Chao Xia, Yonghui Wang, Tianyuan Jiang, Yan Hu, Yang Chen, Xinrun Ma, Xuemei Zhang, Yanhong Gao
Background
It has been observed that Slo1 knockout mice have reduced motor function, and people with certain Slo1 mutations have movement problems, but there is no answer whether the movement disorder is caused by the loss of Slo1 in the nervous system, or skeletal muscle, or both. Here, to ascertain in which tissues Slo1 functions to regulate motor function and offer deeper insight in treating related movement disorder, we generated skeletal muscle-specific Slo1 knockout mice, studied the functional changes in Slo1-deficient skeletal muscle and explored the underlying mechanism.
Methods
We used skeletal muscle-specific Slo1 knockout mice (Myf5-Cre; Slo1flox/flox mice, called CKO) as in vivo models to examine the role of Slo1 in muscle growth and muscle regeneration. The forelimb grip strength test was used to assess skeletal muscle function and treadmill exhaustion test was used to test whole-body endurance. Mouse primary myoblasts derived from CKO (myoblast/CKO) mice were used to extend the findings to in vitro effects on myoblast differentiation and fusion. Quantitative real-time PCR, western blot and immunofluorescence approaches were used to analyse Slo1 expression during myoblast differentiation and muscle regeneration. To investigate the involvement of genes in the regulation of muscle dysfunction induced by Slo1 deletion, RNA-seq analysis was performed in primary myoblasts. Immunoprecipitation and mass spectrometry were used to identify the protein interacting with Slo1. A dual-luciferase reporter assay was used to identify whether Slo1 deletion affects NFAT activity.
Results
We found that the body weight and size of CKO mice were not significantly different from those of Slo1flox/flox mice (called WT). Deficiency of Slo1 in muscles leads to reduced endurance (~30% reduction, P < 0.05) and strength (~30% reduction, P < 0.001). Although there was no difference in the general morphology of the muscles, electron microscopy revealed a considerable reduction in the content of mitochondria in the soleus muscle (~40% reduction, P < 0.01). We found that Slo1 was expressed mainly on the cell membrane and showed higher expression in slow-twitch fibres. Slo1 protein expression is progressively reduced during muscle postnatal development and regeneration after injury, and the expression is strongly reduced during myoblast differentiation. Slo1 deletion impaired myoblast differentiation and slow-twitch fibre formation. Mechanistically, RNA-seq analysis showed that Slo1 influences the expression of g
{"title":"Slo1 deficiency impaired skeletal muscle regeneration and slow-twitch fibre formation","authors":"Chao Xia, Yonghui Wang, Tianyuan Jiang, Yan Hu, Yang Chen, Xinrun Ma, Xuemei Zhang, Yanhong Gao","doi":"10.1002/jcsm.13253","DOIUrl":"https://doi.org/10.1002/jcsm.13253","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>It has been observed that Slo1 knockout mice have reduced motor function, and people with certain Slo1 mutations have movement problems, but there is no answer whether the movement disorder is caused by the loss of Slo1 in the nervous system, or skeletal muscle, or both. Here, to ascertain in which tissues Slo1 functions to regulate motor function and offer deeper insight in treating related movement disorder, we generated skeletal muscle-specific Slo1 knockout mice, studied the functional changes in Slo1-deficient skeletal muscle and explored the underlying mechanism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used skeletal muscle-specific Slo1 knockout mice (Myf5-Cre; Slo1<sup>flox/flox</sup> mice, called CKO) as in vivo models to examine the role of Slo1 in muscle growth and muscle regeneration. The forelimb grip strength test was used to assess skeletal muscle function and treadmill exhaustion test was used to test whole-body endurance. Mouse primary myoblasts derived from CKO (myoblast/CKO) mice were used to extend the findings to in vitro effects on myoblast differentiation and fusion. Quantitative real-time PCR, western blot and immunofluorescence approaches were used to analyse Slo1 expression during myoblast differentiation and muscle regeneration. To investigate the involvement of genes in the regulation of muscle dysfunction induced by Slo1 deletion, RNA-seq analysis was performed in primary myoblasts. Immunoprecipitation and mass spectrometry were used to identify the protein interacting with Slo1. A dual-luciferase reporter assay was used to identify whether Slo1 deletion affects NFAT activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that the body weight and size of CKO mice were not significantly different from those of Slo1<sup>flox/flox</sup> mice (called WT). Deficiency of Slo1 in muscles leads to reduced endurance (~30% reduction, <i>P</i> < 0.05) and strength (~30% reduction, <i>P</i> < 0.001). Although there was no difference in the general morphology of the muscles, electron microscopy revealed a considerable reduction in the content of mitochondria in the soleus muscle (~40% reduction, <i>P</i> < 0.01). We found that Slo1 was expressed mainly on the cell membrane and showed higher expression in slow-twitch fibres. Slo1 protein expression is progressively reduced during muscle postnatal development and regeneration after injury, and the expression is strongly reduced during myoblast differentiation. Slo1 deletion impaired myoblast differentiation and slow-twitch fibre formation. Mechanistically, RNA-seq analysis showed that Slo1 influences the expression of g","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1737-1752"},"PeriodicalIF":8.9,"publicationDate":"2023-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13253","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5777911","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}
Lisa Bagnall, Oliver Grundmann, Marilyn G. Teolis, Saun-Joo L. Yoon
Cancer cachexia is a severe multifactorial syndrome1 that affects up to 80% of patients with advanced cancer, causing death in 20–80% with no effective treatments.2, 3 It causes multi-organ alteration and loss of skeletal and cardiac (myocardium) muscle mass.4, 5 Cardiac muscle wasting may result from cardiac protein loss associated with increased oxygen consumption and energy expenditure, resulting in cardiac insufficiency.5 It is hypothesized that significant tissue inflammation and oxidative stress during cancer progression cause cardiac wasting-associated cardiomyopathy, such as a thinned ventricular wall, local tissue hypoxia and arrhythmias.6 This review provided available evidence of cancer-induced cardiac cachexia in human and non-human models by examining biomarkers and the contributing factors to the development and progression of cardiac cachexia. Investigation of the potential biomarkers affecting cardiac muscle wasting is essential for improving patient outcomes.
