Mélissa Gentreau, Mahitab Sakr, Salahuddin Mohammad, Ahmed M. Alsehli, Olga E. Titova, Gull Rukh, Helgi B. Schiöth
Background
Statins are cholesterol-lowering drugs widely prescribed for preventing cardiovascular diseases. They may cause adverse effects on skeletal muscle, but it remains unclear whether they affect muscle function and mass. We aimed to evaluate the association between statin use and muscle function and mass, and whether the pharmacogenomic score (PGS) of statin response modifies these associations.
Methods
We included 297 977 participants from the UK Biobank. Grip strength was measured using a Jamar J00105 hydraulic hand dynamometer, and the appendicular lean mass (ALM) was estimated using bioelectrical impedance analysis. We performed linear regression to evaluate the cross-sectional and longitudinal associations between statin use and (changes in) grip strength or ALM, adjusting for demographic, lifestyle and health factors. We tested the interaction with the PGS and stratified the analysis by PGS tertile.
Results
Participants averaged 56.4 (± 8) years, and 46% were male. Statin use was associated with lower baseline grip strength (β = −0.68 kg [−0.89, −0.48]) and ALM (β = −0.19 kg [−0.22, −0.16]). Among 35 557 participants with follow-up data (10 ± 5 years), continuous statin use was associated with an accelerated decline in grip strength (β = −0.32 kg/year [−0.49, −0.14]) and ALM (β = −0.06 kg/year [−0.08, −0.03]) compared with never users. The PGS showed a potential modifying effect at baseline (p = 0.058 for grip strength and p = 0.068 for ALM) but did not significantly influence the rate of decline over time.
Conclusions
Continuous statin use is associated with a decline in muscle function and mass over time (25% decline in grip strength and 73% decline in ALM compared to never-users), irrespective of genetic susceptibility to statin response. This study emphasizes the importance of monitoring musculoskeletal health in statin users and supports further research into the potential role of a healthy diet and regular physical activity in preserving muscle function, which may also reinforce the cardiovascular benefits of statin therapy.
{"title":"Statin Use Is Associated With a Decline in Muscle Function and Mass Over Time, Irrespective of Statin Pharmacogenomic Score","authors":"Mélissa Gentreau, Mahitab Sakr, Salahuddin Mohammad, Ahmed M. Alsehli, Olga E. Titova, Gull Rukh, Helgi B. Schiöth","doi":"10.1002/jcsm.70132","DOIUrl":"10.1002/jcsm.70132","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Statins are cholesterol-lowering drugs widely prescribed for preventing cardiovascular diseases. They may cause adverse effects on skeletal muscle, but it remains unclear whether they affect muscle function and mass. We aimed to evaluate the association between statin use and muscle function and mass, and whether the pharmacogenomic score (PGS) of statin response modifies these associations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We included 297 977 participants from the UK Biobank. Grip strength was measured using a Jamar J00105 hydraulic hand dynamometer, and the appendicular lean mass (ALM) was estimated using bioelectrical impedance analysis. We performed linear regression to evaluate the cross-sectional and longitudinal associations between statin use and (changes in) grip strength or ALM, adjusting for demographic, lifestyle and health factors. We tested the interaction with the PGS and stratified the analysis by PGS tertile.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Participants averaged 56.4 (± 8) years, and 46% were male. Statin use was associated with lower baseline grip strength (β = −0.68 kg [−0.89, −0.48]) and ALM (β = −0.19 kg [−0.22, −0.16]). Among 35 557 participants with follow-up data (10 ± 5 years), continuous statin use was associated with an accelerated decline in grip strength (β = −0.32 kg/year [−0.49, −0.14]) and ALM (β = −0.06 kg/year [−0.08, −0.03]) compared with never users. The PGS showed a potential modifying effect at baseline (<i>p</i> = 0.058 for grip strength and <i>p</i> = 0.068 for ALM) but did not significantly influence the rate of decline over time.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Continuous statin use is associated with a decline in muscle function and mass over time (25% decline in grip strength and 73% decline in ALM compared to never-users), irrespective of genetic susceptibility to statin response. This study emphasizes the importance of monitoring musculoskeletal health in statin users and supports further research into the potential role of a healthy diet and regular physical activity in preserving muscle function, which may also reinforce the cardiovascular benefits of statin therapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70132","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145558973","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}
Abbey L. Politeski, Alexander Q.L Rico, Jack Cambell, Julio G. Cisneros Medrano, Ben Witmer, Risha Gupta, Noah A. Fiorucci, Katherine M. Lycett, Hannah C. Smith, Hannah M. Kavanagh, Cayleih E. Robertson, Ingrid K. M. Brenner, Aaron B. A. Shafer, Holly E. Bates, Kirk Hillsley, Stephanie W. Tobin
<div> <section> <h3> Background</h3> <p>The monocrotaline (MCT) model of cardiac cachexia is a pharmaceutical approach to pulmonary hypertension that has been used to study heart failure and muscle wasting in rodents; however, little is known of how this pyrrolizidine alkaloid leads to peripheral changes in organ function and body mass, and sex differences have not been adequately compared.</p> </section> <section> <h3> Methods</h3> <p>Ten- to 12-week-old male and female C57BL/6N mice were treated weekly with MCT (200 mg/kg) for 8 weeks. Body weight, feeding behaviour and stool output were monitored weekly. In the final week, endurance was measured via a treadmill fatigue study. Upon termination, organs were weighed and processed for histochemistry and downstream gene expression analysis.</p> </section> <section> <h3> Results</h3> <p>Males were more susceptible to MCT-induced weight loss. No change in gross heart or skeletal muscle mass was observed in either sex, though lung mass was elevated in both sexes and cardiomyocyte size was larger in males (<i>p</i> < 0.05). MCT reduced the cross-sectional area of the tibialis anterior muscle in both sexes (<i>p</i> < 0.05), but this did not correspond to changes in endurance, as the treadmill fatigue study revealed no change in total time or distance run in response to MCT in either sex. RNA-seq analysis of the gastrocnemius muscle showed no significant changes in gene expression when compared within either the male or female cohort (<i>n</i> = 3), but when pooled (<i>n</i> = 6), MCT reduced gene pathways associated with mitochondrial function, adipogenesis and DNA repair and upregulated pathways associated with inflammation. Total fat mass was reduced by 40% in male mice in response to MCT, mainly because of significant reductions in inguinal white and brown interscapular adipose tissue mass. This was independent of food intake and intestinal distress, as no differences in stool wet:dry output or feeding behaviours were observed in either sex. Gene expression and immunohistochemical analysis of inguinal fat suggest that adipose tissue within males is particularly sensitive to MCT, as <i>Tnfa</i>, <i>Ppargc1a</i> and <i>Zfp516</i> were upregulated, and there was a significant interaction between sex and MCT on <i>Retn</i> and <i>Pnpl2a</i> (aka Atgl) expression.</p> </section> <section> <h3> Conclusions</h3> <p>These data suggest sex-dependent physiological responses of mice to MCT, where adipose tissue loss is more pronounced in males as a result of adipose tissue inflammation and metabolic activa
