Hailun Xie, Guotian Ruan, Lishuang Wei, Heyang Zhang, Yizhong Ge, Shiqi Lin, Mengmeng Song, Qi Zhang, Xi Zhang, Ziwen Wang, Chenan Liu, Jinyu Shi, Xiaoyue Liu, Ming Yang, Xin Zheng, Yue Chen, Xiaowei Zhang, Li Deng, Hanping Shi
Background
The original weight loss grading system (WLGS) was developed in western population, which did not perform effectively in cancer patients from China. This study aimed to develop and validate the modified WLGS (mWLGS) in the prognostic assessment of cancer patients in China.
Methods
A prospective multicentre real-world cohort study involving 16 842 patients diagnosed with cancer was conducted. Cox regression was used to calculate the hazard ratios for overall survival. Logistic linear regression was used to assess the odds ratio for 90-day outcomes.
Results
We calculated survival risks for the 25 mWLGS groups and clustered the approximate survival risks. Finally, we revised the prognostic grading system for mWLGS to include five grades of 0–4. Compared with the original WLGS, the mWLGS had a better prognostic differentiation effect in predicting the prognosis of patients with cancer. The survival rate gradually deteriorated with increasing grade of mWLGS, with the survival rate of grade 0 decreasing from 76.4% to 48.2% for grade 4 (76.4 vs. 72.8 vs. 66.1 vs. 57.0 vs. 48.2%, respectively). The mWLGS provides effective prognostic stratification for most site-specific cancers, especially lung and gastrointestinal cancers. High-grade mWLGS is independently associated with an increased risk of poor quality of life and adverse 90-day outcomes. Multivariate Cox regression analysis showed that the mWLGS was an independent prognostic factor for cancer patients in the validation cohorts.
Conclusions
Compared with the original WLGS, the mWLGS can better stratify the prognosis of cancer patients. mWLGS is a useful tool for predicting survival, 90-day outcomes, and quality of life in patients with cancer. These analyses may provide new insights into the application of WLGS in cancer patients in China.
{"title":"Development and applicability of modified weight loss grading system in cancer: a real-world cohort study","authors":"Hailun Xie, Guotian Ruan, Lishuang Wei, Heyang Zhang, Yizhong Ge, Shiqi Lin, Mengmeng Song, Qi Zhang, Xi Zhang, Ziwen Wang, Chenan Liu, Jinyu Shi, Xiaoyue Liu, Ming Yang, Xin Zheng, Yue Chen, Xiaowei Zhang, Li Deng, Hanping Shi","doi":"10.1002/jcsm.13287","DOIUrl":"10.1002/jcsm.13287","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The original weight loss grading system (WLGS) was developed in western population, which did not perform effectively in cancer patients from China. This study aimed to develop and validate the modified WLGS (mWLGS) in the prognostic assessment of cancer patients in China.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A prospective multicentre real-world cohort study involving 16 842 patients diagnosed with cancer was conducted. Cox regression was used to calculate the hazard ratios for overall survival. Logistic linear regression was used to assess the odds ratio for 90-day outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We calculated survival risks for the 25 mWLGS groups and clustered the approximate survival risks. Finally, we revised the prognostic grading system for mWLGS to include five grades of 0–4. Compared with the original WLGS, the mWLGS had a better prognostic differentiation effect in predicting the prognosis of patients with cancer. The survival rate gradually deteriorated with increasing grade of mWLGS, with the survival rate of grade 0 decreasing from 76.4% to 48.2% for grade 4 (76.4 vs. 72.8 vs. 66.1 vs. 57.0 vs. 48.2%, respectively). The mWLGS provides effective prognostic stratification for most site-specific cancers, especially lung and gastrointestinal cancers. High-grade mWLGS is independently associated with an increased risk of poor quality of life and adverse 90-day outcomes. Multivariate Cox regression analysis showed that the mWLGS was an independent prognostic factor for cancer patients in the validation cohorts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Compared with the original WLGS, the mWLGS can better stratify the prognosis of cancer patients. mWLGS is a useful tool for predicting survival, 90-day outcomes, and quality of life in patients with cancer. These analyses may provide new insights into the application of WLGS in cancer patients in China.</p>\u0000 </section>\u0000 </div>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"2090-2097"},"PeriodicalIF":8.9,"publicationDate":"2023-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13287","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9764397","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}
George F. Pavis, Doaa R. Abdelrahman, Andrew J. Murton, Benjamin T. Wall, Francis B. Stephens, Marlou L. Dirks
Background
The decline in postabsorptive and postprandial muscle protein fractional synthesis rates (FSR) does not quantitatively account for muscle atrophy during uncomplicated, short-term disuse, when atrophy rates are the highest. We sought to determine whether 2 days of unilateral knee immobilization affects mixed muscle protein fractional breakdown rates (FBR) during postabsorptive and simulated postprandial conditions.
Methods
Twenty-three healthy, male participants (age: 22 ± 1 year; height: 179 ± 1 cm; body mass: 73.4 ± 1.5 kg; body mass index 22.8 ± 0.5 kg·m−2) took part in this randomized, controlled study. After 48 h of unilateral knee immobilization, primed continuous intravenous l-[15N]-phenylalanine and l-[ring-2H5]-phenylalanine infusions were used for parallel determinations of FBR and FSR, respectively, in a postabsorptive (saline infusion; FAST) or simulated postprandial state (67.5 mg·kg body mass−1·h−1 amino acid infusion; FED). Bilateral m. vastus lateralis biopsies from the control (CON) and immobilized (IMM) legs, and arterialized-venous blood samples, were collected throughout.
Results
Amino acid infusion rapidly increased plasma phenylalanine (59 ± 9%), leucine (76 ± 5%), isoleucine (109 ± 7%) and valine (42 ± 4%) concentrations in FED only (all P < 0.001), which was sustained for the remainder of infusion. Serum insulin concentrations peaked at 21.8 ± 2.2 mU·L−1 at 15 min in FED only (P < 0.001) and were 60% greater in FED than FAST (P < 0.01). Immobilization did not influence FBR in either FAST (CON: 0.150 ± 0.018; IMM: 0.143 ± 0.017%·h−1) or FED (CON: 0.134 ± 0.012; IMM: 0.160 ± 0.018%·h−1; all effects P > 0.05). However, immobilization decreased FSR (P < 0.05) in both FAST (0.071 ± 0.004 vs. 0.086 ± 0.007%·h−1; IMM vs CON, respectively) and FED (0.066 ± 0.016 vs. 0.119 ± 0.016%·h−1; IMM vs CON, respectively). Consequently, immobilization decreased net muscle protein balance (P < 0.05) and to a greater extent in FED (CON: −0.012 ± 0.025; IMM: −0.095 ± 0.023%·h−1; P < 0.05) than FAST (CON: −0.064 ± 0.020; IMM: −0.072 ± 0.017%·h−1).
