible process involving the gradual decline of cellular functions in all tissues. In male mice, age-related loss of muscle force is accompanied by the formation of tubular aggregates, which are honeycomb-like structures composed of membrane tubules, proteins and Ca<sup>2+</sup> deposits. Tubular aggregates are also found in tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), two clinically overlapping human disorders affecting skeletal muscle, bones, skin, spleen and platelets. TAM/STRMK is caused by gain-of-function mutations in the ubiquitously expressed Ca<sup>2+</sup> sensor STIM1 and results in excessive extracellular Ca<sup>2+</sup> entry and the dysregulation of Ca<sup>2+</sup> homeostasis.</p> </section> <section> <h3> Methods</h3> <p>To understand the correlation between ageing, tubular aggregate formation, Ca<sup>2+</sup> and STIM1, we conducted comparative analyses of WT and <i>Stim1</i><sup><i>+/−</i></sup> male mice until 18 months of age. We examined growth, general and specific muscle force, fatigability and muscle structure.</p> </section> <section> <h3> Results</h3> <p><i>Stim1</i><sup><i>+/−</i></sup> mice were born with the expected Mendelian ratio and showed unremarkable postnatal development with normal body and organ weight. However, at 18 months, <i>Stim1</i><sup><i>+/−</i></sup> mice manifested delayed muscle contraction (<i>Δ</i> = 28%, <i>p</i> < 0.05) and relaxation (<i>Δ</i> = 40%, <i>p</i> < 0.01) kinetics as well as exacerbated fatigue (<i>Δ</i> = 28%, <i>p</i> < 0.05) compared with age-matched controls. Morphological investigations of <i>Stim1</i><sup><i>+/−</i></sup> muscle sections by light and electron microscopy uncovered a shift towards slow myofibres and mitochondrial proliferation accompanied by enhanced SDH activity (<i>Δ</i> = 27%, <i>p</i> < 0.0001), an almost twofold increase in ROS production (<i>p</i> < 0.05), and signs of mitophagy—all representing histopathological hallmarks of age-related deterioration of muscle function known as sarcopenia. Strikingly, tubular aggregates—though abundant in WT muscles at 18 months—were absent in <i>Stim1</i><sup><i>+/−</i></sup> mice.</p> </section> <section> <h3> Conclusions</h3> <p>Taken together, STIM1 depletion by 50% had no discernible effect on muscle function in young adult male mice, but compromised muscle performance and resistance to fatigue at later life stages. These findings highlight a critical role of STIM1 and Ca<sup>2+</sup> balance in the maintenance of muscle phy
衰老是一个不可逆的过程，涉及所有组织中细胞功能的逐渐下降。在雄性小鼠中，与年龄相关的肌肉力量丧失伴随着管状聚集体的形成，管状聚集体是由膜小管、蛋白质和Ca2+沉积物组成的蜂窝状结构。在管状聚集体肌病（TAM）和Stormorken综合征（STRMK）中也发现了管状聚集体，这两种临床重叠的人类疾病影响骨骼肌、骨骼、皮肤、脾脏和血小板。TAM/STRMK是由无处不在表达的Ca2+传感器STIM1的功能获得突变引起的，并导致细胞外Ca2+进入过多和Ca2+稳态失调。方法为了了解衰老、小管聚集体形成、Ca2+和STIM1之间的相关性，我们对18月龄的WT和STIM1 +/-雄性小鼠进行了比较分析。我们检查了生长、一般和特定肌肉力量、疲劳和肌肉结构。结果stim1 +/-小鼠出生时符合预期的孟德尔比率，出生后发育不显著，身体和器官重量正常。然而，在18个月时，与年龄匹配的对照组相比，Stim1+/-小鼠表现出肌肉收缩（Δ = 28%, p < 0.05）和松弛（Δ = 40%, p < 0.01）动力学延迟以及疲劳加剧（Δ = 28%, p < 0.05）。通过光镜和电镜对Stim1+/-肌肉切片的形态学研究发现，随着SDH活性的增强（Δ = 27%, p < 0.0001）， ROS生成几乎增加了两倍（p < 0.05），以及线粒体自噬的迹象，这些都代表了与年龄相关的肌肉功能恶化的组织病理学标志，即肌肉减少症。引人注目的是，尽管在18个月大的WT肌肉中大量存在管状聚集体，但在Stim1+/-小鼠中却没有。综上所述，STIM1减少50%对年轻成年雄性小鼠的肌肉功能没有明显影响，但会损害晚年的肌肉性能和抗疲劳能力。这些发现强调了STIM1和Ca2+平衡在维持肌肉生理、纤维类型组成和线粒体生物能量学中的关键作用。Stim1+/-小鼠中管状聚集体的缺失表明管状聚集体可能发挥保护作用，并可能有助于预防与年龄相关的肌肉改变。
{"title":"STIM1 Reduction Prevents Tubular Aggregate Formation and Compromises Muscle Performance in Ageing Mice","authors":"Laura Pérez-Guàrdia, Roberto Silva-Rojas, Jocelyn Laporte, Johann Böhm","doi":"10.1002/jcsm.70151","DOIUrl":"10.1002/jcsm.70151","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Ageing is an irreversible process involving the gradual decline of cellular functions in all tissues. In male mice, age-related loss of muscle force is accompanied by the formation of tubular aggregates, which are honeycomb-like structures composed of membrane tubules, proteins and Ca<sup>2+</sup> deposits. Tubular aggregates are also found in tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), two clinically overlapping human disorders affecting skeletal muscle, bones, skin, spleen and platelets. TAM/STRMK is caused by gain-of-function mutations in the ubiquitously expressed Ca<sup>2+</sup> sensor STIM1 and results in excessive extracellular Ca<sup>2+</sup> entry and the dysregulation of Ca<sup>2+</sup> homeostasis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To understand the correlation between ageing, tubular aggregate formation, Ca<sup>2+</sup> and STIM1, we conducted comparative analyses of WT and <i>Stim1</i><sup><i>+/−</i></sup> male mice until 18 months of age. We examined growth, general and specific muscle force, fatigability and muscle structure.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>Stim1</i><sup><i>+/−</i></sup> mice were born with the expected Mendelian ratio and showed unremarkable postnatal development with normal body and organ weight. However, at 18 months, <i>Stim1</i><sup><i>+/−</i></sup> mice manifested delayed muscle contraction (<i>Δ</i> = 28%, <i>p</i> < 0.05) and relaxation (<i>Δ</i> = 40%, <i>p</i> < 0.01) kinetics as well as exacerbated fatigue (<i>Δ</i> = 28%, <i>p</i> < 0.05) compared with age-matched controls. Morphological investigations of <i>Stim1</i><sup><i>+/−</i></sup> muscle sections by light and electron microscopy uncovered a shift towards slow myofibres and mitochondrial proliferation accompanied by enhanced SDH activity (<i>Δ</i> = 27%, <i>p</i> < 0.0001), an almost twofold increase in ROS production (<i>p</i> < 0.05), and signs of mitophagy—all representing histopathological hallmarks of age-related deterioration of muscle function known as sarcopenia. Strikingly, tubular aggregates—though abundant in WT muscles at 18 months—were absent in <i>Stim1</i><sup><i>+/−</i></sup> mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Taken together, STIM1 depletion by 50% had no discernible effect on muscle function in young adult male mice, but compromised muscle performance and resistance to fatigue at later life stages. These findings highlight a critical role of STIM1 and Ca<sup>2+</sup> balance in the maintenance of muscle phy","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70151","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696640","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}
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