Jiahao Zhu, Dan Zhou, Yaoyao Nie, Jing Wang, Ye Yang, Dingwan Chen, Min Yu, Yingjun Li
Background
Observational studies have demonstrated a strong bidirectional association between frailty and depression, but it remains unclear whether this association reflects causality. This study aimed to examine the bidirectional causal relationship between frailty and depression.
Methods
Using genome-wide association study summary data, two-sample Mendelian randomization was performed to test for the potential bidirectional causality between frailty, as defined by both the frailty index and the frailty phenotype, and depression. Several frailty-related traits were additionally investigated, including weaker hand grip strength, slower walking pace and physical inactivity. Findings were replicated using an independent depression data source and verified using multiple sensitivity analyses.
Results
Genetically predicted higher frailty index (odds ratio [OR], 1.86; P < 0.001), higher frailty phenotype score (OR, 2.79; P < 0.001), lower grip strength (OR, 1.23; P = 0.003), slower walking pace (OR, 1.55; P = 0.027) and physical inactivity (OR, 1.44; P = 0.003) all were associated with a higher risk of depression. As for the reverse direction, genetic liability to depression showed consistent associations with a higher frailty index (beta, 0.167; P < 0.001) and a higher frailty phenotype score (beta, 0.067; P = 0.001), but not with other frailty-related traits that were investigated. The results were stable across sensitivity analyses and across depression datasets.
Conclusions
Our findings add novel evidence supporting the bidirectional causal association between frailty and depression. Improving balance and muscle strength and increasing physical activity may be beneficial in both depression and frailty.
{"title":"Assessment of the bidirectional causal association between frailty and depression: A Mendelian randomization study","authors":"Jiahao Zhu, Dan Zhou, Yaoyao Nie, Jing Wang, Ye Yang, Dingwan Chen, Min Yu, Yingjun Li","doi":"10.1002/jcsm.13319","DOIUrl":"10.1002/jcsm.13319","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Observational studies have demonstrated a strong bidirectional association between frailty and depression, but it remains unclear whether this association reflects causality. This study aimed to examine the bidirectional causal relationship between frailty and depression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using genome-wide association study summary data, two-sample Mendelian randomization was performed to test for the potential bidirectional causality between frailty, as defined by both the frailty index and the frailty phenotype, and depression. Several frailty-related traits were additionally investigated, including weaker hand grip strength, slower walking pace and physical inactivity. Findings were replicated using an independent depression data source and verified using multiple sensitivity analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Genetically predicted higher frailty index (odds ratio [OR], 1.86; <i>P</i> < 0.001), higher frailty phenotype score (OR, 2.79; <i>P</i> < 0.001), lower grip strength (OR, 1.23; <i>P</i> = 0.003), slower walking pace (OR, 1.55; <i>P</i> = 0.027) and physical inactivity (OR, 1.44; <i>P</i> = 0.003) all were associated with a higher risk of depression. As for the reverse direction, genetic liability to depression showed consistent associations with a higher frailty index (beta, 0.167; <i>P</i> < 0.001) and a higher frailty phenotype score (beta, 0.067; <i>P</i> = 0.001), but not with other frailty-related traits that were investigated. The results were stable across sensitivity analyses and across depression datasets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings add novel evidence supporting the bidirectional causal association between frailty and depression. Improving balance and muscle strength and increasing physical activity may be beneficial in both depression and frailty.</p>\u0000 </section>\u0000 </div>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"2327-2334"},"PeriodicalIF":8.9,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13319","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10159238","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}
Kristen M. Beavers, Allison E. Avery, Mahalakshmi Shankaran, William J. Evans, S. Delanie Lynch, Caitlyn Dwyer, Marjorie Howard, Daniel P. Beavers, Ashley A. Weaver, Leon Lenchik, Peggy M. Cawthon
Background
Traditionally, weight loss (WL) trials utilize dual energy X-ray absorptiometry (DXA) to measure lean mass. This method assumes lean mass, as the sum of all non-bone and non-fat tissue, is a reasonable proxy for muscle mass. In contrast, the D3-creatine (D3Cr) dilution method directly measures whole body skeletal muscle mass, although this method has yet to be applied in the context of a geriatric WL trial. The purpose of this project was to (1) describe estimates of change and variability in D3Cr muscle mass in older adults participating in an intentional WL intervention and (2) relate its change to other measures of body composition as well as muscle function and strength.
Methods
The INVEST in Bone Health trial (NCT04076618), used as a scaffold for this ancillary pilot project, is a three-armed, 12-month randomized, controlled trial designed to determine the effects of resistance training or weighted vest use during intentional WL on a battery of musculoskeletal health outcomes among 150 older adults living with obesity. A convenience sample of 24 participants (n = 8/arm) are included in this analysis. At baseline and 6 months, participants were weighed, ingested a 30 mg D3Cr tracer dose, provided a fasted urine sample 3–6 days post-dosage, underwent DXA (total body fat and lean masses, appendicular lean mass) and computed tomography (mid-thigh and trunk muscle/intermuscular fat areas) scans, and performed 400-m walk, stair climb, knee extensor strength, and grip strength tests.