Conclusions
We conclude that merely 2 days of leg immobilization does not modulate postabsorptive and s
{"title":"Short-term disuse does not affect postabsorptive or postprandial muscle protein fractional breakdown rates","authors":"George F. Pavis, Doaa R. Abdelrahman, Andrew J. Murton, Benjamin T. Wall, Francis B. Stephens, Marlou L. Dirks","doi":"10.1002/jcsm.13284","DOIUrl":"10.1002/jcsm.13284","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The decline in postabsorptive and postprandial muscle protein fractional synthesis rates (FSR) does not quantitatively account for muscle atrophy during uncomplicated, short-term disuse, when atrophy rates are the highest. We sought to determine whether 2 days of unilateral knee immobilization affects mixed muscle protein fractional breakdown rates (FBR) during postabsorptive and simulated postprandial conditions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Twenty-three healthy, male participants (age: 22 ± 1 year; height: 179 ± 1 cm; body mass: 73.4 ± 1.5 kg; body mass index 22.8 ± 0.5 kg·m<sup>−2</sup>) took part in this randomized, controlled study. After 48 h of unilateral knee immobilization, primed continuous intravenous <span>l</span>-[<sup>15</sup>N]-phenylalanine and <span>l</span>-[<i>ring</i>-<sup>2</sup>H<sub>5</sub>]-phenylalanine infusions were used for parallel determinations of FBR and FSR, respectively, in a postabsorptive (saline infusion; FAST) or simulated postprandial state (67.5 mg·kg body mass<sup>−1</sup>·h<sup>−1</sup> amino acid infusion; FED). Bilateral <i>m. vastus lateralis</i> biopsies from the control (CON) and immobilized (IMM) legs, and arterialized-venous blood samples, were collected throughout.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Amino acid infusion rapidly increased plasma phenylalanine (59 ± 9%), leucine (76 ± 5%), isoleucine (109 ± 7%) and valine (42 ± 4%) concentrations in FED only (all <i>P</i> < 0.001), which was sustained for the remainder of infusion. Serum insulin concentrations peaked at 21.8 ± 2.2 mU·L<sup>−1</sup> at 15 min in FED only (<i>P</i> < 0.001) and were 60% greater in FED than FAST (<i>P</i> < 0.01). Immobilization did not influence FBR in either FAST (CON: 0.150 ± 0.018; IMM: 0.143 ± 0.017%·h<sup>−1</sup>) or FED (CON: 0.134 ± 0.012; IMM: 0.160 ± 0.018%·h<sup>−1</sup>; all effects <i>P</i> > 0.05). However, immobilization decreased FSR (<i>P</i> < 0.05) in both FAST (0.071 ± 0.004 vs. 0.086 ± 0.007%·h<sup>−1</sup>; IMM vs CON, respectively) and FED (0.066 ± 0.016 vs. 0.119 ± 0.016%·h<sup>−1</sup>; IMM vs CON, respectively). Consequently, immobilization decreased net muscle protein balance (<i>P</i> < 0.05) and to a greater extent in FED (CON: −0.012 ± 0.025; IMM: −0.095 ± 0.023%·h<sup>−1</sup>; <i>P</i> < 0.05) than FAST (CON: −0.064 ± 0.020; IMM: −0.072 ± 0.017%·h<sup>−1</sup>).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We conclude that merely 2 days of leg immobilization does not modulate postabsorptive and s","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"2064-2075"},"PeriodicalIF":8.9,"publicationDate":"2023-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13284","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9773108","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}
Robinson Ramírez-Vélez, Maria Iriarte-Fernández, Guzman Santafé, Armando Malanda, John R. Beard, Antonio Garcia-Hermoso, Mikel Izquierdo
Background
The World Health Organization proposed the concept of intrinsic capacity (IC; the composite of all the physical and mental capacities of the individual) as central for healthy ageing. However, little research has investigated the interaction and joint associations of IC with cardiovascular disease (CVD) incidence and CVD mortality in middle- and older-aged adults.
Methods
Using data from 443 130 UK Biobank participants, we analysed seven biomarkers capturing the level of functioning of five domains of IC to calculate a total IC score (ranging from 0 [better IC] to +4 points [poor IC]). Associations between IC score and incidence of six long-term CVD conditions (hypertension, stroke/transient ischaemic attack stroke, peripheral vascular disease, atrial fibrillation/flutter, coronary artery disease and heart failure), and grouped mortality from these conditions were estimated using Cox proportional models, with a 1-year landmark analysis to triangulate the findings.
Results
Over 10.6 years of follow-up, CVD morbidity grouped (n = 384 380 participants for the final analytic sample) was associated with IC scores (0 to +4): mean hazard ratio (HR) [95% confidence interval, CI] 1.11 [1.08–1.14], 1.20 [1.16–1.24], 1.29 [1.23–1.36] and 1.56 [1.45–1.59] in men (C-index = 0.68), and 1.17 [1.13–1.20], 1.30 [1.26–1.36], 1.52 [1.45–1.59] and 1.78 [1.67–1.89] in women (C-index = 0.70). In regard to mortality, our results indicated that the higher IC score (+4 points) was associated with a significant increase in subsequent CVD mortality (mean HR [95% CI]: 2.10 [1.81–2.43] in men [C-index = 0.75] and 2.29 [1.85–2.84] in women [C-index = 0.78]). Results of all sensitivity analyses by full sample, sex and age categories were largely consistent independent of major confounding factors (P < 0.001).
Conclusions
IC deficit score is a powerful predictor of functional trajectories and vulnerabilities of the individual in relation to CVD incidence and premature death. Monitoring an individual's IC score may provide an early-warning system to initiate preventive efforts.
{"title":"Association of intrinsic capacity with incidence and mortality of cardiovascular disease: Prospective study in UK Biobank","authors":"Robinson Ramírez-Vélez, Maria Iriarte-Fernández, Guzman Santafé, Armando Malanda, John R. Beard, Antonio Garcia-Hermoso, Mikel Izquierdo","doi":"10.1002/jcsm.13283","DOIUrl":"10.1002/jcsm.13283","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The World Health Organization proposed the concept of intrinsic capacity (IC; the composite of all the physical and mental capacities of the individual) as central for healthy ageing. However, little research has investigated the interaction and joint associations of IC with cardiovascular disease (CVD) incidence and CVD mortality in middle- and older-aged adults.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using data from 443 130 UK Biobank participants, we analysed seven biomarkers capturing the level of functioning of five domains of IC to calculate a total IC score (ranging from 0 [better IC] to +4 points [poor IC]). Associations between IC score and incidence of six long-term CVD conditions (hypertension, stroke/transient ischaemic attack stroke, peripheral vascular disease, atrial fibrillation/flutter, coronary artery disease and heart failure), and grouped mortality from these conditions were estimated using Cox proportional models, with a 1-year landmark analysis to triangulate the findings.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Over 10.6 years of follow-up, CVD morbidity grouped (<i>n</i> = 384 380 participants for the final analytic sample) was associated with IC scores (0 to +4): mean hazard ratio (HR) [95% confidence interval, CI] 1.11 [1.08–1.14], 1.20 [1.16–1.24], 1.29 [1.23–1.36] and 1.56 [1.45–1.59] in men (C-index = 0.68), and 1.17 [1.13–1.20], 1.30 [1.26–1.36], 1.52 [1.45–1.59] and 1.78 [1.67–1.89] in women (C-index = 0.70). In regard to mortality, our results indicated that the higher IC score (+4 points) was associated with a significant increase in subsequent CVD mortality (mean HR [95% CI]: 2.10 [1.81–2.43] in men [C-index = 0.75] and 2.29 [1.85–2.84] in women [C-index = 0.78]). Results of all sensitivity analyses by full sample, sex and age categories were largely consistent independent of major confounding factors (<i>P</i> < 0.001).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>IC deficit score is a powerful predictor of functional trajectories and vulnerabilities of the individual in relation to CVD incidence and premature death. Monitoring an individual's IC score may provide an early-warning system to initiate preventive efforts.</p>\u0000 </section>\u0000 </div>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"2054-2063"},"PeriodicalIF":8.9,"publicationDate":"2023-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13283","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10129020","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}
Joanna Sophia J. Vinke, Alan R. Gorter, Michele F. Eisenga, Wendy A. Dam, Peter van der Meer, Jacob van den Born, Stephan J.L. Bakker, Martijn F. Hoes, Martin H. de Borst
Background
Loss of muscle mass is linked with impaired quality of life and an increased risk of morbidity and premature mortality. Iron is essential for cellular processes such as energy metabolism, nucleotide synthesis and numerous enzymatic reactions. As the effects of iron deficiency (ID) on muscle mass and function are largely unknown, we aimed to assess the relation between ID and muscle mass in a large population-based cohort, and subsequently studied effects of ID on cultured skeletal myoblasts and differentiated myocytes.