Our knowledge about the causes of cardiac cachexia in cancer remains limited and the possible mechanisms have only been explored in animal studies to date. A better understanding of the pathophysiology of cardiac cachexia may help to determine if targeted therapies can effectively block the upregulation of various genes and cytokines that initiate and facilitate cancer-induced cardiac cachexia. Understanding the distinct nature of cancer-related cardiac cachexia and what distinguishes it from other causes may also lead to finding targeted, effective treatments. Treating cardiac cachexia early and before clinical changes are noted may improve overall cardiac function and lead to better patient outcomes.
{"title":"Biomarkers and mechanisms associated with cancer-induced cardiac cachexia: A systematic review","authors":"Lisa Bagnall, Oliver Grundmann, Marilyn G. Teolis, Saun-Joo L. Yoon","doi":"10.1002/jcsm.13267","DOIUrl":"https://doi.org/10.1002/jcsm.13267","url":null,"abstract":"<p>Cancer cachexia is a severe multifactorial syndrome<span><sup>1</sup></span> that affects up to 80% of patients with advanced cancer, causing death in 20–80% with no effective treatments.<span><sup>2, 3</sup></span> It causes multi-organ alteration and loss of skeletal and cardiac (myocardium) muscle mass.<span><sup>4, 5</sup></span> Cardiac muscle wasting may result from cardiac protein loss associated with increased oxygen consumption and energy expenditure, resulting in cardiac insufficiency.<span><sup>5</sup></span> It is hypothesized that significant tissue inflammation and oxidative stress during cancer progression cause cardiac wasting-associated cardiomyopathy, such as a thinned ventricular wall, local tissue hypoxia and arrhythmias.<span><sup>6</sup></span> This review provided available evidence of cancer-induced cardiac cachexia in human and non-human models by examining biomarkers and the contributing factors to the development and progression of cardiac cachexia. Investigation of the potential biomarkers affecting cardiac muscle wasting is essential for improving patient outcomes.</p><p>Our knowledge about the causes of cardiac cachexia in cancer remains limited and the possible mechanisms have only been explored in animal studies to date. A better understanding of the pathophysiology of cardiac cachexia may help to determine if targeted therapies can effectively block the upregulation of various genes and cytokines that initiate and facilitate cancer-induced cardiac cachexia. Understanding the distinct nature of cancer-related cardiac cachexia and what distinguishes it from other causes may also lead to finding targeted, effective treatments. Treating cardiac cachexia early and before clinical changes are noted may improve overall cardiac function and lead to better patient outcomes.</p><p>The authors have no conflicts of interest.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1900-1905"},"PeriodicalIF":8.9,"publicationDate":"2023-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13267","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5656013","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}
The relationship between muscle wasting and mortality risk in the general population remains unclear. Our study was conducted to examine and quantify the associations between muscle wasting and all-cause and cause-specific mortality risks. PubMed, Web of Science and Cochrane Library were searched until 22 March 2023 for main data sources and references of retrieved relevant articles. Prospective studies investigating the associations of muscle wasting with risks of all-cause and cause-specific mortality in the general population were eligible. A random-effect model was used to calculate the pooled relative risk (RR) and 95% confidence intervals (CIs) for the lowest versus normal categories of muscle mass. Subgroup analyses and meta-regression were performed to investigate the potential sources of heterogeneities among studies. Dose–response analyses were conducted to evaluate the relationship between muscle mass and mortality risk. Forty-nine prospective studies were included in the meta-analysis. A total of 61 055 deaths were ascertained among 878 349 participants during the 2.5- to 32-year follow-up. Muscle wasting was associated with higher mortality risks of all causes (RR = 1.36, 95% CI, 1.28 to 1.44, I2 = 94.9%, 49 studies), cardiovascular disease (CVD) (RR = 1.29, 95% CI, 1.05 to 1.58, I2 = 88.1%, 8 studies), cancer (RR = 1.14, 95% CI, 1.02 to 1.27, I2 = 38.7%, 3 studies) and respiratory disease (RR = 1.36, 95% CI, 1.11 to 1.67, I2 = 62.8%, 3 studies). Subgroup analyses revealed that muscle wasting, regardless of muscle strength, was significantly associated with a higher all-cause mortality risk. Meta-regression showed that risks of muscle wasting-related all-cause mortality (P = 0.06) and CVD mortality (P = 0.09) were lower in studies with longer follow-ups. An approximately inverse linear dose–response relationship was observed between mid-arm muscle circumference and all-cause mortality risk (P < 0.01 for non-linearity). Muscle wasting was associated with higher mortality risks of all causes, CVD, cancer and respiratory disease in the general population. Early detection and treatment for muscle wasting might be crucial for reducing mortality risk and promoting healthy longevity.
{"title":"Association of muscle wasting with mortality risk among adults: A systematic review and meta-analysis of prospective studies","authors":"Huan-Huan Zhou, Yuxiao Liao, Zhao Peng, Fang Liu, Qi Wang, Wei Yang","doi":"10.1002/jcsm.13263","DOIUrl":"https://doi.org/10.1002/jcsm.13263","url":null,"abstract":"<p>The relationship between muscle wasting and mortality risk in the general population remains unclear. Our study was conducted to examine and quantify the associations between muscle wasting and all-cause and cause-specific mortality risks. PubMed, Web of Science and Cochrane Library were searched until 22 March 2023 for main data sources and references of retrieved relevant articles. Prospective studies investigating the associations of muscle wasting with risks of all-cause and cause-specific mortality in the general population were eligible. A random-effect model was used to calculate the pooled relative risk (RR) and 95% confidence intervals (CIs) for the lowest versus normal categories of muscle mass. Subgroup analyses and meta-regression were performed to investigate the potential sources of heterogeneities among studies. Dose–response analyses were conducted to evaluate the relationship between muscle mass and mortality risk. Forty-nine prospective studies were included in the meta-analysis. A total of 61 055 deaths were ascertained among 878 349 participants during the 2.5- to 32-year follow-up. Muscle wasting was associated with higher mortality risks of all causes (RR = 1.36, 95% CI, 1.28 to 1.44, <i>I</i><sup>2</sup> = 94.9%, 49 studies), cardiovascular disease (CVD) (RR = 1.29, 95% CI, 1.05 to 1.58, <i>I</i><sup>2</sup> = 88.1%, 8 studies), cancer (RR = 1.14, 95% CI, 1.02 to 1.27, <i>I</i><sup>2</sup> = 38.7%, 3 studies) and respiratory disease (RR = 1.36, 95% CI, 1.11 to 1.67, <i>I</i><sup>2</sup> = 62.8%, 3 studies). Subgroup analyses revealed that muscle wasting, regardless of muscle strength, was significantly associated with a higher all-cause mortality risk. Meta-regression showed that risks of muscle wasting-related all-cause mortality (<i>P</i> = 0.06) and CVD mortality (<i>P</i> = 0.09) were lower in studies with longer follow-ups. An approximately inverse linear dose–response relationship was observed between mid-arm muscle circumference and all-cause mortality risk (<i>P</i> < 0.01 for non-linearity). Muscle wasting was associated with higher mortality risks of all causes, CVD, cancer and respiratory disease in the general population. Early detection and treatment for muscle wasting might be crucial for reducing mortality risk and promoting healthy longevity.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1596-1612"},"PeriodicalIF":8.9,"publicationDate":"2023-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13263","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5779216","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}
Androgens are anabolic steroid hormones that exert their function by binding to the androgen receptor (AR). We have previously established that AR deficiency in limb muscles impairs sarcomere myofibrillar organization and decreases muscle strength in male mice. However, despite numerous studies performed in men and rodents, the signalling pathways controlled by androgens via their receptor in skeletal muscles remain poorly understood.