{"title":"The Monocrotaline Model of Hypertension Leads to Cachexia in Male but Not Female Mice","authors":"Abbey L. Politeski, Alexander Q.L Rico, Jack Cambell, Julio G. Cisneros Medrano, Ben Witmer, Risha Gupta, Noah A. Fiorucci, Katherine M. Lycett, Hannah C. Smith, Hannah M. Kavanagh, Cayleih E. Robertson, Ingrid K. M. Brenner, Aaron B. A. Shafer, Holly E. Bates, Kirk Hillsley, Stephanie W. Tobin","doi":"10.1002/jcsm.70129","DOIUrl":"10.1002/jcsm.70129","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The monocrotaline (MCT) model of cardiac cachexia is a pharmaceutical approach to pulmonary hypertension that has been used to study heart failure and muscle wasting in rodents; however, little is known of how this pyrrolizidine alkaloid leads to peripheral changes in organ function and body mass, and sex differences have not been adequately compared.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Ten- to 12-week-old male and female C57BL/6N mice were treated weekly with MCT (200 mg/kg) for 8 weeks. Body weight, feeding behaviour and stool output were monitored weekly. In the final week, endurance was measured via a treadmill fatigue study. Upon termination, organs were weighed and processed for histochemistry and downstream gene expression analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Males were more susceptible to MCT-induced weight loss. No change in gross heart or skeletal muscle mass was observed in either sex, though lung mass was elevated in both sexes and cardiomyocyte size was larger in males (<i>p</i> < 0.05). MCT reduced the cross-sectional area of the tibialis anterior muscle in both sexes (<i>p</i> < 0.05), but this did not correspond to changes in endurance, as the treadmill fatigue study revealed no change in total time or distance run in response to MCT in either sex. RNA-seq analysis of the gastrocnemius muscle showed no significant changes in gene expression when compared within either the male or female cohort (<i>n</i> = 3), but when pooled (<i>n</i> = 6), MCT reduced gene pathways associated with mitochondrial function, adipogenesis and DNA repair and upregulated pathways associated with inflammation. Total fat mass was reduced by 40% in male mice in response to MCT, mainly because of significant reductions in inguinal white and brown interscapular adipose tissue mass. This was independent of food intake and intestinal distress, as no differences in stool wet:dry output or feeding behaviours were observed in either sex. Gene expression and immunohistochemical analysis of inguinal fat suggest that adipose tissue within males is particularly sensitive to MCT, as <i>Tnfa</i>, <i>Ppargc1a</i> and <i>Zfp516</i> were upregulated, and there was a significant interaction between sex and MCT on <i>Retn</i> and <i>Pnpl2a</i> (aka Atgl) expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These data suggest sex-dependent physiological responses of mice to MCT, where adipose tissue loss is more pronounced in males as a result of adipose tissue inflammation and metabolic activa","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70129","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145558970","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}
Emerging evidence suggests that air quality may impact muscle health. However, most studies are limited by cross-sectional designs or short follow-ups. We assessed the association of long-term exposure to ambient air pollutants with changes in muscle mass and strength in older adults.
Methods
We included 3249 participants from the SNAC-K longitudinal study (mean age 74.3 years; 35.8% males). Muscle strength (measured through handgrip and chair stand tests), muscle mass (derived from calf circumference) and physical performance (assessed through walking speed at a usual pace) were assessed over a 12-year period. Probable sarcopenia was defined as reduced muscle strength as per the EWGSOP2 criteria. Residential exposure to PM2.5, PM10 and nitrogen oxide (NOx) was estimated for the 5 years preceding baseline. Cox regressions and linear mixed models examined the association of air pollutant exposure with, respectively, probable sarcopenia and longitudinal changes in muscle parameters.
Results
Over 12 years, the cumulative incidence of probable sarcopenia increased with higher exposure (above vs. below the median values) to NOx (36% vs. 28%), PM2.5 (35% vs. 28%) and PM10 (35% vs. 28%). The association between air pollutant levels and the risk of probable sarcopenia was nonlinear (pnonlinearity = 0.002 for NOx, 0.001 for PM2.5 and 0.003 for PM10), with an increased risk showing a plateau at very high levels. Higher exposures were associated with an increased risk of developing probable sarcopenia, by 25% for NOx and PM2.5 (HR 95% CI: 1.07–1.47 for both) to 33% (HR 95% CI: 1.14–1.56) for PM10. Elevated pollutant exposure was associated with significantly greater annual declines in lower-limb strength (chair stand test: 0.40–0.48 s) and walking speed (0.004 m/s).
Conclusions
Long-term exposure to moderate levels of ambient air pollutants may increase the risk of probable sarcopenia and accelerate declines in lower-limb strength and physical performance in older adults.
新出现的证据表明，空气质量可能会影响肌肉健康。然而，大多数研究受限于横断面设计或短期随访。我们评估了长期暴露于环境空气污染物与老年人肌肉质量和力量变化的关系。方法：我们纳入了来自SNAC‐K纵向研究的3249名参与者（平均年龄74.3岁，35.8%为男性）。肌肉力量（通过握力和椅架测试测量）、肌肉质量（来自小腿围）和身体表现（通过以通常速度行走的速度评估）在12年的时间内进行评估。根据EWGSOP2标准，可能的肌肉减少症被定义为肌肉力量减少。在基线之前的5年，对PM2.5、PM10和氮氧化物（NOx）的居住暴露量进行了估计。Cox回归和线性混合模型分别检验了空气污染物暴露与可能的肌肉减少症和肌肉参数的纵向变化之间的关系。在12年中，随着氮氧化物（36% vs. 28%）、PM2.5 （35% vs. 28%）和PM10 （35% vs. 28%）暴露量的增加（高于中位数vs低于中位数），可能的肌肉减少症的累积发病率增加。空气污染物水平与可能的肌肉减少症风险之间的关系是非线性的（p非线性= 0.002的氮氧化物，0.001的PM2.5和0.003的PM10），增加的风险在非常高的水平上呈现平台。较高的暴露与可能发生肌肉减少症的风险增加有关，氮氧化物和PM2.5的风险增加25% (HR 95% CI: 1.07-1.47)， PM10的风险增加33% （HR 95% CI: 1.14-1.56）。污染物暴露的增加与下肢强度（椅子站立测试：0.40-0.48秒）和步行速度（0.004米/秒）的年下降显著增加相关。结论：长期暴露于中等水平的环境空气污染物可能会增加老年人肌肉减少症的风险，并加速下肢力量和身体机能的下降。