Methods
In a population-based cohort of 8592 adults, iron status was assessed by plasma ferritin and transferrin saturation, and muscle mass was estimated using 24-h urinary creatinine excretion rate (CER). The relationships of ferritin and transferrin saturation with CER were assessed by multivariable logistic regression. Furthermore, mouse C2C12 skeletal myoblasts and differentiated myocytes were subjected to deferoxamine with or without ferric citrate. Myoblast proliferation was measured with a colorimetric 5-bromo-2′-deoxy-uridine ELISA assay. Myocyte differentiation was assessed using Myh7-stainings. Myocyte energy metabolism, oxygen consumption rate and extracellular acidification rate were assessed using Seahorse mitochondrial flux analysis, and apoptosis rate with fluorescence-activated cell sorting. RNA sequencing (RNAseq) was used to identify ID-related gene and pathway enrichment in myoblasts and myocytes.
Results
Participants in the lowest age- and sex-specific quintile of plasma ferritin (OR vs middle quintile 1.62, 95% CI 1.25–2.10, P < 0.001) or transferrin saturation (OR 1.34, 95% CI 1.03–1.75, P = 0.03) had a significantly higher risk of being in the lowest age- and sex-specific quintile of CER, independent of body mass index, estimated GFR, haemoglobin, hs-CRP, urinary urea excretion, alcohol consumption and smoking status. In C2C12 myoblasts, deferoxamine-induced ID reduced myoblast proliferation rate (P-trend <0.001) but did not affect differentiation. In myocytes, deferoxamine reduced myoglobin protein expression (−52%, P < 0.001) and tended to reduce mitochondrial oxygen consumption capacity (−28%, P = 0.10). Deferoxamine induced gene expression of cellular atrophy markers Trim63 (+20%, P = 0.002) and Fbxo32 (+27%, P = 0.048), which was reversed by ferric citrate (−31%, P = 0.04 and −26%, P = 0.004, respectively). RNAseq indicated that both in myoblasts and myocytes, ID predominantly affected genes involved in gly
背景:肌肉量减少与生活质量下降、发病率和过早死亡风险增加有关。铁对于能量代谢、核苷酸合成和许多酶促反应等细胞过程至关重要。由于铁缺乏(ID)对肌肉质量和功能的影响在很大程度上是未知的，我们的目的是在一个基于大量人群的队列中评估ID和肌肉质量之间的关系，并随后研究ID对培养的骨骼肌母细胞和分化肌细胞的影响。方法在8592名成人人群队列中，通过血浆铁蛋白和转铁蛋白饱和度评估铁状态，并通过24小时尿肌酐排泄率(CER)评估肌肉质量。采用多变量logistic回归评估铁蛋白和转铁蛋白饱和度与CER的关系。此外，小鼠C2C12骨骼肌母细胞和分化的肌细胞分别受到含或不含柠檬酸铁的去铁胺的影响。用5-溴-2 ' -脱氧尿苷ELISA法测定成肌细胞增殖。使用myh7染色评估肌细胞分化。采用海马线粒体通量分析评估心肌细胞能量代谢、耗氧量和细胞外酸化率，采用荧光活化细胞分选评估细胞凋亡率。采用RNA测序(RNAseq)技术鉴定成肌细胞和肌细胞中id相关基因及其富集途径。结果血浆铁蛋白最低年龄和性别五分位数的参与者(OR vs中五分位数1.62,95% CI 1.25-2.10, P <0.001)或转铁蛋白饱和度(or 1.34, 95% CI 1.03-1.75, P = 0.03)处于最低年龄和性别特异性五分位数的CER风险显著较高，与体重指数、估计GFR、血红蛋白、hs-CRP、尿尿素排泄、饮酒和吸烟状况无关。在C2C12成肌细胞中，去铁胺诱导的ID降低了成肌细胞的增殖率(P-trend <0.001)，但不影响分化。在肌细胞中，去铁胺降低了肌红蛋白的表达(- 52%，P <0.001)，并有降低线粒体耗氧能力的趋势(- 28%，P = 0.10)。去铁胺诱导细胞萎缩标志物Trim63 (+20%， P = 0.002)和Fbxo32 (+27%， P = 0.048)的基因表达，柠檬酸铁(- 31%，P = 0.04和- 26%，P = 0.004)逆转了这一作用。RNAseq表明，在成肌细胞和肌细胞中，ID主要影响糖酵解能量代谢、细胞周期调控和细胞凋亡相关基因;与柠檬酸铁共处理逆转了这些作用。结论:在常住人群中，ID与较低的肌肉质量有关，与血红蛋白水平和潜在的混杂因素无关。ID损害成肌细胞增殖和有氧糖酵解能力，并诱导肌细胞萎缩和凋亡的标志物。这些发现表明，ID会导致肌肉质量的减少。
{"title":"Iron deficiency is related to lower muscle mass in community-dwelling individuals and impairs myoblast proliferation","authors":"Joanna Sophia J. Vinke, Alan R. Gorter, Michele F. Eisenga, Wendy A. Dam, Peter van der Meer, Jacob van den Born, Stephan J.L. Bakker, Martijn F. Hoes, Martin H. de Borst","doi":"10.1002/jcsm.13277","DOIUrl":"https://doi.org/10.1002/jcsm.13277","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Loss of muscle mass is linked with impaired quality of life and an increased risk of morbidity and premature mortality. Iron is essential for cellular processes such as energy metabolism, nucleotide synthesis and numerous enzymatic reactions. As the effects of iron deficiency (ID) on muscle mass and function are largely unknown, we aimed to assess the relation between ID and muscle mass in a large population-based cohort, and subsequently studied effects of ID on cultured skeletal myoblasts and differentiated myocytes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In a population-based cohort of 8592 adults, iron status was assessed by plasma ferritin and transferrin saturation, and muscle mass was estimated using 24-h urinary creatinine excretion rate (CER). The relationships of ferritin and transferrin saturation with CER were assessed by multivariable logistic regression. Furthermore, mouse C2C12 skeletal myoblasts and differentiated myocytes were subjected to deferoxamine with or without ferric citrate. Myoblast proliferation was measured with a colorimetric 5-bromo-2′-deoxy-uridine ELISA assay. Myocyte differentiation was assessed using Myh7-stainings. Myocyte energy metabolism, oxygen consumption rate and extracellular acidification rate were assessed using Seahorse mitochondrial flux analysis, and apoptosis rate with fluorescence-activated cell sorting. RNA sequencing (RNAseq) was used to identify ID-related gene and pathway enrichment in myoblasts and myocytes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Participants in the lowest age- and sex-specific quintile of plasma ferritin (OR vs middle quintile 1.62, 95% CI 1.25–2.10, <i>P</i> < 0.001) or transferrin saturation (OR 1.34, 95% CI 1.03–1.75, <i>P</i> = 0.03) had a significantly higher risk of being in the lowest age- and sex-specific quintile of CER, independent of body mass index, estimated GFR, haemoglobin, hs-CRP, urinary urea excretion, alcohol consumption and smoking status. In C2C12 myoblasts, deferoxamine-induced ID reduced myoblast proliferation rate (<i>P</i>-trend <0.001) but did not affect differentiation. In myocytes, deferoxamine reduced myoglobin protein expression (−52%, <i>P</i> < 0.001) and tended to reduce mitochondrial oxygen consumption capacity (−28%, <i>P</i> = 0.10). Deferoxamine induced gene expression of cellular atrophy markers <i>Trim63</i> (+20%, <i>P</i> = 0.002) and <i>Fbxo32</i> (+27%, <i>P</i> = 0.048), which was reversed by ferric citrate (−31%, <i>P</i> = 0.04 and −26%, <i>P</i> = 0.004, respectively). RNAseq indicated that both in myoblasts and myocytes, ID predominantly affected genes involved in gly","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1865-1879"},"PeriodicalIF":8.9,"publicationDate":"2023-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13277","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6111097","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}
Sara Hadzibegovic, Jan Porthun, Alessia Lena, Pia Weinl?nder, Laura C. Lück, Sophia K. Potthoff, Lukas R?snick, Ann-Kathrin Fr?hlich, Luisa Valentina Ramer, Frederike Sonntag, Ursula Wilkenshoff, Johann Ahn, Ulrich Keller, Lars Bullinger, Amir A. Mahabadi, Matthias Totzeck, Tienush Rassaf, Stephan von Haehling, Andrew J.S. Coats, Stefan D. Anker, Eric J. Roeland, Ulf Landmesser, Markus S. Anker
Background
Hand grip strength (HGS) is a widely used functional test for the assessment of strength and functional status in patients with cancer, in particular with cancer cachexia. The aim was to prospectively evaluate the prognostic value of HGS in patients with mostly advanced cancer with and without cachexia and to establish reference values for a European-based population.