Methods
Male ARskm−/y (n = 7–12) and female ARskm−/− mice (n = 9), in which AR is selectively ablated in myofibres of musculoskeletal tissue, and male AR(i)skm−/y, in which AR is selectively ablated in post-mitotic skeletal muscle myofibres (n = 6), were generated. Longitudinal monitoring of body weight, blood glucose, insulin, lipids and lipoproteins was performed, alongside metabolomic analyses. Glucose metabolism was evaluated in C2C12 cells treated with 5α-dihydrotestosterone (DHT) and the anti-androgen flutamide (n = 6). Histological analyses on macroscopic and ultrastructural levels of longitudinal and transversal muscle sections were conducted. The transcriptome of gastrocnemius muscles from control and ARskm−/y mice was analysed at the age of 9 weeks (P < 0.05, 2138 differentially expressed genes) and validated by RT-qPCR analysis. The AR (4691 peaks with false discovery rate [FDR] < 0.1) and H3K4me2 (47 225 peaks with FDR < 0.05) cistromes in limb muscles were determined in 11-week-old wild-type mice.
Results
We show that disrupting the androgen/AR axis impairs in vivo glycolytic activity and fastens the development of type 2 diabetes in male, but not in female mice. In agreement, treatment with DHT increases glycolysis in C2C12 myotubes by 30%, whereas flutamide has an opposite effect. Fatty acids are less efficiently metabolized in skeletal muscles of ARskm−/y mice and accumulate in cytoplasm, despite increased transcript levels of genes encoding key enzymes of beta-oxidation and mitochondrial content. Impaired glucose and fatty acid metabolism in AR-deficient muscle fibres is associated with 30% increased lysine and branched-chain amino acid catabolism, decreased polyamine biosynthesis and disrupted glutamate transamination. This metabolic switch generates ammonia (2-fold increase) and oxidative stress (30% increased H2O2 levels), which impacts mitochondrial functions and causes necrosis in <1% fibres. We unravel that AR directly activates the transcription of genes invo
{"title":"Androgen receptor coordinates muscle metabolic and contractile functions","authors":"Kamar Ghaibour, Mélanie Schuh, Sirine Souali-Crespo, Céline Chambon, Anouk Charlot, Joe Rizk, Daniela Rovito, Anna-Isavella Rerra, Qingshuang Cai, Nadia Messaddeq, Joffrey Zoll, Delphine Duteil, Daniel Metzger","doi":"10.1002/jcsm.13251","DOIUrl":"https://doi.org/10.1002/jcsm.13251","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Androgens are anabolic steroid hormones that exert their function by binding to the androgen receptor (AR). We have previously established that AR deficiency in limb muscles impairs sarcomere myofibrillar organization and decreases muscle strength in male mice. However, despite numerous studies performed in men and rodents, the signalling pathways controlled by androgens via their receptor in skeletal muscles remain poorly understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Male AR<sup>skm−/y</sup> (<i>n</i> = 7–12) and female AR<sup>skm−/−</sup> mice (<i>n</i> = 9), in which AR is selectively ablated in myofibres of musculoskeletal tissue, and male AR<sup>(i)skm−/y</sup>, in which AR is selectively ablated in post-mitotic skeletal muscle myofibres (<i>n</i> = 6), were generated. Longitudinal monitoring of body weight, blood glucose, insulin, lipids and lipoproteins was performed, alongside metabolomic analyses. Glucose metabolism was evaluated in C2C12 cells treated with 5α-dihydrotestosterone (DHT) and the anti-androgen flutamide (<i>n</i> = 6). Histological analyses on macroscopic and ultrastructural levels of longitudinal and transversal muscle sections were conducted. The transcriptome of gastrocnemius muscles from control and AR<sup>skm−/y</sup> mice was analysed at the age of 9 weeks (<i>P</i> < 0.05, 2138 differentially expressed genes) and validated by RT-qPCR analysis. The AR (4691 peaks with false discovery rate [FDR] < 0.1) and H3K4me2 (47 225 peaks with FDR < 0.05) cistromes in limb muscles were determined in 11-week-old wild-type mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We show that disrupting the androgen/AR axis impairs in vivo glycolytic activity and fastens the development of type 2 diabetes in male, but not in female mice. In agreement, treatment with DHT increases glycolysis in C2C12 myotubes by 30%, whereas flutamide has an opposite effect. Fatty acids are less efficiently metabolized in skeletal muscles of AR<sup>skm−/y</sup> mice and accumulate in cytoplasm, despite increased transcript levels of genes encoding key enzymes of beta-oxidation and mitochondrial content. Impaired glucose and fatty acid metabolism in AR-deficient muscle fibres is associated with 30% increased lysine and branched-chain amino acid catabolism, decreased polyamine biosynthesis and disrupted glutamate transamination. This metabolic switch generates ammonia (2-fold increase) and oxidative stress (30% increased H<sub>2</sub>O<sub>2</sub> levels), which impacts mitochondrial functions and causes necrosis in <1% fibres. We unravel that AR directly activates the transcription of genes invo","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1707-1720"},"PeriodicalIF":8.9,"publicationDate":"2023-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13251","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5956259","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}
Yi Li, Niklas D?rmann, Bj?rn Brinschwitz, Melanie Kny, Elisa Martin, Kirsten Bartels, Ning Li, Priyanka Voori Giri, Stefan Schwanz, Michael Boschmann, Susanne Hille, Britta Fielitz, Tobias Wollersheim, Julius Grunow, Stephan B. Felix, Steffen Weber-Carstens, Friedrich C. Luft, Oliver J. Müller, Jens Fielitz
Background
Sepsis-induced intensive care unit-acquired weakness (ICUAW) features profound muscle atrophy and attenuated muscle regeneration related to malfunctioning satellite cells. Transforming growth factor beta (TGF-β) is involved in both processes. We uncovered an increased expression of the TGF-β receptor II (TβRII)-inhibitor SPRY domain-containing and SOCS-box protein 1 (SPSB1) in skeletal muscle of septic mice. We hypothesized that SPSB1-mediated inhibition of TβRII signalling impairs myogenic differentiation in response to inflammation.