Results
Participants were older (68.0 ± 4.4 years), mostly White (75.0%), predominantly female (66.7%), and living with obesity (body mass index: 33.8 ± 2.7 kg/m2). Six month total body WL was −10.3 (95% confidence interval, CI: −12.7, −7.9) kg. All DXA and computed tomography-derived body composition measures were significantly decreased from baseline, yet D3Cr muscle mass did not change [+0.5 (95% CI: −2.0, 3.0) kg]. Of muscle function and strength measures, only grip strength significantly changed [+2.5 (95% CI: 1.0, 4.0) kg] from baseline.
Conclusions
Among 24 older adults, significant WL with or without weighted vest use or resistance training over a 6-month period was associated with significant declines in all bioimaging metrics, while D3Cr muscle mass and muscle function and strength were preserved. Treatment assignment for the t
{"title":"Application of the D3-creatine muscle mass assessment tool to a geriatric weight loss trial: A pilot study","authors":"Kristen M. Beavers, Allison E. Avery, Mahalakshmi Shankaran, William J. Evans, S. Delanie Lynch, Caitlyn Dwyer, Marjorie Howard, Daniel P. Beavers, Ashley A. Weaver, Leon Lenchik, Peggy M. Cawthon","doi":"10.1002/jcsm.13322","DOIUrl":"https://doi.org/10.1002/jcsm.13322","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Traditionally, weight loss (WL) trials utilize dual energy X-ray absorptiometry (DXA) to measure lean mass. This method assumes lean mass, as the sum of all non-bone and non-fat tissue, is a reasonable proxy for muscle mass. In contrast, the D<sub>3</sub>-creatine (D<sub>3</sub>Cr) dilution method directly measures whole body skeletal muscle mass, although this method has yet to be applied in the context of a geriatric WL trial. The purpose of this project was to (1) describe estimates of change and variability in D<sub>3</sub>Cr muscle mass in older adults participating in an intentional WL intervention and (2) relate its change to other measures of body composition as well as muscle function and strength.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The INVEST in Bone Health trial (NCT04076618), used as a scaffold for this ancillary pilot project, is a three-armed, 12-month randomized, controlled trial designed to determine the effects of resistance training or weighted vest use during intentional WL on a battery of musculoskeletal health outcomes among 150 older adults living with obesity. A convenience sample of 24 participants (<i>n</i> = 8/arm) are included in this analysis. At baseline and 6 months, participants were weighed, ingested a 30 mg D<sub>3</sub>Cr tracer dose, provided a fasted urine sample 3–6 days post-dosage, underwent DXA (total body fat and lean masses, appendicular lean mass) and computed tomography (mid-thigh and trunk muscle/intermuscular fat areas) scans, and performed 400-m walk, stair climb, knee extensor strength, and grip strength tests.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Participants were older (68.0 ± 4.4 years), mostly White (75.0%), predominantly female (66.7%), and living with obesity (body mass index: 33.8 ± 2.7 kg/m<sup>2</sup>). Six month total body WL was −10.3 (95% confidence interval, CI: −12.7, −7.9) kg. All DXA and computed tomography-derived body composition measures were significantly decreased from baseline, yet D<sub>3</sub>Cr muscle mass did not change [+0.5 (95% CI: −2.0, 3.0) kg]. Of muscle function and strength measures, only grip strength significantly changed [+2.5 (95% CI: 1.0, 4.0) kg] from baseline.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Among 24 older adults, significant WL with or without weighted vest use or resistance training over a 6-month period was associated with significant declines in all bioimaging metrics, while D<sub>3</sub>Cr muscle mass and muscle function and strength were preserved. Treatment assignment for the t","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"2350-2358"},"PeriodicalIF":8.9,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13322","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41229545","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}
Hidenori Arai, Keisuke Maeda, Hidetaka Wakabayashi, Tateaki Naito, Masaaki Konishi, Prasert Assantachai, Wai Tung Auyeung, Chalobol Chalermsri, Wei Chen, Justin Chew, Ming-Yueh Chou, Chih-Cheng Hsu, Allyn Hum, In Gyu Hwang, Toshimi Kaido, Lin Kang, Shahrul Bahyah Kamaruzzaman, Miji Kim, Jenny Shun Wah Lee, Wei-Ju Lee, Chih-Kuang Liang, Wee Shiong Lim, Jae-Young Lim, Yen Peng Lim, Raymond See-Kit Lo, Terence Ong, Wen-Harn Pan, Li-Ning Peng, Pornpoj Pramyothin, Nurul Huda Razalli, Masakazu Saitoh, Suzana Shahar, Han Ping Shi, Heng-Hsin Tung, Yasuhito Uezono, Stephan von Haehling, Chang Won Won, Jean Woo, Liang-Kung Chen