Methods
In this prospective study, 333 patients with cancer (85% stage III/IV) and 65 healthy controls of similar age and sex were enrolled. None of the study participants had significant cardiovascular disease or active infection at baseline. Repetitive HGS assessment was performed using a hand dynamometer to measure the maximal HGS (kilograms). Presence of cancer cachexia was defined when patients had ≥5% weight loss within 6 months or when body mass index was <20.0 kg/m2 with ≥2% weight loss (Fearon's criteria). Cox proportional hazard analyses were performed to assess the relationship of maximal HGS to all-cause mortality and to determine cut-offs for HGS with the best predictive power. We also assessed associations with additional relevant clinical and functional outcome measures at baseline, including anthropometric measures, physical function (Karnofsky Performance Status and Eastern Cooperative of Oncology Group), physical activity (4-m gait speed test and 6-min walk test), patient-reported outcomes (EQ-5D-5L and Visual Analogue Scale appetite/pain) and nutrition status (Mini Nutritional Assessment).
Results
The mean age was 60 ± 14 years; 163 (51%) were female, and 148 (44%) had cachexia at baseline. Patients with cancer showed 18% lower HGS than healthy controls (31.2 ± 11.9 vs. 37.9 ± 11.6 kg, P < 0.001). Patients with cancer cachexia had 16% lower HGS than those without cachexia (28.3 ± 10.1 vs. 33.6 ± 12.3 kg, P < 0.001). Patients with cancer were followed for a mean of 17 months (range 6–50), and 182 (55%) patients died during follow-up (2-year mortality rate 53%) (95% confidence interval 48–59%). Reduced maximal HGS was associated with increased mortality (per −5 kg; hazard ratio [HR] 1.19; 1.10–1.28; P < 0.0001; independently of age, sex, cancer stage, cancer entity and presence of cachexia). HGS was also a predictor of mortality in patients with cachexia (per −5 kg; HR 1.20; 1.08–1.33; P = 0.001) and without cachexia (per −5 kg; HR 1.18; 1.04–1.34; P = 0.010). The cut-off for maximal HGS with the best predictive power for poor survival was <25.1 kg for females (sensitivity 54%, specificity 63%)
{"title":"Hand grip strength in patients with advanced cancer: A prospective study","authors":"Sara Hadzibegovic, Jan Porthun, Alessia Lena, Pia Weinl?nder, Laura C. Lück, Sophia K. Potthoff, Lukas R?snick, Ann-Kathrin Fr?hlich, Luisa Valentina Ramer, Frederike Sonntag, Ursula Wilkenshoff, Johann Ahn, Ulrich Keller, Lars Bullinger, Amir A. Mahabadi, Matthias Totzeck, Tienush Rassaf, Stephan von Haehling, Andrew J.S. Coats, Stefan D. Anker, Eric J. Roeland, Ulf Landmesser, Markus S. Anker","doi":"10.1002/jcsm.13248","DOIUrl":"https://doi.org/10.1002/jcsm.13248","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hand grip strength (HGS) is a widely used functional test for the assessment of strength and functional status in patients with cancer, in particular with cancer cachexia. The aim was to prospectively evaluate the prognostic value of HGS in patients with mostly advanced cancer with and without cachexia and to establish reference values for a European-based population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this prospective study, 333 patients with cancer (85% stage III/IV) and 65 healthy controls of similar age and sex were enrolled. None of the study participants had significant cardiovascular disease or active infection at baseline. Repetitive HGS assessment was performed using a hand dynamometer to measure the maximal HGS (kilograms). Presence of cancer cachexia was defined when patients had ≥5% weight loss within 6 months or when body mass index was <20.0 kg/m<sup>2</sup> with ≥2% weight loss (Fearon's criteria). Cox proportional hazard analyses were performed to assess the relationship of maximal HGS to all-cause mortality and to determine cut-offs for HGS with the best predictive power. We also assessed associations with additional relevant clinical and functional outcome measures at baseline, including anthropometric measures, physical function (Karnofsky Performance Status and Eastern Cooperative of Oncology Group), physical activity (4-m gait speed test and 6-min walk test), patient-reported outcomes (EQ-5D-5L and Visual Analogue Scale appetite/pain) and nutrition status (Mini Nutritional Assessment).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The mean age was 60 ± 14 years; 163 (51%) were female, and 148 (44%) had cachexia at baseline. Patients with cancer showed 18% lower HGS than healthy controls (31.2 ± 11.9 vs. 37.9 ± 11.6 kg, <i>P</i> < 0.001). Patients with cancer cachexia had 16% lower HGS than those without cachexia (28.3 ± 10.1 vs. 33.6 ± 12.3 kg, <i>P</i> < 0.001). Patients with cancer were followed for a mean of 17 months (range 6–50), and 182 (55%) patients died during follow-up (2-year mortality rate 53%) (95% confidence interval 48–59%). Reduced maximal HGS was associated with increased mortality (per −5 kg; hazard ratio [HR] 1.19; 1.10–1.28; <i>P</i> < 0.0001; independently of age, sex, cancer stage, cancer entity and presence of cachexia). HGS was also a predictor of mortality in patients with cachexia (per −5 kg; HR 1.20; 1.08–1.33; <i>P</i> = 0.001) and without cachexia (per −5 kg; HR 1.18; 1.04–1.34; <i>P</i> = 0.010). The cut-off for maximal HGS with the best predictive power for poor survival was <25.1 kg for females (sensitivity 54%, specificity 63%)","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1682-1694"},"PeriodicalIF":8.9,"publicationDate":"2023-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13248","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6151241","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}
Mingchong Liu, Chensong Yang, Yutao Pan, Guixin Sun
As we all know, it has been proven that tobacco smoking is associated with many diseases, including sarcopenia.1 However, tobacco smoking as a lifestyle always affects our bodies for a quite long time, which is a great challenge for researchers to conduct a randomized controlled trial to identify the causal roles of tobacco smoking in diseases. We therefore read the recent paper by Park et al. This is a well-designed Mendelian randomization (MR) study, using genome-wide association studies (GWASs), which may prove the evidence of causal associations of tobacco smoking with telomere attrition and sarcopenia. These findings suggested that ever being a regular smoker in life (smoking initiation) was causally associated with shorter leucocyte telomere length (LTL), lower appendicular lean mass index (ALM), slower walking pace, and lower time spent on moderate-to-vigorous physical activity (MVPA).2