{"title":"Air Pollution Exposure and Muscle Mass and Strength Decline in Older Adults: Results From a Swedish Population–Based Study","authors":"Caterina Trevisan, Caterina Gregorio, Anna-Karin Welmer, Stefano Volpato, Kristina Eneroth, Tom Bellander, Davide Liborio Vetrano, Debora Rizzuto","doi":"10.1002/jcsm.70111","DOIUrl":"10.1002/jcsm.70111","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Emerging evidence suggests that air quality may impact muscle health. However, most studies are limited by cross-sectional designs or short follow-ups. We assessed the association of long-term exposure to ambient air pollutants with changes in muscle mass and strength in older adults.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We included 3249 participants from the SNAC-K longitudinal study (mean age 74.3 years; 35.8% males). Muscle strength (measured through handgrip and chair stand tests), muscle mass (derived from calf circumference) and physical performance (assessed through walking speed at a usual pace) were assessed over a 12-year period. Probable sarcopenia was defined as reduced muscle strength as per the EWGSOP2 criteria. Residential exposure to PM2.5, PM10 and nitrogen oxide (NOx) was estimated for the 5 years preceding baseline. Cox regressions and linear mixed models examined the association of air pollutant exposure with, respectively, probable sarcopenia and longitudinal changes in muscle parameters.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Over 12 years, the cumulative incidence of probable sarcopenia increased with higher exposure (above vs. below the median values) to NOx (36% vs. 28%), PM2.5 (35% vs. 28%) and PM10 (35% vs. 28%). The association between air pollutant levels and the risk of probable sarcopenia was nonlinear (<i>p</i><sub>nonlinearity</sub> = 0.002 for NOx, 0.001 for PM2.5 and 0.003 for PM10), with an increased risk showing a plateau at very high levels. Higher exposures were associated with an increased risk of developing probable sarcopenia, by 25% for NOx and PM2.5 (HR 95% CI: 1.07–1.47 for both) to 33% (HR 95% CI: 1.14–1.56) for PM10. Elevated pollutant exposure was associated with significantly greater annual declines in lower-limb strength (chair stand test: 0.40–0.48 s) and walking speed (0.004 m/s).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Long-term exposure to moderate levels of ambient air pollutants may increase the risk of probable sarcopenia and accelerate declines in lower-limb strength and physical performance in older adults.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70111","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145553740","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 Hermitte, Hortense de Calbiac, Gilles Moulay, Antoine Mérien, Jeanne Lainé, Hélène Polvèche, Michel Cailleret, Stéphane Vassilopoulos, Edor Kabashi, Denis Furling, Cécile Martinat, Morgan Gazzola
<div> <section> <h3> Background</h3> <p>Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder characterized by CTG repeat expansion in the 3′ untranslated region of the <i>dystrophia myotonica protein kinase</i> coding gene. The presence of expanded CTG repeats in DMPK mRNAs leads to the sequestration of RNA-binding factors such as the Muscleblind-like (MBNL) proteins, resulting in widespread splicing defects that contribute to progressive muscle weakness and myotonia. Previously, we identified misregulation of <i>SORBS1</i> exon 25 splicing in both DM1 and MBNL1/2 double-knockout human-induced pluripotent stem cells (hiPSC)-derived skeletal muscle cells, suggesting a potential role in DM1 physiopathology.</p> </section> <section> <h3> Methods</h3> <p>We investigated <i>SORBS1</i> exon 25 splicing misregulation in human skeletal muscle biopsies from DM1 patients and healthy controls. The functional consequence of <i>SORBS1</i> exon 25 exclusion was assessed in mice, zebrafish and hiPSC-derived skeletal muscle cells using an antisense oligonucleotide-mediated exon-skipping strategy.</p> </section> <section> <h3> Results</h3> <p>In human congenital DM1 fetal skeletal muscle biopsies, <i>SORBS1</i> exon 25 inclusion was reduced by 52.6 ± 10% compared to controls (<i>p < 0.001</i>). Analysis of RNA sequencing data from the DMseq database further revealed significant misregulation in tibialis anterior biopsies from 40 adult DM1 patients, with a 15.8 ± 3.7% decrease in splice inclusion (<i>p < 0.0001</i>). In mice, forced exclusion of <i>Sorbs1</i> exon 25 led to neuromuscular junction degeneration, with increased denervation (10.5% ± 3.4%, <i>p < 0.01</i>) and postsynaptic destabilization (5.7% ± 2.5%, <i>p < 0.05</i>). In zebrafish, <i>sorbs1</i> exon 25 misregulation significantly impaired locomotion, reducing trajectory, distance (57.9% ± 12%, <i>p < 0.0001</i>) and velocity (14% ± 0.5%, <i>p < 0.05</i>), while also disrupting acetylcholine receptor cluster morphology. Similarly, forced <i>SORBS1</i> exon 25 exclusion in hiPSC-derived skeletal muscle cells diminished the formation of large acetylcholine receptor clusters upon agrin stimulation by 34% <i>±</i> 4.5% (<i>p < 0.0001</i>).</p> </section> <section> <h3> Conclusion</h3> <p>Our study identifies <i>SORBS1</i> alternative splicing as an essential MBNL-regulated event during skeletal muscle development, potentially involved in neuromuscular junction formation and maintenance. The aberrant splicing of <i>SORBS1</i> exon 25 in DM1 expands our understanding
{"title":"Alternative Splicing of SORBS1 Affects Neuromuscular Junction Integrity in Myotonic Dystrophy Type 1","authors":"Caroline Hermitte, Hortense de Calbiac, Gilles Moulay, Antoine Mérien, Jeanne Lainé, Hélène Polvèche, Michel Cailleret, Stéphane Vassilopoulos, Edor Kabashi, Denis Furling, Cécile Martinat, Morgan Gazzola","doi":"10.1002/jcsm.70112","DOIUrl":"10.1002/jcsm.70112","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder characterized by CTG repeat expansion in the 3′ untranslated region of the <i>dystrophia myotonica protein kinase</i> coding gene. The presence of expanded CTG repeats in DMPK mRNAs leads to the sequestration of RNA-binding factors such as the Muscleblind-like (MBNL) proteins, resulting in widespread splicing defects that contribute to progressive muscle weakness and myotonia. Previously, we identified misregulation of <i>SORBS1</i> exon 25 splicing in both DM1 and MBNL1/2 double-knockout human-induced pluripotent stem cells (hiPSC)-derived skeletal muscle cells, suggesting a potential role in DM1 physiopathology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We investigated <i>SORBS1</i> exon 25 splicing misregulation in human skeletal muscle biopsies from DM1 patients and healthy controls. The functional consequence of <i>SORBS1</i> exon 25 exclusion was assessed in mice, zebrafish and hiPSC-derived skeletal muscle cells using an antisense oligonucleotide-mediated exon-skipping strategy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In human congenital DM1 fetal skeletal muscle biopsies, <i>SORBS1</i> exon 25 inclusion was reduced by 52.6 ± 10% compared to controls (<i>p < 0.001</i>). Analysis of RNA sequencing data from the DMseq database further revealed significant misregulation in tibialis anterior biopsies from 40 adult DM1 patients, with a 15.8 ± 3.7% decrease in splice inclusion (<i>p < 0.0001</i>). In mice, forced exclusion of <i>Sorbs1</i> exon 25 led to neuromuscular junction degeneration, with increased denervation (10.5% ± 3.4%, <i>p < 0.01</i>) and postsynaptic destabilization (5.7% ± 2.5%, <i>p < 0.05</i>). In zebrafish, <i>sorbs1</i> exon 25 misregulation significantly impaired locomotion, reducing trajectory, distance (57.9% ± 12%, <i>p < 0.0001</i>) and velocity (14% ± 0.5%, <i>p < 0.05</i>), while also disrupting acetylcholine receptor cluster morphology. Similarly, forced <i>SORBS1</i> exon 25 exclusion in hiPSC-derived skeletal muscle cells diminished the formation of large acetylcholine receptor clusters upon agrin stimulation by 34% <i>±</i> 4.5% (<i>p < 0.0001</i>).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study identifies <i>SORBS1</i> alternative splicing as an essential MBNL-regulated event during skeletal muscle development, potentially involved in neuromuscular junction formation and maintenance. The aberrant splicing of <i>SORBS1</i> exon 25 in DM1 expands our understanding","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70112","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535646","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}