Methods
We performed gene expression analyses in skeletal muscle of cecal ligation and puncture- (CLP) and sham-operated mice, as well as vastus lateralis of critically ill and control patients. Pro-inflammatory cytokines and specific pathway inhibitors were used to quantitate Spsb1 expression in myocytes. Retroviral expression plasmids were used to investigate the effects of SPSB1 on TGF-β/TβRII signalling and myogenesis in primary and immortalized myoblasts and differentiated myotubes. For mechanistical analyses we used coimmunoprecipitation, ubiquitination, protein half-life, and protein synthesis assays. Differentiation and fusion indices were determined by immunocytochemistry, and differentiation factors were quantified by qRT-PCR and Western blot analyses.
Results
SPSB1 expression was increased in skeletal muscle of ICUAW patients and septic mice. Tumour necrosis factor (TNF), interleukin-1β (IL-1β), and IL-6 increased the Spsb1 expression in C2C12 myotubes. TNF- and IL-1β-induced Spsb1 expression was mediated by NF-κB, whereas IL-6 increased the Spsb1 expression via the glycoprotein 130/JAK2/STAT3 pathway. All cytokines reduced myogenic differentiation. SPSB1 avidly interacted with TβRII, resulting in TβRII ubiquitination and destabilization. SPSB1 impaired TβRII-Akt-Myogenin signalling and diminished protein synthesis in myocytes. Overexpression of SPSB1 decreased the expression of early (Myog, Mymk, Mymx) and late (Myh1, 3, 7) differentiation-markers. As a result, myoblast fusion and myogenic differentiation were impaired. These effects were mediated by the SPRY- and SOCS-box domains of SPSB1. Co-expression of SPSB1 with Akt or Myogenin reversed the inhibitory effects of SPSB1 on protein synthesis and myogenic differentiation. Downregulation of Spsb1 by AAV9-mediated shRNA attenuated muscle weight loss and atrophy gene expression in skeletal muscle of septic mice.
{"title":"SPSB1-mediated inhibition of TGF-β receptor-II impairs myogenesis in inflammation","authors":"Yi Li, Niklas D?rmann, Bj?rn Brinschwitz, Melanie Kny, Elisa Martin, Kirsten Bartels, Ning Li, Priyanka Voori Giri, Stefan Schwanz, Michael Boschmann, Susanne Hille, Britta Fielitz, Tobias Wollersheim, Julius Grunow, Stephan B. Felix, Steffen Weber-Carstens, Friedrich C. Luft, Oliver J. Müller, Jens Fielitz","doi":"10.1002/jcsm.13252","DOIUrl":"https://doi.org/10.1002/jcsm.13252","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sepsis-induced intensive care unit-acquired weakness (ICUAW) features profound muscle atrophy and attenuated muscle regeneration related to malfunctioning satellite cells. Transforming growth factor beta (TGF-β) is involved in both processes. We uncovered an increased expression of the TGF-β receptor II (TβRII)-inhibitor SPRY domain-containing and SOCS-box protein 1 (SPSB1) in skeletal muscle of septic mice. We hypothesized that SPSB1-mediated inhibition of TβRII signalling impairs myogenic differentiation in response to inflammation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed gene expression analyses in skeletal muscle of cecal ligation and puncture- (CLP) and sham-operated mice, as well as <i>vastus lateralis</i> of critically ill and control patients. Pro-inflammatory cytokines and specific pathway inhibitors were used to quantitate <i>Spsb1</i> expression in myocytes. Retroviral expression plasmids were used to investigate the effects of SPSB1 on TGF-β/TβRII signalling and myogenesis in primary and immortalized myoblasts and differentiated myotubes. For mechanistical analyses we used coimmunoprecipitation, ubiquitination, protein half-life, and protein synthesis assays. Differentiation and fusion indices were determined by immunocytochemistry, and differentiation factors were quantified by qRT-PCR and Western blot analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p><i>SPSB1</i> expression was increased in skeletal muscle of ICUAW patients and septic mice. Tumour necrosis factor (TNF), interleukin-1β (IL-1β), and IL-6 increased the <i>Spsb1</i> expression in C2C12 myotubes. TNF- and IL-1β-induced <i>Spsb1</i> expression was mediated by NF-κB, whereas IL-6 increased the <i>Spsb1</i> expression via the glycoprotein 130/JAK2/STAT3 pathway. All cytokines reduced myogenic differentiation. SPSB1 avidly interacted with TβRII, resulting in TβRII ubiquitination and destabilization. SPSB1 impaired TβRII-Akt-Myogenin signalling and diminished protein synthesis in myocytes. Overexpression of SPSB1 decreased the expression of early (<i>Myog</i>, <i>Mymk</i>, <i>Mymx</i>) and late (<i>Myh1</i>, <i>3</i>, <i>7</i>) differentiation-markers. As a result, myoblast fusion and myogenic differentiation were impaired. These effects were mediated by the SPRY- and SOCS-box domains of SPSB1. Co-expression of SPSB1 with Akt or Myogenin reversed the inhibitory effects of SPSB1 on protein synthesis and myogenic differentiation. Downregulation of <i>Spsb1</i> by AAV9-mediated shRNA attenuated muscle weight loss and atrophy gene expression in skeletal muscle of septic mice.</p>\u0000 </section>\u0000 ","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1721-1736"},"PeriodicalIF":8.9,"publicationDate":"2023-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13252","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5779221","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}
Ling Wang, Minghui Yang, Yufeng Ge, Yandong Liu, Yongbin Su, Zhe Guo, Pengju Huang, Jian Geng, Gang Wang, Glen M. Blake, Bo He, Lu Yin, Xiaoguang Cheng, Xinbao Wu, Klaus Engelke, Annegreet G. Vlug
Background
Mortality following hip fracture is high and incompletely understood. We hypothesize that hip musculature size and quality are related to mortality following hip fracture. This study aims to investigate the associations of hip muscle area and density from hip CT with death following hip fracture as well as assess the dependence of this association on time after hip fracture.