However, in this study, the high sample overlapping rate in the two-sample mendelian randomization raised concern about the conclusion: the data sources in the study were from UK Biobank (N = 337 138, for aging and sarcopenia) and a GWAS meta-analysis study named GSCAN (N = 1.2 million, for tobacco smoking).3 We carefully read the raw study of the GSCAN, and unfortunately, in the 1.2 million samples, 383 613 were from UK Biobank. According to the calculation methods for the maximum estimated value for sample overlapping rate, the cohort of aging and sarcopenia (337 138 samples) may be fully overlapped with samples for smoking (383 613 samples), which means the maximum estimated sample overlapping rate might be 100%. It was the violation of the essential assumptions of two-sample MR. The bias caused by sample overlapping should not be ignored.4
Interestingly, the raw data provided by GSCAN contains a dataset without UK Biobank cohorts (https://conservancy.umn.edu/handle/11299/201564). Therefore, using the GSCAN data without UK Biobank, we tried to re-perform the MR study by Park et al. Briefly, the data including 848 460 individuals for exposure (tobacco smoking) were from the GSCAN data without UK Biobank individuals. For outcomes, similar to Park's study, we used the summary GWAS data of the UK Biobank from the IEU database.5 Except for handgrip strength, the phenotypes of other outcomes were as same as the previous study: including LTL (N = 472 174, datasets ID: ieu-b-4879), adjusted appendicular lean mass (N = 450 243, datasets ID: GCST90000025), walking pace (N = 459 915, datasets ID: ukb-b-4711), moderate to vigorous physical activity (N = 377 234, datasets ID: GCST006097). In the study by Park et al., handgrip strength was defined as the average value of two hands. Because we did not have access to the detailed UK Biobank data, our study's phenotypes of handgrip strength were d
{"title":"Comment on ‘Causal linkage of tobacco smoking with ageing: Mendelian randomization analysis towards telomere attrition and sarcopenia’ by Park et al.","authors":"Mingchong Liu, Chensong Yang, Yutao Pan, Guixin Sun","doi":"10.1002/jcsm.13279","DOIUrl":"https://doi.org/10.1002/jcsm.13279","url":null,"abstract":"<p>As we all know, it has been proven that tobacco smoking is associated with many diseases, including sarcopenia.<span><sup>1</sup></span> However, tobacco smoking as a lifestyle always affects our bodies for a quite long time, which is a great challenge for researchers to conduct a randomized controlled trial to identify the causal roles of tobacco smoking in diseases. We therefore read the recent paper by Park et al. This is a well-designed Mendelian randomization (MR) study, using genome-wide association studies (GWASs), which may prove the evidence of causal associations of tobacco smoking with telomere attrition and sarcopenia. These findings suggested that ever being a regular smoker in life (smoking initiation) was causally associated with shorter leucocyte telomere length (LTL), lower appendicular lean mass index (ALM), slower walking pace, and lower time spent on moderate-to-vigorous physical activity (MVPA).<span><sup>2</sup></span></p><p>However, in this study, the high sample overlapping rate in the two-sample mendelian randomization raised concern about the conclusion: the data sources in the study were from UK Biobank (<i>N</i> = 337 138, for aging and sarcopenia) and a GWAS meta-analysis study named GSCAN (<i>N</i> = 1.2 million, for tobacco smoking).<span><sup>3</sup></span> We carefully read the raw study of the GSCAN, and unfortunately, in the 1.2 million samples, 383 613 were from UK Biobank. According to the calculation methods for the maximum estimated value for sample overlapping rate, the cohort of aging and sarcopenia (337 138 samples) may be fully overlapped with samples for smoking (383 613 samples), which means the maximum estimated sample overlapping rate might be 100%. It was the violation of the essential assumptions of two-sample MR. The bias caused by sample overlapping should not be ignored.<span><sup>4</sup></span></p><p>Interestingly, the raw data provided by GSCAN contains a dataset without UK Biobank cohorts (https://conservancy.umn.edu/handle/11299/201564). Therefore, using the GSCAN data without UK Biobank, we tried to re-perform the MR study by Park et al. Briefly, the data including 848 460 individuals for exposure (tobacco smoking) were from the GSCAN data without UK Biobank individuals. For outcomes, similar to Park's study, we used the summary GWAS data of the UK Biobank from the IEU database.<span><sup>5</sup></span> Except for handgrip strength, the phenotypes of other outcomes were as same as the previous study: including LTL (<i>N</i> = 472 174, datasets ID: ieu-b-4879), adjusted appendicular lean mass (<i>N</i> = 450 243, datasets ID: GCST90000025), walking pace (<i>N</i> = 459 915, datasets ID: ukb-b-4711), moderate to vigorous physical activity (<i>N</i> = 377 234, datasets ID: GCST006097). In the study by Park et al., handgrip strength was defined as the average value of two hands. Because we did not have access to the detailed UK Biobank data, our study's phenotypes of handgrip strength were d","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1912-1914"},"PeriodicalIF":8.9,"publicationDate":"2023-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13279","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5688040","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}
As individuals age, skeletal muscle mass and function, including lean body mass and grip strength, and respiratory muscle mass and strength, tend to decline.1, 2 The term ‘respiratory sarcopenia’ emerged during a discussion on sarcopenia. Respiratory sarcopenia should encompass respiratory muscle mass and strength or function to adhere to the original sarcopenia definition, which considers whole-body muscle mass, grip strength, and gait speed. However, the decreasing respiratory muscle mass associated with aging has not been adequately discussed. The concept may appear simple; however, defining respiratory sarcopenia has not been extensively explored.
Inspiratory and expiratory maximal mouth pressure measurement as direct evidence of respiratory muscle strength is simple; however, access to relevant measuring equipment is limited. Moreover, evaluating respiratory muscle mass is challenging, and the respiratory sarcopenia using low respiratory muscle mass cannot be virtually established. Therefore, we proposed defining respiratory sarcopenia using the peak expiratory flow rate (PEFR) as an alternative to directly measuring respiratory muscle strength.3 Subsequently, the Japanese Working Group of Respiratory Sarcopenia of the Japanese Association of Rehabilitation Nutrition (JARN) published criteria for respiratory sarcopenia, which was defined based on a decline in the maximal mouth pressure and respiratory muscle mass and the presence of whole-body-sarcopenia, as measured using skeletal muscle mass, strength, and physical performance.4 However, this definition has not been established due to a lack of consensus. Moreover, to the best of our knowledge, the future health-related outcomes of respiratory sarcopenia have never been evaluated. Therefore, this survey confirmed whether respiratory sarcopenia, defined using PEFR and the JARN criteria, is associated with future mortality among community-dwelling older adults.