Peter O. Isesele, Bhumi J. Bhatt, Vickie E. Baracos, Sambasivarao Damaraju, Vera C. Mazurak
<div> <section> <h3> Background</h3> <p>Skeletal muscle loss is a well-recognized consequence of cancer, and chemotherapy exacerbates myotoxicity through multiple mechanisms. Retaining muscle mass improves tumour response to therapies and tolerance to chemotherapy; hence, interventions to mitigate myotoxicity warrant investigations. This study aimed to investigate the protective effects of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) provided in the form of fish oil on chemotherapy-induced myotoxicity using next-generation RNA sequencing (NGS).</p> </section> <section> <h3> Methods</h3> <p>Fischer 344 rats were fed either a standard diet (STD) for the entire study or switched to a diet containing fish oil (2.3 g/100 g of diet) when chemotherapy (irinotecan + 5-fluorouracil) was initiated. All rats received the Ward colon tumour and tumours were allowed to grow for 2 weeks. Comparisons were made between (1) tumour-bearing rats on a standard diet (TUMOUR STD), (2) tumour-bearing rats that received chemotherapy on a standard diet (CHEMO STD) and (3) tumour-bearing rats that received chemotherapy on a fish oil diet (CHEMO FO). After two cycles of chemotherapy, NGS was performed on gastrocnemius muscle. Differential expression of genes was performed using DEseq2, with a fold-change cut-off ≥ 1.5 and <i>p</i> value < 0.05. Ingenuity pathway analysis (IPA) was used for functional annotation, canonical pathways and upstream regulators analysis.</p> </section> <section> <h3> Results</h3> <p>Transcriptomic analysis revealed distinct alterations in skeletal muscle gene expression profiles. In the CHEMO STD versus TUMOUR STD comparison, 272 genes showed differential expression. Of these, 55% were upregulated and 45% were downregulated. Two cycles of chemotherapy altered genes in the pathways of proliferation of muscle cells (<i>p</i> < 10<sup>−7</sup>), connective tissue disorder (<i>p</i> < 10<sup>−6</sup>), apoptosis (<i>p</i> < 10<sup>−3</sup>) and neurodevelopmental disorders (<i>p</i> < 10<sup>−3</sup>). In the CHEMO FO versus CHEMO STD comparison, 274 genes were differentially expressed (73% upregulated and 27% downregulated). Dietary fish oil exclusively altered immune-related functions, notably downregulating several genes in the leukocyte extravasation pathway (−log<i>p</i> value 5.92, <i>z</i> score −2.83). Upstream regulatory molecules after chemotherapy were predicted to inhibit transcription factors involved in myogenic regeneration, while those fed a diet containing fish oil showed inhibition of inflammation-related cytokines.</p> </section> <section>
{"title":"Pathways Contributing to Chemotherapy-Induced Myotoxicity Are Attenuated by EPA + DHA in a Clinically Relevant Model of Colorectal Cancer","authors":"Peter O. Isesele, Bhumi J. Bhatt, Vickie E. Baracos, Sambasivarao Damaraju, Vera C. Mazurak","doi":"10.1002/jcsm.70110","DOIUrl":"10.1002/jcsm.70110","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Skeletal muscle loss is a well-recognized consequence of cancer, and chemotherapy exacerbates myotoxicity through multiple mechanisms. Retaining muscle mass improves tumour response to therapies and tolerance to chemotherapy; hence, interventions to mitigate myotoxicity warrant investigations. This study aimed to investigate the protective effects of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) provided in the form of fish oil on chemotherapy-induced myotoxicity using next-generation RNA sequencing (NGS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Fischer 344 rats were fed either a standard diet (STD) for the entire study or switched to a diet containing fish oil (2.3 g/100 g of diet) when chemotherapy (irinotecan + 5-fluorouracil) was initiated. All rats received the Ward colon tumour and tumours were allowed to grow for 2 weeks. Comparisons were made between (1) tumour-bearing rats on a standard diet (TUMOUR STD), (2) tumour-bearing rats that received chemotherapy on a standard diet (CHEMO STD) and (3) tumour-bearing rats that received chemotherapy on a fish oil diet (CHEMO FO). After two cycles of chemotherapy, NGS was performed on gastrocnemius muscle. Differential expression of genes was performed using DEseq2, with a fold-change cut-off ≥ 1.5 and <i>p</i> value < 0.05. Ingenuity pathway analysis (IPA) was used for functional annotation, canonical pathways and upstream regulators analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Transcriptomic analysis revealed distinct alterations in skeletal muscle gene expression profiles. In the CHEMO STD versus TUMOUR STD comparison, 272 genes showed differential expression. Of these, 55% were upregulated and 45% were downregulated. Two cycles of chemotherapy altered genes in the pathways of proliferation of muscle cells (<i>p</i> < 10<sup>−7</sup>), connective tissue disorder (<i>p</i> < 10<sup>−6</sup>), apoptosis (<i>p</i> < 10<sup>−3</sup>) and neurodevelopmental disorders (<i>p</i> < 10<sup>−3</sup>). In the CHEMO FO versus CHEMO STD comparison, 274 genes were differentially expressed (73% upregulated and 27% downregulated). Dietary fish oil exclusively altered immune-related functions, notably downregulating several genes in the leukocyte extravasation pathway (−log<i>p</i> value 5.92, <i>z</i> score −2.83). Upstream regulatory molecules after chemotherapy were predicted to inhibit transcription factors involved in myogenic regeneration, while those fed a diet containing fish oil showed inhibition of inflammation-related cytokines.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 ","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70110","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531143","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}
Maria Westerståhl, Gustav Jörnåker, Eva Jansson, Ulrika Aasa, Michael Ingre, Kaveh Pourhamidi, Brun Ulfhake, Thomas Gustafsson