Methods
In this secondary analysis of the prospectively collected CT images and data from the Chinese Second Hip Fracture Evaluation, 459 patients were enrolled between May 2015 and June 2016 and followed up for a median of 4.5 years. Muscle cross-sectional area and density were measured of the gluteus maximus (G.MaxM) and gluteus medius and minimus (G.Med/MinM) and aBMD of the proximal femur. The Goutallier classification (GC) was used for qualitatively assessing muscle fat infiltration. Separate Cox models were used to predict mortality risk adjusted for covariates.
Results
At the end of the follow-up, 85 patients were lost, 81 patients (64% women) had died, and 293 (71% women) survived. The mean age of non-surviving patients at death (82.0 ± 8.1 years) was higher than that of the surviving patients (74.4 ± 9.9 years). The Parker Mobility Score and the American Society of Anesthesiologists scores of the patients that died were respectively lower and higher compared to the surviving patients. Hip fracture patients received different surgical procedures, and no significant difference in the percentage of hip arthroplasty was observed between the dead and the surviving patients (P = 0.11). The cumulative survival was significantly lower for patients with low G.MaxM area and density and low G.Med/MinM density, independent of age and clinical risk scores. The GC grades were not associated with the mortality after hip fracture. Muscle density of both G.MaxM (adj. HR 1.83; 95% CI, 1.06–3.17) and G.Med/MinM (adj. HR 1.98; 95% CI, 1.14–3.46) was associated with mortality in the 1st year after hip fracture. G.MaxM area (adj. HR 2.11; 95% CI, 1.08–4.14) was associated with mortality in the 2nd and later years after hip fracture.
Conclusion
Our results for the first time show that hip muscle size and density are associated with mortality in older hip fracture patients, independent of age and clinical risk scores. This is an important finding to better understand the factors contributing to the high mortality in older hip fracture
{"title":"Muscle size and density are independently associated with death after hip fracture: A prospective cohort study","authors":"Ling Wang, Minghui Yang, Yufeng Ge, Yandong Liu, Yongbin Su, Zhe Guo, Pengju Huang, Jian Geng, Gang Wang, Glen M. Blake, Bo He, Lu Yin, Xiaoguang Cheng, Xinbao Wu, Klaus Engelke, Annegreet G. Vlug","doi":"10.1002/jcsm.13261","DOIUrl":"https://doi.org/10.1002/jcsm.13261","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Mortality following hip fracture is high and incompletely understood. We hypothesize that hip musculature size and quality are related to mortality following hip fracture. This study aims to investigate the associations of hip muscle area and density from hip CT with death following hip fracture as well as assess the dependence of this association on time after hip fracture.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this secondary analysis of the prospectively collected CT images and data from the Chinese Second Hip Fracture Evaluation, 459 patients were enrolled between May 2015 and June 2016 and followed up for a median of 4.5 years. Muscle cross-sectional area and density were measured of the gluteus maximus (G.MaxM) and gluteus medius and minimus (G.Med/MinM) and aBMD of the proximal femur. The Goutallier classification (GC) was used for qualitatively assessing muscle fat infiltration. Separate Cox models were used to predict mortality risk adjusted for covariates.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>At the end of the follow-up, 85 patients were lost, 81 patients (64% women) had died, and 293 (71% women) survived. The mean age of non-surviving patients at death (82.0 ± 8.1 years) was higher than that of the surviving patients (74.4 ± 9.9 years). The Parker Mobility Score and the American Society of Anesthesiologists scores of the patients that died were respectively lower and higher compared to the surviving patients. Hip fracture patients received different surgical procedures, and no significant difference in the percentage of hip arthroplasty was observed between the dead and the surviving patients (<i>P</i> = 0.11). The cumulative survival was significantly lower for patients with low G.MaxM area and density and low G.Med/MinM density, independent of age and clinical risk scores. The GC grades were not associated with the mortality after hip fracture. Muscle density of both G.MaxM (adj. HR 1.83; 95% CI, 1.06–3.17) and G.Med/MinM (adj. HR 1.98; 95% CI, 1.14–3.46) was associated with mortality in the 1st year after hip fracture. G.MaxM area (adj. HR 2.11; 95% CI, 1.08–4.14) was associated with mortality in the 2nd and later years after hip fracture.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our results for the first time show that hip muscle size and density are associated with mortality in older hip fracture patients, independent of age and clinical risk scores. This is an important finding to better understand the factors contributing to the high mortality in older hip fracture","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1824-1835"},"PeriodicalIF":8.9,"publicationDate":"2023-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13261","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5764193","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}
The liver is a central organ that controls metabolic nutrition, whereas tumour burden and hepatic function are well-known major prognostic factors in hepatocellular carcinoma (HCC) patients.1, 2 Nutritional status generally becomes worse with progression of hepatic function decline and conditions such as protein-energy malnutrition (PEM) often complicated in liver cirrhosis (LC) patients.3 As a result of such a worsened status, muscle volume loss (MVL) often develops in chronic liver disease (CLD) patients.4 MVL has been recognized as an important prognostic factor in HCC patients treated either curatively or palliatively.5 However, special technologies, such as computer software for use with computed tomography (CT) or devices for bioelectrical impedance analysis (BIA), are generally needed for assessment of muscle volume; thus, many institutions have difficulties accessing such methods because of their expense. Previously, a nutritional assessment index termed geriatric nutritional risk index (GNRI),6 which is calculated with use of only serum albumin level, height and body weight, was developed.
The present study aimed to elucidate the clinical usefulness of GNRI as an easy nutritional assessment method using well-known clinical factors to predict a high risk of MVL in CLD patients with HCC.