We assessed respiratory sarcopenia-related mortality after a 5-year follow-up of 470 participants (185 men aged 75.2 ± 5.5 years and 285 women aged 74.2 ± 5.4 years) who participated in a comprehensive health checkup program called ‘The Otassha Study’ conducted in the Tokyo Metropolitan Institute for Geriatrics and Gerontology in 2015. Participants who underwent spirometry and sarcopenia assessment were included; however, patients with chronic obstructive pulmonary disease (COPD) were excluded.
An electronic spirometer (Autospiro AS-507, Minato, Osaka, Japan) was used to measure pulmonary function. The PEFR as a percentage of the predicted value (%PEFR), vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), VC as a percentage of the predicted value (%VC), FVC as a percentage of the predicted value (%FVC), lower limit of normal FVC (FVCLLN), and FEV1/FVC were assessed.
{"title":"Respiratory sarcopenia is a predictor of all-cause mortality in community-dwelling older adults—The Otassha Study","authors":"Takeshi Kera, Hisashi Kawai, Manami Ejiri, Kumiko Ito, Hirohiko Hirano, Yoshinori Fujiwara, Kazushige Ihara, Shuichi Obuchi","doi":"10.1002/jcsm.13266","DOIUrl":"https://doi.org/10.1002/jcsm.13266","url":null,"abstract":"<p>As individuals age, skeletal muscle mass and function, including lean body mass and grip strength, and respiratory muscle mass and strength, tend to decline.<span><sup>1, 2</sup></span> The term ‘respiratory sarcopenia’ emerged during a discussion on sarcopenia. Respiratory sarcopenia should encompass respiratory muscle mass and strength or function to adhere to the original sarcopenia definition, which considers whole-body muscle mass, grip strength, and gait speed. However, the decreasing respiratory muscle mass associated with aging has not been adequately discussed. The concept may appear simple; however, defining respiratory sarcopenia has not been extensively explored.</p><p>Inspiratory and expiratory maximal mouth pressure measurement as direct evidence of respiratory muscle strength is simple; however, access to relevant measuring equipment is limited. Moreover, evaluating respiratory muscle mass is challenging, and the respiratory sarcopenia using low respiratory muscle mass cannot be virtually established. Therefore, we proposed defining respiratory sarcopenia using the peak expiratory flow rate (PEFR) as an alternative to directly measuring respiratory muscle strength.<span><sup>3</sup></span> Subsequently, the Japanese Working Group of Respiratory Sarcopenia of the Japanese Association of Rehabilitation Nutrition (JARN) published criteria for respiratory sarcopenia, which was defined based on a decline in the maximal mouth pressure and respiratory muscle mass and the presence of whole-body-sarcopenia, as measured using skeletal muscle mass, strength, and physical performance.<span><sup>4</sup></span> However, this definition has not been established due to a lack of consensus. Moreover, to the best of our knowledge, the future health-related outcomes of respiratory sarcopenia have never been evaluated. Therefore, this survey confirmed whether respiratory sarcopenia, defined using PEFR and the JARN criteria, is associated with future mortality among community-dwelling older adults.</p><p>We assessed respiratory sarcopenia-related mortality after a 5-year follow-up of 470 participants (185 men aged 75.2 ± 5.5 years and 285 women aged 74.2 ± 5.4 years) who participated in a comprehensive health checkup program called ‘The Otassha Study’ conducted in the Tokyo Metropolitan Institute for Geriatrics and Gerontology in 2015. Participants who underwent spirometry and sarcopenia assessment were included; however, patients with chronic obstructive pulmonary disease (COPD) were excluded.</p><p>An electronic spirometer (Autospiro AS-507, Minato, Osaka, Japan) was used to measure pulmonary function. The PEFR as a percentage of the predicted value (%PEFR), vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 s (FEV<sub>1</sub>), VC as a percentage of the predicted value (%VC), FVC as a percentage of the predicted value (%FVC), lower limit of normal FVC (FVC<sub>LLN</sub>), and FEV<sub>1</sub>/FVC were assessed.</p><p>A","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1894-1899"},"PeriodicalIF":8.9,"publicationDate":"2023-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13266","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6232689","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}
Jae-Sung You, Yongdeok Kim, Soohyun Lee, Rashid Bashir, Jie Chen
Background
Duchenne muscular dystrophy (DMD), caused by dystrophin deficiency, leads to progressive and fatal muscle weakness through yet-to-be-fully deciphered molecular perturbations. Emerging evidence implicates RhoA/Rho-associated protein kinase (ROCK) signalling in DMD pathology, yet its direct role in DMD muscle function, and related mechanisms, are unknown.
Methods
Three-dimensionally engineered dystrophin-deficient mdx skeletal muscles and mdx mice were used to test the role of ROCK in DMD muscle function in vitro and in situ, respectively. The role of ARHGEF3, one of the RhoA guanine nucleotide exchange factors (GEFs), in RhoA/ROCK signalling and DMD pathology was examined by generating Arhgef3 knockout mdx mice. The role of RhoA/ROCK signalling in mediating the function of ARHGEF3 was determined by evaluating the effects of wild-type or GEF-inactive ARHGEF3 overexpression with ROCK inhibitor treatment. To gain more mechanistic insights, autophagy flux and the role of autophagy were assessed in various conditions with chloroquine.
Results
Inhibition of ROCK with Y-27632 improved muscle force production in 3D-engineered mdx muscles (+25% from three independent experiments, P < 0.05) and in mice (+25%, P < 0.001). Unlike suggested by previous studies, this improvement was independent of muscle differentiation or quantity and instead related to increased muscle quality. We found that ARHGEF3 was elevated and responsible for RhoA/ROCK activation in mdx muscles, and that depleting ARHGEF3 in mdx mice restored muscle quality (up to +36%, P < 0.01) and morphology without affecting regeneration. Conversely, overexpressing ARHGEF3 further compromised mdx muscle quality (−13% vs. empty vector control, P < 0.01) in GEF activity- and ROCK-dependent manner. Notably, ARHGEF3/ROCK inhibition exerted the effects by rescuing autophagy which is commonly impaired in dystrophic muscles.
Conclusions
Our findings uncover a new pathological mechanism of muscle weakness in DMD involving the ARHGEF3-ROCK-autophagy pathway and the therapeutic potential of targeting ARHGEF3 in DMD.