<div> <section> <h3> Background</h3> <p>As we age, there is a progressive decline in skeletal muscle tissue and function that can become clinically significant in the sixth decade of life affecting independent living and health. Longitudinal observations in elite athletes show that peak physical performance is reached before the age of about 35 years despite continuous training, suggesting that the tissue processes underlying muscle dysfunction may begin decades before they become clinically relevant. To answer the question of whether the pattern of performance decline in athletes also applies to the general population, a population-based longitudinal study is needed.</p> </section> <section> <h3> Methods</h3> <p>In the Swedish population cohort (SPAF), 427 individuals (48% women) born in 1958 underwent repeated objective assessments of physical capacity from age 16 to 63 years. Linear mixed models were used to estimate age- and sex-specific changes in the original cohort during the study period.</p> </section> <section> <h3> Results</h3> <p>The estimated maximal aerobic capacity and muscular endurance (bench press repetitions) peaked at ages 26–36 in both sexes and declined gradually, starting at 0.3%–0.6% per year and accelerating to 2.0%–2.5% per year (main effect of age <i>p</i> < 0.001 and sex <i>p</i> < 0.01), with no sex difference in decline rates. Muscle power was measured using the Sargent jump test, with men having their peak at age 27, and women at age 19. Group variance in physical performance increased markedly with age, with relative aerobic capacity showing a 25-fold increase, jump height a nearly 5-fold increase, and muscular endurance a threefold increase in variance from adolescence to age 63. The rate of decline was small initially (0.2%–0.5% per year) but increased with age (2.2% per year), in both sexes (main effect of age <i>p</i> < 0.001 and sex <i>p</i> < 0.001), with no difference between the sexes. The overall decline in physical capacity from peak to age 63 ranged from 30% to 48%. Higher leisure-time physical activity at age 16 and becoming active in adulthood were associated with better performance across all outcomes (<i>p</i> = 0.00–0.02); having a university degree was positively associated with absolute aerobic capacity (<i>p</i> = 0.04) and muscular endurance (<i>p</i> = 0.02).</p> </section> <section> <h3> Conclusions</h3> <p>The Swedish population cohort SPAF shows the same pattern of changes in physical capacity in adulthood as previously demonstrated for elite athletes. This confirms the concept tha
{"title":"Rise and Fall of Physical Capacity in a General Population: A 47-Year Longitudinal Study","authors":"Maria Westerståhl, Gustav Jörnåker, Eva Jansson, Ulrika Aasa, Michael Ingre, Kaveh Pourhamidi, Brun Ulfhake, Thomas Gustafsson","doi":"10.1002/jcsm.70134","DOIUrl":"10.1002/jcsm.70134","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>As we age, there is a progressive decline in skeletal muscle tissue and function that can become clinically significant in the sixth decade of life affecting independent living and health. Longitudinal observations in elite athletes show that peak physical performance is reached before the age of about 35 years despite continuous training, suggesting that the tissue processes underlying muscle dysfunction may begin decades before they become clinically relevant. To answer the question of whether the pattern of performance decline in athletes also applies to the general population, a population-based longitudinal study is needed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In the Swedish population cohort (SPAF), 427 individuals (48% women) born in 1958 underwent repeated objective assessments of physical capacity from age 16 to 63 years. Linear mixed models were used to estimate age- and sex-specific changes in the original cohort during the study period.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The estimated maximal aerobic capacity and muscular endurance (bench press repetitions) peaked at ages 26–36 in both sexes and declined gradually, starting at 0.3%–0.6% per year and accelerating to 2.0%–2.5% per year (main effect of age <i>p</i> < 0.001 and sex <i>p</i> < 0.01), with no sex difference in decline rates. Muscle power was measured using the Sargent jump test, with men having their peak at age 27, and women at age 19. Group variance in physical performance increased markedly with age, with relative aerobic capacity showing a 25-fold increase, jump height a nearly 5-fold increase, and muscular endurance a threefold increase in variance from adolescence to age 63. The rate of decline was small initially (0.2%–0.5% per year) but increased with age (2.2% per year), in both sexes (main effect of age <i>p</i> < 0.001 and sex <i>p</i> < 0.001), with no difference between the sexes. The overall decline in physical capacity from peak to age 63 ranged from 30% to 48%. Higher leisure-time physical activity at age 16 and becoming active in adulthood were associated with better performance across all outcomes (<i>p</i> = 0.00–0.02); having a university degree was positively associated with absolute aerobic capacity (<i>p</i> = 0.04) and muscular endurance (<i>p</i> = 0.02).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The Swedish population cohort SPAF shows the same pattern of changes in physical capacity in adulthood as previously demonstrated for elite athletes. This confirms the concept tha","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70134","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531142","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>Appendicular circumferences (ACs) are critical predictors of skeletal health, cardiovascular disease risk and mortality. Currently, comprehensive reference values and associated factors for thigh (TC), calf (CC), upper arm (UAC) and forearm (FC) circumferences remain unestablished in Chinese adults.</p> </section> <section> <h3> Methods</h3> <p>This community-based cross-sectional study (China National Health Survey, April 2023–November 2024) enrolled 8915 adults (≥20 years) for reference value development and 10 632 for association analysis. ACs were measured via 3D scanning, body composition via bioelectrical impedance analysis and handgrip strength using a Jamar dynamometer. Sex-specific centile curves (P2.5–P97.5) were generated using lambda-mu-sigma methods. Propensity score matching balanced age distributions for sex and menopause subgroup comparisons. Multivariate logistic regression was used to examine factors associated with low appendicular circumference (lowest 5th percentile).</p> </section> <section> <h3> Results</h3> <p>Median (25th and 75th) values for men were TC: 59.27 cm (55.09, 64.18), CC: 39.20 cm (37.17, 41.59), UAC: 28.31 cm (26.75, 30.10) and FC: 27.02 cm (25.67, 28.29); for women, TC: 52.45 cm (49.50, 55.74), CC: 35.71 cm (33.95, 37.76), UAC: 27.71 cm (25.74, 30.10) and FC: 24.64 cm (23.33, 26.07). Age trajectories showed sex-specific patterns: TC, CC and UAC peaked at 20–29 years with subsequent decline, while FC peaked at 40–49 years. BMI-adjusted circumferences exhibited divergent aging trajectories by sex. Postmenopausal women had significantly lower appendicular skeletal muscle mass (ASM), appendicular skeletal muscle mass index (ASMI), handgrip strength and CC than age-matched premenopausal women (all <i>p</i> values < 0.05). All ACs strongly correlated with muscle mass, fat mass and muscle strength (all <i>p</i> values < 0.001), with UAC and FC showing the strongest ASM and ASMI correlations in men (correlation coefficient: 0.757 and 0.735). Factors associated with low ACs included rural residence, lower education, low BMI, elevated body fat (positively linked to low CC, especially ≥ 60 years) and cardiometabolic disorders (diabetes, hypertension, hyperuricemia, dyslipidemia).</p> </section> <section> <h3> Conclusions</h3> <p>This study establishes the first age- and sex-stratified percentile references for ACs in Chinese adults. These results reveal significant sex disparities in absolute and BMI-adjusted measures, providing essential tools for sarcopenia screening, lifes