Four hundred forty two HCC patients, who underwent CT examinations performed at our hospital from January 2017 to June 2022 and within 1 month before starting treatment for HCC, were enrolled. None had a past history of HCC. Their records were kept in an institutional database and analysed in a retrospective manner.
The present results showed that the frequency of MVL, which has been defined as pre-sarcopenia,16 increased as nutritional status (GNRI) worsened (P < 0.001). Although the GNRI was originally created for assessing geriatric nutritional status, the present study was conducted under the consideration that it also reflects the effects of muscle loss. When the cut-off GNRI score for predicting MVL was analysed according to gender, those values were approximated (males 99.7, females 99.4). The GNRI uses different formulas for calculating standard weight for males and females, which may have contributed to those results. Thus, the cut-off GNRI score for MVL was 99.7 (approximately equal to the cut-off value for GNRI mild decline) in all patients, with the same score found in patients without ascites. For the GNRI normal status patients with MVL (28/283: 9.9%), that was thought to be mainly due to aging, because those with MVL were older (77 vs. 72 years, P = 0.006).
Recently, decreased muscle has been commonly reported as a complication in CLD patients.17 Hanai et al. noted a hazard ratio (HR) of mortality from sarcopenia of 3.03 (95% CI: 1.4
{"title":"Simple method for predicting muscle volume loss using geriatric nutritional risk index in hepatocellular carcinoma patients","authors":"Atsushi Hiraoka, Hideko Ohama, Fujimasa Tada, Yoshiko Fukunishi, Emi Yanagihara, Kanako Kato, Masaya Kato, Hironobu Saneto, Hirofumi Izumoto, Hidetaro Ueki, Takeaki Yoshino, Shogo Kitahata, Tomoe Kawamura, Taira Kuroda, Yoshifumi Suga, Hideki Miyata, Masashi Hirooka, Masanori Abe, Bunzo Matsuura, Tomoyuki Ninomiya, Yoichi Hiasa","doi":"10.1002/jcsm.13268","DOIUrl":"https://doi.org/10.1002/jcsm.13268","url":null,"abstract":"<p>The liver is a central organ that controls metabolic nutrition, whereas tumour burden and hepatic function are well-known major prognostic factors in hepatocellular carcinoma (HCC) patients.<span><sup>1, 2</sup></span> Nutritional status generally becomes worse with progression of hepatic function decline and conditions such as protein-energy malnutrition (PEM) often complicated in liver cirrhosis (LC) patients.<span><sup>3</sup></span> As a result of such a worsened status, muscle volume loss (MVL) often develops in chronic liver disease (CLD) patients.<span><sup>4</sup></span> MVL has been recognized as an important prognostic factor in HCC patients treated either curatively or palliatively.<span><sup>5</sup></span> However, special technologies, such as computer software for use with computed tomography (CT) or devices for bioelectrical impedance analysis (BIA), are generally needed for assessment of muscle volume; thus, many institutions have difficulties accessing such methods because of their expense. Previously, a nutritional assessment index termed geriatric nutritional risk index (GNRI),<span><sup>6</sup></span> which is calculated with use of only serum albumin level, height and body weight, was developed.</p><p>The present study aimed to elucidate the clinical usefulness of GNRI as an easy nutritional assessment method using well-known clinical factors to predict a high risk of MVL in CLD patients with HCC.</p><p>Four hundred forty two HCC patients, who underwent CT examinations performed at our hospital from January 2017 to June 2022 and within 1 month before starting treatment for HCC, were enrolled. None had a past history of HCC. Their records were kept in an institutional database and analysed in a retrospective manner.</p><p>The present results showed that the frequency of MVL, which has been defined as pre-sarcopenia,<span><sup>16</sup></span> increased as nutritional status (GNRI) worsened (<i>P</i> < 0.001). Although the GNRI was originally created for assessing geriatric nutritional status, the present study was conducted under the consideration that it also reflects the effects of muscle loss. When the cut-off GNRI score for predicting MVL was analysed according to gender, those values were approximated (males 99.7, females 99.4). The GNRI uses different formulas for calculating standard weight for males and females, which may have contributed to those results. Thus, the cut-off GNRI score for MVL was 99.7 (approximately equal to the cut-off value for GNRI mild decline) in all patients, with the same score found in patients without ascites. For the GNRI normal status patients with MVL (28/283: 9.9%), that was thought to be mainly due to aging, because those with MVL were older (77 vs. 72 years, <i>P</i> = 0.006).</p><p>Recently, decreased muscle has been commonly reported as a complication in CLD patients.<span><sup>17</sup></span> Hanai et al. noted a hazard ratio (HR) of mortality from sarcopenia of 3.03 (95% CI: 1.4","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1906-1911"},"PeriodicalIF":8.9,"publicationDate":"2023-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13268","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5708349","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}
Mark A. Burton, Elie Antoun, Emma S. Garratt, Leo Westbury, Alica Baczynska, Elaine M. Dennison, Nicholas C. Harvey, Cyrus Cooper, Harnish P. Patel, Keith M. Godfrey, Karen A. Lillycrop, EpiGen Global Research Consortium
Background
Amongst healthy older people, a number of correlates of impaired skeletal muscle mass and function have been defined. Although the prevalence of obesity is increasing markedly in this age group, information is sparse about the particular impacts of obesity on ageing skeletal muscle or the molecular mechanisms that underlie this and associated disease risk.
Methods
Here, we examined genome-wide transcriptional changes using RNA sequencing in muscle biopsies from 40 older community-dwelling men from the Hertfordshire Sarcopenia Study with regard to obesity (body mass index [BMI] >30 kg/m2, n = 7), overweight (BMI 25–30, n = 19), normal weight (BMI < 25, n = 14), and per cent and total fat mass. In addition, we used EPIC DNA methylation array data to investigate correlations between DNA methylation and gene expression in aged skeletal muscle tissue and investigated the relationship between genes within altered regulatory pathways and muscle histological parameters.
Results
Individuals with obesity demonstrated a prominent modified transcriptional signature in muscle tissue, with a total of 542 differentially expressed genes associated with obesity (false discovery rate ≤0.05), of which 425 genes were upregulated when compared with normal weight. Upregulated genes were enriched in immune response (P = 3.18 × 10−41) and inflammation (leucocyte activation, P = 1.47 × 10−41; tumour necrosis factor, P = 2.75 × 10−15) signalling pathways and downregulated genes enriched in longevity (P = 1.5 × 10−3) and AMP-activated protein kinase (AMPK) (P = 4.5 × 10−3) signalling pathways. Furthermore, differentially expressed genes in both longevity and AMPK signalling pathways were associated with a change in DNA methylation, with a total of 256 and 360 significant cytosine–phosphate–guanine–gene correlations identified, respectively. Similar changes in the muscle transcriptome were observed with respect to per cent fat mass and total fat mass. Obesity was further associated with a significant increase in type II fast-fibre area (P = 0.026), of which key regulatory genes within both longevity and AMPK pathways were significantly associated.