{"title":"RhoA/ROCK signalling activated by ARHGEF3 promotes muscle weakness via autophagy in dystrophic mdx mice","authors":"Jae-Sung You, Yongdeok Kim, Soohyun Lee, Rashid Bashir, Jie Chen","doi":"10.1002/jcsm.13278","DOIUrl":"https://doi.org/10.1002/jcsm.13278","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Duchenne muscular dystrophy (DMD), caused by dystrophin deficiency, leads to progressive and fatal muscle weakness through yet-to-be-fully deciphered molecular perturbations. Emerging evidence implicates RhoA/Rho-associated protein kinase (ROCK) signalling in DMD pathology, yet its direct role in DMD muscle function, and related mechanisms, are unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Three-dimensionally engineered dystrophin-deficient <i>mdx</i> skeletal muscles and <i>mdx</i> mice were used to test the role of ROCK in DMD muscle function <i>in vitro</i> and <i>in situ</i>, respectively. The role of ARHGEF3, one of the RhoA guanine nucleotide exchange factors (GEFs), in RhoA/ROCK signalling and DMD pathology was examined by generating <i>Arhgef3</i> knockout <i>mdx</i> mice. The role of RhoA/ROCK signalling in mediating the function of ARHGEF3 was determined by evaluating the effects of wild-type or GEF-inactive ARHGEF3 overexpression with ROCK inhibitor treatment. To gain more mechanistic insights, autophagy flux and the role of autophagy were assessed in various conditions with chloroquine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Inhibition of ROCK with Y-27632 improved muscle force production in 3D-engineered <i>mdx</i> muscles (+25% from three independent experiments, <i>P</i> < 0.05) and in mice (+25%, <i>P</i> < 0.001). Unlike suggested by previous studies, this improvement was independent of muscle differentiation or quantity and instead related to increased muscle quality. We found that ARHGEF3 was elevated and responsible for RhoA/ROCK activation in <i>mdx</i> muscles, and that depleting ARHGEF3 in <i>mdx</i> mice restored muscle quality (up to +36%, <i>P</i> < 0.01) and morphology without affecting regeneration. Conversely, overexpressing ARHGEF3 further compromised <i>mdx</i> muscle quality (−13% vs. empty vector control, <i>P</i> < 0.01) in GEF activity- and ROCK-dependent manner. Notably, ARHGEF3/ROCK inhibition exerted the effects by rescuing autophagy which is commonly impaired in dystrophic muscles.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings uncover a new pathological mechanism of muscle weakness in DMD involving the ARHGEF3-ROCK-autophagy pathway and the therapeutic potential of targeting ARHGEF3 in DMD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1880-1893"},"PeriodicalIF":8.9,"publicationDate":"2023-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13278","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5673867","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}
Che Wang, Xinru Guo, Xieguanxuan Xu, Shuang Liang, Wenling Wang, Fanglei Zhu, Siyang Wang, Jie Wu, Li Zhang, Xuefeng Sun, Xiangmei Chen, Guangyan Cai, The Chinese observational prospective study of ageing population with chronic kidney disease (C-OPTION)
Background
Frailty and sarcopenia are prevalent in chronic kidney disease (CKD) populations and could increase the risk for adverse health outcomes. Few studies assess the correlation between frailty, sarcopenia and CKD in non-dialysis patients. Therefore, this study aimed to determine frailty-associated factors in elderly CKD stage I–IV patients, expected to early identify and intervene in the frailty of elderly CKD patients.
Methods
A total of 774 elderly CKD I–IV patients (>60 years of age) recruited from 29 clinical centers in China between March 2017 and September 2019 were included in this study. We established a Frailty Index (FI) model to evaluate frailty risk and verified the distributional property of FI in the study population. Sarcopenia was defined according to the criteria of the Asian Working Group for Sarcopenia 2019. Multinomial logistic regression analysis was used to assess the associated factors for frailty.
Results
Seven hundred seventy-four patients (median age 67 years, 66.0% males) were included in this analysis, with a median estimated glomerular filtration rate of 52.8 mL/min/1.73 m2. The prevalence of sarcopenia was 30.6%. The FI exhibited a right-skewed distribution. The age-related slope of FI was 1.4% per year on a logarithmic scale (r2 = 0.706, 95% CI 0.9, 1.8, P < 0.001). The upper limit of FI was around 0.43. The FI was related to mortality (HR = 1.06, 95% CI 1.00, 1.12, P = 0.041). Multivariate multinomial logistic regression analysis showed that sarcopenia, advanced age, CKD stage II–IV, low level of serum albumin and increased waist–hip ratio were significantly associated with high FI status, while advanced age and CKD stage III–IV were significantly associated with for median FI status. Moreover, the results from the subgroup were consistent with the leading results.
Conclusions
Sarcopenia was independently associated with an increased risk for frailty in elderly CKD I-IV patients. Patients with sarcopenia, advanced age, high CKD stage, high waist–hip ratio and low serum albumin level should be assessed for frailty.
背景:虚弱和肌肉减少症在慢性肾脏疾病(CKD)人群中普遍存在，并可能增加不良健康结果的风险。很少有研究评估非透析患者虚弱、肌肉减少和CKD之间的相关性。因此，本研究旨在确定老年CKD I-IV期患者的衰弱相关因素，以期早期识别和干预老年CKD患者的衰弱。方法2017年3月至2019年9月，从中国29个临床中心招募774例老年CKD I-IV患者(60岁)纳入本研究。我们建立了虚弱指数(FI)模型来评估虚弱风险，并验证了FI在研究人群中的分布特性。肌少症是根据2019年亚洲肌少症工作组的标准定义的。采用多项logistic回归分析评估与衰弱相关的因素。结果774例患者(中位年龄67岁，66.0%为男性)纳入本分析，估计肾小球滤过率中位数为52.8 mL/min/1.73 m2。肌肉减少症患病率为30.6%。FI呈右偏态分布。在对数尺度上，FI的年龄相关斜率为每年1.4% (r2 = 0.706, 95% CI 0.9, 1.8, P <0.001)。FI的上限约为0.43。FI与死亡率相关(HR = 1.06, 95% CI 1.00, 1.12, P = 0.041)。多因素logistic回归分析显示，骨骼肌减少、高龄、CKD II-IV期、血清白蛋白水平低、腰臀比增高与高FI状态显著相关，高龄和CKD III-IV期与中位FI状态显著相关。此外，亚组的结果与领先结果一致。结论:老年CKD I-IV患者肌少症与衰弱风险增加独立相关。骨骼肌减少、高龄、CKD分期高、腰臀比高、血清白蛋白水平低的患者应进行虚弱评估。
{"title":"Association between sarcopenia and frailty in elderly patients with chronic kidney disease","authors":"Che Wang, Xinru Guo, Xieguanxuan Xu, Shuang Liang, Wenling Wang, Fanglei Zhu, Siyang Wang, Jie Wu, Li Zhang, Xuefeng Sun, Xiangmei Chen, Guangyan Cai, The Chinese observational prospective study of ageing population with chronic kidney disease (C-OPTION)","doi":"10.1002/jcsm.13275","DOIUrl":"https://doi.org/10.1002/jcsm.13275","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Frailty and sarcopenia are prevalent in chronic kidney disease (CKD) populations and could increase the risk for adverse health outcomes. Few studies assess the correlation between frailty, sarcopenia and CKD in non-dialysis patients. Therefore, this study aimed to determine frailty-associated factors in elderly CKD stage I–IV patients, expected to early identify and intervene in the frailty of elderly CKD patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A total of 774 elderly CKD I–IV patients (>60 years of age) recruited from 29 clinical centers in China between March 2017 and September 2019 were included in this study. We established a Frailty Index (FI) model to evaluate frailty risk and verified the distributional property of FI in the study population. Sarcopenia was defined according to the criteria of the Asian Working Group for Sarcopenia 2019. Multinomial logistic regression analysis was used to assess the associated factors for frailty.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Seven hundred seventy-four patients (median age 67 years, 66.0% males) were included in this analysis, with a median estimated glomerular filtration rate of 52.8 mL/min/1.73 m<sup>2</sup>. The prevalence of sarcopenia was 30.6%. The FI exhibited a right-skewed distribution. The age-related slope of FI was 1.4% per year on a logarithmic scale (<i>r</i><sup>2</sup> = 0.706, 95% CI 0.9, 1.8, <i>P</i> < 0.001). The upper limit of FI was around 0.43. The FI was related to mortality (HR = 1.06, 95% CI 1.00, 1.12, <i>P</i> = 0.041). Multivariate multinomial logistic regression analysis showed that sarcopenia, advanced age, CKD stage II–IV, low level of serum albumin and increased waist–hip ratio were significantly associated with high FI status, while advanced age and CKD stage III–IV were significantly associated with for median FI status. Moreover, the results from the subgroup were consistent with the leading results.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Sarcopenia was independently associated with an increased risk for frailty in elderly CKD I-IV patients. Patients with sarcopenia, advanced age, high CKD stage, high waist–hip ratio and low serum albumin level should be assessed for frailty.</p>\u0000 </section>\u0000 </div>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1855-1864"},"PeriodicalIF":8.9,"publicationDate":"2023-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13275","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6148134","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}
Nicole Kiss, Belinda Steer, Marian de van der Schueren, Jenelle Loeliger, Roohallah Alizadehsani, Lara Edbrooke, Irene Deftereos, Erin Laing, Abbas Khosravi
Background
Equipment to assess muscle mass is not available in all health services. Yet we have limited understanding of whether applying the Global Leadership Initiative on Malnutrition (GLIM) criteria without an assessment of muscle mass affects the ability to predict adverse outcomes. This study used machine learning to determine which combinations of GLIM phenotypic and etiologic criteria are most important for the prediction of 30-day mortality and unplanned admission using combinations including and excluding low muscle mass.