背景：阑尾周长（ACs）是骨骼健康、心血管疾病风险和死亡率的重要预测指标。目前，中国成人大腿（TC）、小腿（CC）、上臂（UAC）和前臂（FC）围围的综合参考值和相关因素尚未确定。方法基于社区的横断面研究（中国国家健康调查，2023年4月- 2024年11月）纳入8915名≥20岁成人进行参考值开发，10632名进行关联分析。通过3D扫描测量ac，通过生物电阻抗分析测量身体成分，使用Jamar测力仪测量握力。使用lambda-mu-sigma方法生成性别特异性百分位曲线（P2.5-P97.5）。倾向得分匹配平衡年龄分布的性别和更年期亚组比较。采用多因素logistic回归分析阑尾围低（最低第5百分位）的相关因素。结果男性的中位值（25和75）为TC: 59.27 cm (55.09, 64.18), CC: 39.20 cm (37.17, 41.59), UAC: 28.31 cm (26.75, 30.10), FC: 27.02 cm (25.67, 28.29)；女性：TC: 52.45 cm (49.50, 55.74), CC: 35.71 cm (33.95, 37.76), UAC: 27.71 cm (25.74, 30.10), FC: 24.64 cm（23.33, 26.07）。年龄轨迹表现出性别差异：TC、CC和UAC在20-29岁达到峰值，随后下降，而FC在40-49岁达到峰值。bmi调整后的周长显示出不同性别的衰老轨迹。绝经后妇女的阑尾骨骼肌质量（ASM）、阑尾骨骼肌质量指数（ASMI）、握力和CC均显著低于同龄绝经前妇女（p值均< 0.05）。所有ACs均与肌肉质量、脂肪质量和肌肉力量强相关（p值均< 0.001），其中UAC和FC在男性中表现出最强的ASM和ASMI相关性（相关系数分别为0.757和0.735）。与低ACs相关的因素包括农村居住、低教育程度、低BMI、体脂升高（与低CC呈正相关，尤其是≥60岁）和心脏代谢疾病（糖尿病、高血压、高尿酸血症、血脂异常）。结论：本研究首次建立了中国成人ACs的年龄和性别分层百分位数参考。这些结果揭示了绝对指标和bmi调整指标的显著性别差异，为肌少症筛查、生活方式干预评估和高危人群识别提供了重要工具。
{"title":"3D Body Scanning–Derived Normative Values of Appendicular Circumferences: A Novel Tool for Sarcopenia Screening in Chinese Adults","authors":"Huijing He, Qiaolu Cheng, Zhiyue Zhang, Yaoda Hu, Zhiming Lu, Wei Han, Ji Tu, Ang Li, Zhen Song, Yawen Liu, Tan Xu, Qing Chang, Qiong Ou, Hui Pan, Zichao Wang, Guangliang Shan","doi":"10.1002/jcsm.70135","DOIUrl":"10.1002/jcsm.70135","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Appendicular circumferences (ACs) are critical predictors of skeletal health, cardiovascular disease risk and mortality. Currently, comprehensive reference values and associated factors for thigh (TC), calf (CC), upper arm (UAC) and forearm (FC) circumferences remain unestablished in Chinese adults.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This community-based cross-sectional study (China National Health Survey, April 2023–November 2024) enrolled 8915 adults (≥20 years) for reference value development and 10 632 for association analysis. ACs were measured via 3D scanning, body composition via bioelectrical impedance analysis and handgrip strength using a Jamar dynamometer. Sex-specific centile curves (P2.5–P97.5) were generated using lambda-mu-sigma methods. Propensity score matching balanced age distributions for sex and menopause subgroup comparisons. Multivariate logistic regression was used to examine factors associated with low appendicular circumference (lowest 5th percentile).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Median (25th and 75th) values for men were TC: 59.27 cm (55.09, 64.18), CC: 39.20 cm (37.17, 41.59), UAC: 28.31 cm (26.75, 30.10) and FC: 27.02 cm (25.67, 28.29); for women, TC: 52.45 cm (49.50, 55.74), CC: 35.71 cm (33.95, 37.76), UAC: 27.71 cm (25.74, 30.10) and FC: 24.64 cm (23.33, 26.07). Age trajectories showed sex-specific patterns: TC, CC and UAC peaked at 20–29 years with subsequent decline, while FC peaked at 40–49 years. BMI-adjusted circumferences exhibited divergent aging trajectories by sex. Postmenopausal women had significantly lower appendicular skeletal muscle mass (ASM), appendicular skeletal muscle mass index (ASMI), handgrip strength and CC than age-matched premenopausal women (all <i>p</i> values < 0.05). All ACs strongly correlated with muscle mass, fat mass and muscle strength (all <i>p</i> values < 0.001), with UAC and FC showing the strongest ASM and ASMI correlations in men (correlation coefficient: 0.757 and 0.735). Factors associated with low ACs included rural residence, lower education, low BMI, elevated body fat (positively linked to low CC, especially ≥ 60 years) and cardiometabolic disorders (diabetes, hypertension, hyperuricemia, dyslipidemia).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study establishes the first age- and sex-stratified percentile references for ACs in Chinese adults. These results reveal significant sex disparities in absolute and BMI-adjusted measures, providing essential tools for sarcopenia screening, lifes","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70135","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531174","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}
Fernando Ribeiro, Paulo R. Jannig, Siegfried Labeit, Anselmo S. Moriscot
Background
Mechanical inactivity rapidly induces diaphragm muscle fibres' contractile dysfunction and atrophy. Diaphragm weakness can impair respiratory function, quality of life and increase risks of morbidity and mortality. Muscle RING-finger protein-1 (MuRF1) expression is upregulated during denervation and muscle inactivity and is known to target key muscle proteins for degradation. We previously reported that the small-molecule targeting MuRF1 (MyoMed-205) protects against diaphragm contractile dysfunction and atrophy after 12 h of unilateral diaphragm denervation (UDD) in rats. In this study, we investigated the mechanisms by which MyoMed-205 protects the diaphragm structure and function during early UDD in rats.
Methods
Male Wistar rats were subjected to unilateral diaphragm denervation (UDD) for 12 h. Immediately after UDD, rats received either a placebo (vehicle) or small-molecule targeting MuRF1 (MyoMed-205, 50 mg/kg bw), and outcomes were compared with sham-operated controls. Diaphragm was used for histological, morphometric, transcriptomic (RNA-seq) and protein content (Western blot) analysis.
Results
UDD induced diaphragm slow- (Type I: p = 0.03) and fast-twitch (Type IIa: p = 0.04; Type IIb/x: p = 0.02) fibres atrophy after 12 h, which was prevented by MyoMed-205 (p < 0.05). Mechanistically, UDD perturbed mechanisms involved with myofibre ultrastructure and contractility, mitochondrial function, proteolysis and tissue remodelling in the diaphragm. MyoMed-205 enhanced the activation of mechanisms required for sarcomere integrity, calcium handling, antioxidant defence, chaperone-mediated unfolded protein response and muscle growth. MyoMed-205 also mitigated intramuscular fat deposition and pro-fibrotic responses triggered by UDD.
Conclusions
Small-molecule targeting MuRF1 (MyoMed-205) protects against diaphragm muscle contractile dysfunction and atrophy after 12 h of UDD. Herein, we demonstrate that this protective effect involved augmented activation of signalling pathways controlling muscle structure and function, chaperone-mediated unfolded protein and muscle growth, while mitigating intramuscular fat deposition and pro-fibrotic responses triggered by UDD at the transcriptional and/or protein level.