Conclusions
We provide for the first time a global transcriptomic profile of skeletal muscle in older people with and without obesity, demonstratin
{"title":"Adiposity is associated with widespread transcriptional changes and downregulation of longevity pathways in aged skeletal muscle","authors":"Mark A. Burton, Elie Antoun, Emma S. Garratt, Leo Westbury, Alica Baczynska, Elaine M. Dennison, Nicholas C. Harvey, Cyrus Cooper, Harnish P. Patel, Keith M. Godfrey, Karen A. Lillycrop, EpiGen Global Research Consortium","doi":"10.1002/jcsm.13255","DOIUrl":"https://doi.org/10.1002/jcsm.13255","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Amongst healthy older people, a number of correlates of impaired skeletal muscle mass and function have been defined. Although the prevalence of obesity is increasing markedly in this age group, information is sparse about the particular impacts of obesity on ageing skeletal muscle or the molecular mechanisms that underlie this and associated disease risk.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we examined genome-wide transcriptional changes using RNA sequencing in muscle biopsies from 40 older community-dwelling men from the Hertfordshire Sarcopenia Study with regard to obesity (body mass index [BMI] >30 kg/m<sup>2</sup>, <i>n</i> = 7), overweight (BMI 25–30, <i>n</i> = 19), normal weight (BMI < 25, <i>n</i> = 14), and per cent and total fat mass. In addition, we used EPIC DNA methylation array data to investigate correlations between DNA methylation and gene expression in aged skeletal muscle tissue and investigated the relationship between genes within altered regulatory pathways and muscle histological parameters.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Individuals with obesity demonstrated a prominent modified transcriptional signature in muscle tissue, with a total of 542 differentially expressed genes associated with obesity (false discovery rate ≤0.05), of which 425 genes were upregulated when compared with normal weight. Upregulated genes were enriched in immune response (<i>P</i> = 3.18 × 10<sup>−41</sup>) and inflammation (leucocyte activation, <i>P</i> = 1.47 × 10<sup>−41</sup>; tumour necrosis factor, <i>P</i> = 2.75 × 10<sup>−15</sup>) signalling pathways and downregulated genes enriched in longevity (<i>P</i> = 1.5 × 10<sup>−3</sup>) and AMP-activated protein kinase (AMPK) (<i>P</i> = 4.5 × 10<sup>−3</sup>) signalling pathways. Furthermore, differentially expressed genes in both longevity and AMPK signalling pathways were associated with a change in DNA methylation, with a total of 256 and 360 significant cytosine–phosphate–guanine–gene correlations identified, respectively. Similar changes in the muscle transcriptome were observed with respect to per cent fat mass and total fat mass. Obesity was further associated with a significant increase in type II fast-fibre area (<i>P</i> = 0.026), of which key regulatory genes within both longevity and AMPK pathways were significantly associated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We provide for the first time a global transcriptomic profile of skeletal muscle in older people with and without obesity, demonstratin","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1762-1774"},"PeriodicalIF":8.9,"publicationDate":"2023-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13255","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5719736","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}
Frédéric Pigneur, Mario Di Palma, Bruno Raynard, Aymeric Guibal, Frédéric Cohen, Nassima Daidj, Richard Aziza, Mostafa El Hajjam, Guillaume Louis, Fran?ois Goldwasser, Elise Deluche
Background
A common method for diagnosing sarcopenia involves estimating the muscle mass by computed tomography (CT) via measurements of the cross-sectional muscle area (CSMA) of all muscles at the third lumbar vertebra (L3) level. Recently, single-muscle measurements of the psoas major muscle at L3 have emerged as a surrogate for sarcopenia detection, but its reliability and accuracy remain to be demonstrated.
Methods
This prospective cross-sectional study involved 29 healthcare establishments and recruited patients with metastatic cancers. The correlation between skeletal muscle index (SMI = CSMA of all muscles at L3/height2, cm2/m2) and psoas muscle index (PMI = CSMA of psoas at L3/height2, cm2/m2) was determined (Pearson's r). ROC curves were prepared based on SMI data from a development population (n = 488) to estimate suitable PMI thresholds. International low SMI cut-offs according to gender were studied for males (<55cm2/m2) and for females (<39 cm2/m2). Youden's index (J) and Cohen's kappa (κ) were calculated to estimate the test's accuracy and reliability. PMI cut-offs were validated in a validation population (n = 243) by estimating the percentage concordance of sarcopenia diagnoses with the SMI thresholds.
Results
Seven hundred and sixty-six patients were analysed (mean age 65.0 ± 11.8 years, 50.1% female). Low SMI prevalence was 69.1%. Correlation between the SMI and PMI for the entire population was 0.69 (n = 731, P < 0.01). PMI cut-offs for sarcopenia were estimated in the development population at <6.6cm2/m2 in males and at <4.8 cm2/m2 for females. The J and κ coefficients for PMI diagnostic tests were weak. The PMI cut-offs were tested in the validation population where 33.3% of the PMI measurements were dichotomously discordant.
Conclusions
A diagnostic test employing single-muscle measurements of the psoas major muscle as a surrogate for sarcopenia detection was evaluated but found to be unreliable. The CSMA of all muscles must be considered for evaluating cancer sarcopenia at L3.