Methods
In a cohort of 2801 participants from two cancer malnutrition point prevalence studies, we applied the GLIM criteria with and without muscle mass. Phenotypic criteria were assessed using ≥5% unintentional weight loss, body mass index, subjective assessment of muscle stores from the PG-SGA. Aetiologic criteria included self-reported reduced food intake and inflammation (metastatic disease). Machine learning approaches were applied to predict 30-day mortality and unplanned admission using models with and without muscle mass.
Results
Participants with missing data were excluded, leaving 2494 for analysis [49.6% male, mean (SD) age: 62.3 (14.2) years]. Malnutrition prevalence was 19.5% and 17.5% when muscle mass was included and excluded, respectively. However, 48 (10%) of malnourished participants were missed if muscle mass was excluded. For the nine GLIM combinations that excluded low muscle mass the most important combinations to predict mortality were (1) weight loss and inflammation and (2) weight loss and reduced food intake. Machine learning metrics were similar in models excluding or including muscle mass to predict mortality (average accuracy: 84% vs. 88%; average sensitivity: 41% vs. 38%; average specificity: 85% vs. 89%). Weight loss and reduced food intake was the most important combination to predict unplanned hospital admission. Machine learning metrics were almost identical in models excluding or including muscle mass to predict unplanned hospital admission, with small differences observed only if reported to one decimal place (average accuracy: 77% vs. 77%; average sensitivity: 29% vs. 29%; average specificity: 84% vs. 84%).
Conclusions
Our results indicate predictive ability is maintained, although the ability to identify all malnourished patients is compromised, when muscle mass is excluded from the GLIM diagnosis. This has important implications for assessme
背景:并非所有卫生服务机构都有评估肌肉质量的设备。然而，在不评估肌肉质量的情况下应用全球营养不良领导倡议(GLIM)标准是否会影响预测不良后果的能力，我们的理解有限。本研究使用机器学习来确定GLIM表型和病因标准的哪些组合对预测30天死亡率和非计划入院最重要，包括和不包括低肌肉量的组合。方法对来自两项癌症营养不良点患病率研究的2801名参与者进行队列研究，我们应用了有和没有肌肉质量的GLIM标准。表型标准通过≥5%的意外体重减轻、体重指数、PG-SGA对肌肉储存的主观评估来评估。病因标准包括自我报告的食物摄入减少和炎症(转移性疾病)。使用有和没有肌肉质量的模型，应用机器学习方法预测30天死亡率和计划外入院。结果排除资料缺失的受试者，留下2494例进行分析[49.6%为男性，平均(SD)年龄:62.3(14.2)岁]。包括肌肉质量和不包括肌肉质量时，营养不良患病率分别为19.5%和17.5%。然而，如果排除肌肉质量，48(10%)营养不良的参与者被遗漏。对于排除低肌肉量的九种GLIM组合，预测死亡率最重要的组合是(1)体重减轻和炎症(2)体重减轻和食物摄入量减少。机器学习指标在排除或包括肌肉质量的模型中相似，以预测死亡率(平均准确率:84% vs. 88%;平均灵敏度:41% vs. 38%;平均特异性:85% vs 89%)。体重减轻和食物摄入减少是预测意外住院最重要的组合。机器学习指标在排除或包括肌肉质量的模型中几乎相同，用于预测计划外住院，只有在报告到小数点后一位时才会观察到微小的差异(平均准确率:77% vs. 77%;平均灵敏度:29% vs. 29%;平均特异性:84% vs. 84%)。结论:我们的研究结果表明，当肌肉质量被排除在GLIM诊断之外时，尽管识别所有营养不良患者的能力受到损害，但预测能力仍然存在。这对缺乏肌肉质量评估设备的卫生服务部门的评估具有重要意义。我们的研究结果支持GLIM方法的稳健性，并且在必要时可以灵活地排除某些表型或病因成分，尽管有些病例会被遗漏。
{"title":"Machine learning models to predict outcomes at 30-days using Global Leadership Initiative on Malnutrition combinations with and without muscle mass in people with cancer","authors":"Nicole Kiss, Belinda Steer, Marian de van der Schueren, Jenelle Loeliger, Roohallah Alizadehsani, Lara Edbrooke, Irene Deftereos, Erin Laing, Abbas Khosravi","doi":"10.1002/jcsm.13259","DOIUrl":"https://doi.org/10.1002/jcsm.13259","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Equipment to assess muscle mass is not available in all health services. Yet we have limited understanding of whether applying the Global Leadership Initiative on Malnutrition (GLIM) criteria without an assessment of muscle mass affects the ability to predict adverse outcomes. This study used machine learning to determine which combinations of GLIM phenotypic and etiologic criteria are most important for the prediction of 30-day mortality and unplanned admission using combinations including and excluding low muscle mass.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In a cohort of 2801 participants from two cancer malnutrition point prevalence studies, we applied the GLIM criteria with and without muscle mass. Phenotypic criteria were assessed using ≥5% unintentional weight loss, body mass index, subjective assessment of muscle stores from the PG-SGA. Aetiologic criteria included self-reported reduced food intake and inflammation (metastatic disease). Machine learning approaches were applied to predict 30-day mortality and unplanned admission using models with and without muscle mass.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Participants with missing data were excluded, leaving 2494 for analysis [49.6% male, mean (SD) age: 62.3 (14.2) years]. Malnutrition prevalence was 19.5% and 17.5% when muscle mass was included and excluded, respectively. However, 48 (10%) of malnourished participants were missed if muscle mass was excluded. For the nine GLIM combinations that excluded low muscle mass the most important combinations to predict mortality were (1) weight loss and inflammation and (2) weight loss and reduced food intake. Machine learning metrics were similar in models excluding or including muscle mass to predict mortality (average accuracy: 84% vs. 88%; average sensitivity: 41% vs. 38%; average specificity: 85% vs. 89%). Weight loss and reduced food intake was the most important combination to predict unplanned hospital admission. Machine learning metrics were almost identical in models excluding or including muscle mass to predict unplanned hospital admission, with small differences observed only if reported to one decimal place (average accuracy: 77% vs. 77%; average sensitivity: 29% vs. 29%; average specificity: 84% vs. 84%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our results indicate predictive ability is maintained, although the ability to identify all malnourished patients is compromised, when muscle mass is excluded from the GLIM diagnosis. This has important implications for assessme","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 4","pages":"1815-1823"},"PeriodicalIF":8.9,"publicationDate":"2023-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13259","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5909718","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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