{"title":"Small-Molecule Targeting MuRF1 Protects Against Denervation-Induced Diaphragmatic Dysfunction: Underlying Molecular Mechanisms","authors":"Fernando Ribeiro, Paulo R. Jannig, Siegfried Labeit, Anselmo S. Moriscot","doi":"10.1002/jcsm.70119","DOIUrl":"10.1002/jcsm.70119","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Mechanical inactivity rapidly induces diaphragm muscle fibres' contractile dysfunction and atrophy. Diaphragm weakness can impair respiratory function, quality of life and increase risks of morbidity and mortality. Muscle RING-finger protein-1 (MuRF1) expression is upregulated during denervation and muscle inactivity and is known to target key muscle proteins for degradation. We previously reported that the small-molecule targeting MuRF1 (MyoMed-205) protects against diaphragm contractile dysfunction and atrophy after 12 h of unilateral diaphragm denervation (UDD) in rats. In this study, we investigated the mechanisms by which MyoMed-205 protects the diaphragm structure and function during early UDD in rats.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Male Wistar rats were subjected to unilateral diaphragm denervation (UDD) for 12 h. Immediately after UDD, rats received either a placebo (vehicle) or small-molecule targeting MuRF1 (MyoMed-205, 50 mg/kg bw), and outcomes were compared with sham-operated controls. Diaphragm was used for histological, morphometric, transcriptomic (RNA-seq) and protein content (Western blot) analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>UDD induced diaphragm slow- (Type I: <i>p</i> = 0.03) and fast-twitch (Type IIa: <i>p</i> = 0.04; Type IIb/x: <i>p</i> = 0.02) fibres atrophy after 12 h, which was prevented by MyoMed-205 (<i>p</i> < 0.05). Mechanistically, UDD perturbed mechanisms involved with myofibre ultrastructure and contractility, mitochondrial function, proteolysis and tissue remodelling in the diaphragm. MyoMed-205 enhanced the activation of mechanisms required for sarcomere integrity, calcium handling, antioxidant defence, chaperone-mediated unfolded protein response and muscle growth. MyoMed-205 also mitigated intramuscular fat deposition and pro-fibrotic responses triggered by UDD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Small-molecule targeting MuRF1 (MyoMed-205) protects against diaphragm muscle contractile dysfunction and atrophy after 12 h of UDD. Herein, we demonstrate that this protective effect involved augmented activation of signalling pathways controlling muscle structure and function, chaperone-mediated unfolded protein and muscle growth, while mitigating intramuscular fat deposition and pro-fibrotic responses triggered by UDD at the transcriptional and/or protein level.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70119","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531655","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}
Petar Naumovski, Bart De Spiegeleer, Aster Wakjira, Christophe Van De Wiele, Vincent Mouly, Katarzyna Goljanek-Whysall, Kauê Santana da Costa, Ewerton Cristhian Lima de Oliveira, Evelien Wynendaele, Anton De Spiegeleer
<div> <section> <h3> Background</h3> <p>Systemic muscle wasting is a prevalent condition that predicts adverse health outcomes in aging and disease. Despite its clinical relevance, the development of predictive biomarkers and effective pharmacological therapies remains limited. Peptides have recently gained attention for their diverse bioactive functions, positioning them as promising biomarkers and therapeutic agents for muscle wasting.</p> </section> <section> <h3> Methods</h3> <p>This scoping review systematically identifies studies examining the direct association between well-defined peptides and clinical components of muscle wasting: muscle mass, strength and physical performance. The review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Scoping Reviews (PRISMA-ScR) guidelines. A comprehensive search of Embase, PubMed and Web of Science was conducted up to 31 October 2024, focusing on original human or animal studies. Studies involving congenital or inherited muscle disorders, inflammatory myopathies and neurodegenerative diseases, such as Parkinson's disease, were excluded. A snowball approach was used to synthesize the presumed cellular pathways of identified peptides.</p> </section> <section> <h3> Results</h3> <p>A total of 126 studies were included: 71 (56.3%) focused on a single muscle wasting component (48 on mass, 16 on strength and 7 on performance), 31 (24.6%) examined two, 16 (12.7%) analysed all three separately, and 8 (6.3%) assessed sarcopenia as a categorical variable.</p> <p>Eighty-seven distinct peptides linked to muscle wasting were identified, ranging from collagen tripeptide (3 amino acids) to insulin (51 amino acids). The most studied peptides are ghrelin (14.3%), brain natriuretic peptide (BNP, 11.1%), C-peptide (11.1%), insulin (10.3%) and Szeto-Schiller 31 (SS-31, 6.3%). Most (62.1%) influence one or more of four key muscle homeostasis pathways (PI3K/Akt/mTOR, ActR/SMAD, IKK/NF-κB and AMPK/PGC1α), which regulate atrophy (via FOXO, NF-κB, SMAD2/3, glucocorticoid receptor and GSK-3β) and hypertrophy (via androgen receptors, PGC-1α and S6K). Flaws in study design and reporting were prevalent, hindering clinical translation. Sex bias was evident, with females comprising 23.9% of participants in human interventional studies and only 9.1% and 12.4% of mice and rats in rodent studies, respectively. Clinical, pre-analytical and analytical reporting gaps were common: 56.6% documented diurnal timing, food intake and activity around peptide collection; none specified storage-to-analysis duration; and only 11.5% reported detection limits for peptide measurements.</p
{"title":"Role of Peptides in Skeletal Muscle Wasting: A Scoping Review","authors":"Petar Naumovski, Bart De Spiegeleer, Aster Wakjira, Christophe Van De Wiele, Vincent Mouly, Katarzyna Goljanek-Whysall, Kauê Santana da Costa, Ewerton Cristhian Lima de Oliveira, Evelien Wynendaele, Anton De Spiegeleer","doi":"10.1002/jcsm.70109","DOIUrl":"10.1002/jcsm.70109","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Systemic muscle wasting is a prevalent condition that predicts adverse health outcomes in aging and disease. Despite its clinical relevance, the development of predictive biomarkers and effective pharmacological therapies remains limited. Peptides have recently gained attention for their diverse bioactive functions, positioning them as promising biomarkers and therapeutic agents for muscle wasting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This scoping review systematically identifies studies examining the direct association between well-defined peptides and clinical components of muscle wasting: muscle mass, strength and physical performance. The review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Scoping Reviews (PRISMA-ScR) guidelines. A comprehensive search of Embase, PubMed and Web of Science was conducted up to 31 October 2024, focusing on original human or animal studies. Studies involving congenital or inherited muscle disorders, inflammatory myopathies and neurodegenerative diseases, such as Parkinson's disease, were excluded. A snowball approach was used to synthesize the presumed cellular pathways of identified peptides.