{"title":"Psoas muscle index is not representative of skeletal muscle index for evaluating cancer sarcopenia","authors":"Frédéric Pigneur, Mario Di Palma, Bruno Raynard, Aymeric Guibal, Frédéric Cohen, Nassima Daidj, Richard Aziza, Mostafa El Hajjam, Guillaume Louis, Fran?ois Goldwasser, Elise Deluche","doi":"10.1002/jcsm.13230","DOIUrl":"https://doi.org/10.1002/jcsm.13230","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>A common method for diagnosing sarcopenia involves estimating the muscle mass by computed tomography (CT) via measurements of the cross-sectional muscle area (CSMA) of all muscles at the third lumbar vertebra (L3) level. Recently, single-muscle measurements of the psoas major muscle at L3 have emerged as a surrogate for sarcopenia detection, but its reliability and accuracy remain to be demonstrated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This prospective cross-sectional study involved 29 healthcare establishments and recruited patients with metastatic cancers. The correlation between skeletal muscle index (SMI = CSMA of all muscles at L3/height<sup>2</sup>, cm<sup>2</sup>/m<sup>2</sup>) and psoas muscle index (PMI = CSMA of psoas at L3/height<sup>2</sup>, cm<sup>2</sup>/m<sup>2</sup>) was determined (Pearson's <i>r</i>). ROC curves were prepared based on SMI data from a development population (<i>n</i> = 488) to estimate suitable PMI thresholds. International low SMI cut-offs according to gender were studied for males (<55cm<sup>2</sup>/m<sup>2</sup>) and for females (<39 cm<sup>2</sup>/m<sup>2</sup>). Youden's index (<i>J</i>) and Cohen's kappa (κ) were calculated to estimate the test's accuracy and reliability. PMI cut-offs were validated in a validation population (<i>n</i> = 243) by estimating the percentage concordance of sarcopenia diagnoses with the SMI thresholds.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Seven hundred and sixty-six patients were analysed (mean age 65.0 ± 11.8 years, 50.1% female). Low SMI prevalence was 69.1%. Correlation between the SMI and PMI for the entire population was 0.69 (<i>n</i> = 731, <i>P</i> < 0.01). PMI cut-offs for sarcopenia were estimated in the development population at <6.6cm<sup>2</sup>/m<sup>2</sup> in males and at <4.8 cm<sup>2</sup>/m<sup>2</sup> for females. The <i>J</i> and κ coefficients for PMI diagnostic tests were weak. The PMI cut-offs were tested in the validation population where 33.3% of the PMI measurements were dichotomously discordant.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>A diagnostic test employing single-muscle measurements of the psoas major muscle as a surrogate for sarcopenia detection was evaluated but found to be unreliable. The CSMA of all muscles must be considered for evaluating cancer sarcopenia at L3.</p>\u0000 </section>\u0000 </div>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1613-1620"},"PeriodicalIF":8.9,"publicationDate":"2023-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13230","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5917441","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}
Measurement of muscle mass is important in the diagnosis of sarcopenia. Current measurement equipment are neither cost-effective nor standardized and cannot be used in a variety of medical settings. Some simple measurement tools have been proposed that are subjective and unvalidated. We aimed to develop and validate a new estimation equation in a more objective and standardized way, based on current proven variables that accurately reflect muscle mass.
Methods
Cross-sectional analysis with The National Health and Nutrition Examination Survey database for equation development and validation. Overall, 9875 participants were included for development (6913 participants) and validation (2962 participants), for whom the database included demographic data, physical measurements, and main biochemical indicators. Appendicular skeletal muscle mass (ASM) was estimated by dual-energy x-ray absorptiometry (DXA) and low muscle mass was defined by reference to five international diagnostic criteria. Linear regression was used to estimate the logarithm of the actual ASM from demographic data, physical measurements, and biochemical indicators.
Results
This study of 9875 participants comprised 4492 females (49.0%), with a weighted mean (SE) age of 41.83 (0.36) years and range of 12 to 85 years. The estimated ASM equations performed well in the validation data set. The variability in estimated ASM was low compared with the actual ASM (R2: Equation 1 = 0.91, Equation 4 = 0.89), with low bias (median difference: Equation 1 = −0.64, Equation 4 = 0.07; root mean square error: Equation 1 = 1.70 [1.69–1.70], Equation 4 = 1.85 [1.84–1.86]), high precision (interquartile range of the differences: Equation 1 = 1.87, Equation 4 = 2.17), and high efficacy in diagnosing low muscle mass (area under the curve: Equation 1 = 0.91 to 0.95, Equation 4 = 0.90 to 0.94).
Conclusions
The estimated ASM equations are accurate and simple and can be routinely applied clinically to estimate ASM and thus assess sarcopenia.
{"title":"A more accurate method to estimate muscle mass: A new estimation equation","authors":"Shanshan Shi, Weihua Chen, Yizhou Jiang, Kaihong Chen, Ying Liao, Kun Huang","doi":"10.1002/jcsm.13254","DOIUrl":"https://doi.org/10.1002/jcsm.13254","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Measurement of muscle mass is important in the diagnosis of sarcopenia. Current measurement equipment are neither cost-effective nor standardized and cannot be used in a variety of medical settings. Some simple measurement tools have been proposed that are subjective and unvalidated. We aimed to develop and validate a new estimation equation in a more objective and standardized way, based on current proven variables that accurately reflect muscle mass.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Cross-sectional analysis with The National Health and Nutrition Examination Survey database for equation development and validation. Overall, 9875 participants were included for development (6913 participants) and validation (2962 participants), for whom the database included demographic data, physical measurements, and main biochemical indicators. Appendicular skeletal muscle mass (ASM) was estimated by dual-energy x-ray absorptiometry (DXA) and low muscle mass was defined by reference to five international diagnostic criteria. Linear regression was used to estimate the logarithm of the actual ASM from demographic data, physical measurements, and biochemical indicators.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>This study of 9875 participants comprised 4492 females (49.0%), with a weighted mean (SE) age of 41.83 (0.36) years and range of 12 to 85 years. The estimated ASM equations performed well in the validation data set. The variability in estimated ASM was low compared with the actual ASM (<i>R</i><sup>2</sup>: Equation 1 = 0.91, Equation 4 = 0.89), with low bias (median difference: Equation 1 = −0.64, Equation 4 = 0.07; root mean square error: Equation 1 = 1.70 [1.69–1.70], Equation 4 = 1.85 [1.84–1.86]), high precision (interquartile range of the differences: Equation 1 = 1.87, Equation 4 = 2.17), and high efficacy in diagnosing low muscle mass (area under the curve: Equation 1 = 0.91 to 0.95, Equation 4 = 0.90 to 0.94).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The estimated ASM equations are accurate and simple and can be routinely applied clinically to estimate ASM and thus assess sarcopenia.</p>\u0000 </section>\u0000 </div>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1753-1761"},"PeriodicalIF":8.9,"publicationDate":"2023-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13254","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5917444","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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