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 126 studies were included: 71 (56.3%) focused on a single muscle wasting component (48 on mass, 16 on strength and 7 on performance), 31 (24.6%) examined two, 16 (12.7%) analysed all three separately, and 8 (6.3%) assessed sarcopenia as a categorical variable.</p>\u0000 \u0000 <p>Eighty-seven distinct peptides linked to muscle wasting were identified, ranging from collagen tripeptide (3 amino acids) to insulin (51 amino acids). The most studied peptides are ghrelin (14.3%), brain natriuretic peptide (BNP, 11.1%), C-peptide (11.1%), insulin (10.3%) and Szeto-Schiller 31 (SS-31, 6.3%). Most (62.1%) influence one or more of four key muscle homeostasis pathways (PI3K/Akt/mTOR, ActR/SMAD, IKK/NF-κB and AMPK/PGC1α), which regulate atrophy (via FOXO, NF-κB, SMAD2/3, glucocorticoid receptor and GSK-3β) and hypertrophy (via androgen receptors, PGC-1α and S6K). Flaws in study design and reporting were prevalent, hindering clinical translation. Sex bias was evident, with females comprising 23.9% of participants in human interventional studies and only 9.1% and 12.4% of mice and rats in rodent studies, respectively. Clinical, pre-analytical and analytical reporting gaps were common: 56.6% documented diurnal timing, food intake and activity around peptide collection; none specified storage-to-analysis duration; and only 11.5% reported detection limits for peptide measurements.</p","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145499048","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}
Akhil Baby, Kalyani Ananthamohan, Brenna N. McIntyre, Sankar Natesan, Taejeong Song
<div> <section> <h3> Background</h3> <p>Skeletal muscle plays a vital role in voluntary movement and locomotion. Fast-twitch muscle fibres are characterized by their rapid contraction kinetics, high-force generation and a distinct gene expression profile compared to slow-twitch fibres. These fibres have a predominant expression of fast skeletal myosin binding protein-C (fMyBP-C). The role of fMyBP-C in skeletal muscle disease and aging remains poorly understood. To address this, our study employs mouse models with fMyBP-C ablation to investigate its significance in skeletal muscle physiology.</p> </section> <section> <h3> Methods</h3> <p>Skeletal muscle samples from wild-type, db/db, MDX and ECC injury model (2–7 months) were analysed to determine the fMyBP-C levels. Next, male <i>Mybpc2</i> knockout (C2<sup>−/−</sup>) mice, both young (3–5 months) and old (22 months), were utilized to investigate the role of fMyBP-C in aging. The effects of C2<sup>−/−</sup> and aging on the fibre type, size and number, as well as the overall muscle structure, were evaluated using immunohistochemistry and electron microscopy. In vivo and ex vivo muscle force generation was assessed to determine the functional impact of C2<sup>−/−</sup> and aging. RNA sequencing was conducted to identify the altered molecular pathways causing the muscle dysfunction in young and old C2<sup>−/−</sup> mice.</p> </section> <section> <h3> Results</h3> <p>The expression of fMyBP-C was reduced (0.25-fold, <i>p</i> < 0.05) in the fast-twitch muscles of db/db mice, with a modest compensatory upregulation of slow skeletal MyBP-C (sMyBP-C) (~1.15-fold, <i>p</i> < 0.05). In MDX mice, fMyBP-C levels remain unchanged, whereas sMyBP-C levels were upregulated (~1.2-fold, <i>p</i> < 0.01). The fMyBP-C expression was 75% higher in the male skeletal muscles (<i>p</i> < 0.01) compared to females. Studies in young male C2<sup>−/−</sup> mice revealed a reduction in isometric tetanic force generation by 25% (<i>p</i> < 0.01) and relaxation rate by 42% (<i>p</i> < 0.001). The C2<sup>−/−</sup> mice also had 12.8% fewer type IIb fibres (<i>p</i> < 0.01), and a 20% reduction in type IIb fibre size (<i>p</i> < 0.01). Similarly, aged male C2<sup>−/−</sup> mice exhibited significant deficits in muscle strength, endurance and survival rate relative to their wild-type counterparts. The aged male C2<sup>−/−</sup> mice displayed a reduced size of type IIa, IIx and IIb muscle fibres compared to aged wild-type mice. RNA sequencing revealed that assembly and trimerization of collagen fibril pathway-related genes were altered in C2<sup>−/−</sup> mice.</p> </section>
{"title":"Fast Myosin Binding Protein-C Is a Vital Regulator in Young and Aged Fast Skeletal Muscle Homeostasis","authors":"Akhil Baby, Kalyani Ananthamohan, Brenna N. McIntyre, Sankar Natesan, Taejeong Song","doi":"10.1002/jcsm.70106","DOIUrl":"10.1002/jcsm.70106","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Skeletal muscle plays a vital role in voluntary movement and locomotion. Fast-twitch muscle fibres are characterized by their rapid contraction kinetics, high-force generation and a distinct gene expression profile compared to slow-twitch fibres. These fibres have a predominant expression of fast skeletal myosin binding protein-C (fMyBP-C). The role of fMyBP-C in skeletal muscle disease and aging remains poorly understood. To address this, our study employs mouse models with fMyBP-C ablation to investigate its significance in skeletal muscle physiology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Skeletal muscle samples from wild-type, db/db, MDX and ECC injury model (2–7 months) were analysed to determine the fMyBP-C levels. Next, male <i>Mybpc2</i> knockout (C2<sup>−/−</sup>) mice, both young (3–5 months) and old (22 months), were utilized to investigate the role of fMyBP-C in aging. The effects of C2<sup>−/−</sup> and aging on the fibre type, size and number, as well as the overall muscle structure, were evaluated using immunohistochemistry and electron microscopy. In vivo and ex vivo muscle force generation was assessed to determine the functional impact of C2<sup>−/−</sup> and aging. RNA sequencing was conducted to identify the altered molecular pathways causing the muscle dysfunction in young and old C2<sup>−/−</sup> mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The expression of fMyBP-C was reduced (0.25-fold, <i>p</i> < 0.05) in the fast-twitch muscles of db/db mice, with a modest compensatory upregulation of slow skeletal MyBP-C (sMyBP-C) (~1.15-fold, <i>p</i> < 0.05). In MDX mice, fMyBP-C levels remain unchanged, whereas sMyBP-C levels were upregulated (~1.2-fold, <i>p</i> < 0.01). The fMyBP-C expression was 75% higher in the male skeletal muscles (<i>p</i> < 0.01) compared to females. Studies in young male C2<sup>−/−</sup> mice revealed a reduction in isometric tetanic force generation by 25% (<i>p</i> < 0.01) and relaxation rate by 42% (<i>p</i> < 0.001). The C2<sup>−/−</sup> mice also had 12.8% fewer type IIb fibres (<i>p</i> < 0.01), and a 20% reduction in type IIb fibre size (<i>p</i> < 0.01). Similarly, aged male C2<sup>−/−</sup> mice exhibited significant deficits in muscle strength, endurance and survival rate relative to their wild-type counterparts. The aged male C2<sup>−/−</sup> mice displayed a reduced size of type IIa, IIx and IIb muscle fibres compared to aged wild-type mice. RNA sequencing revealed that assembly and trimerization of collagen fibril pathway-related genes were altered in C2<sup>−/−</sup> mice.</p>\u0000 </section>\u0000 \u0000 ","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 6","pages":""},"PeriodicalIF":9.1,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.70106","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145499049","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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