Chronic diseases often lead to metabolic disorders, causing anabolic resistance and increased energy consumption, which result in cachexia. Cachexia, in turn, can lead to major clinical consequences such as impaired quality of life, shortened life expectancy, and increased healthcare expenditure. Existing international diagnostic criteria for cachexia employ thresholds derived from Western populations, which may not apply to Asians due to differing body compositions. To address this issue, the Asian Working Group for Cachexia (AWGC) was initiated. The AWGC comprises experts in cachexia research and clinical practice from various Asian countries and aims to develop a consensus on diagnostic criteria and significant clinical outcomes for cachexia in Asia. The AWGC, composed of experts in cachexia research and clinical practice from several Asian countries, undertook three-round Delphi surveys and five meetings to reach a consensus. Discussions were held on etiological diseases, essential diagnostic items for cachexia, including subjective and objective symptoms and biomarkers, and significant clinical outcomes. The consensus highlighted the importance of multiple diagnostic factors for cachexia, including chronic diseases, either or both weight loss or low body mass index, and at least one of the following: anorexia, decreased grip strength (<28 kg in men and <18 kg in women), or elevated C-reactive protein levels (>5 mg/L [0.5 mg/dL]). The AWGC proposed a significant weight change of 2% or more over a 3–6 month period and suggested a tentative cut-off value of 21 kg/m2 for low body mass index in diagnosing cachexia. Critical clinical outcomes were determined to be mortality, quality of life as assessed by tools such as EQ-5D or the Functional Assessment of Anorexia/Cachexia Therapy, and functional status as measured by the Clinical Frailty Scale or Barthel Index, with significant emphasis on patient-reported outcomes. The AWGC consensus offers a comprehensive definition and user-friendly diagnostic criteria for cachexia, tailored specifically for Asian populations. This consensus is set to stimulate future research and enhance the multidisciplinary approach to managing cachexia. With plans to develop further guidelines for the optimal treatment, prevention, and care of cachexia in Asians, the AWGC criteria are expected to drive research across chronic co-morbidities and cancer in Asia, leading to future refinement of diagnostic criteria.
{"title":"Diagnosis and outcomes of cachexia in Asia: Working Consensus Report from the Asian Working Group for Cachexia","authors":"Hidenori Arai, Keisuke Maeda, Hidetaka Wakabayashi, Tateaki Naito, Masaaki Konishi, Prasert Assantachai, Wai Tung Auyeung, Chalobol Chalermsri, Wei Chen, Justin Chew, Ming-Yueh Chou, Chih-Cheng Hsu, Allyn Hum, In Gyu Hwang, Toshimi Kaido, Lin Kang, Shahrul Bahyah Kamaruzzaman, Miji Kim, Jenny Shun Wah Lee, Wei-Ju Lee, Chih-Kuang Liang, Wee Shiong Lim, Jae-Young Lim, Yen Peng Lim, Raymond See-Kit Lo, Terence Ong, Wen-Harn Pan, Li-Ning Peng, Pornpoj Pramyothin, Nurul Huda Razalli, Masakazu Saitoh, Suzana Shahar, Han Ping Shi, Heng-Hsin Tung, Yasuhito Uezono, Stephan von Haehling, Chang Won Won, Jean Woo, Liang-Kung Chen","doi":"10.1002/jcsm.13323","DOIUrl":"10.1002/jcsm.13323","url":null,"abstract":"<p>Chronic diseases often lead to metabolic disorders, causing anabolic resistance and increased energy consumption, which result in cachexia. Cachexia, in turn, can lead to major clinical consequences such as impaired quality of life, shortened life expectancy, and increased healthcare expenditure. Existing international diagnostic criteria for cachexia employ thresholds derived from Western populations, which may not apply to Asians due to differing body compositions. To address this issue, the Asian Working Group for Cachexia (AWGC) was initiated. The AWGC comprises experts in cachexia research and clinical practice from various Asian countries and aims to develop a consensus on diagnostic criteria and significant clinical outcomes for cachexia in Asia. The AWGC, composed of experts in cachexia research and clinical practice from several Asian countries, undertook three-round Delphi surveys and five meetings to reach a consensus. Discussions were held on etiological diseases, essential diagnostic items for cachexia, including subjective and objective symptoms and biomarkers, and significant clinical outcomes. The consensus highlighted the importance of multiple diagnostic factors for cachexia, including chronic diseases, either or both weight loss or low body mass index, and at least one of the following: anorexia, decreased grip strength (<28 kg in men and <18 kg in women), or elevated C-reactive protein levels (>5 mg/L [0.5 mg/dL]). The AWGC proposed a significant weight change of 2% or more over a 3–6 month period and suggested a tentative cut-off value of 21 kg/m<sup>2</sup> for low body mass index in diagnosing cachexia. Critical clinical outcomes were determined to be mortality, quality of life as assessed by tools such as EQ-5D or the Functional Assessment of Anorexia/Cachexia Therapy, and functional status as measured by the Clinical Frailty Scale or Barthel Index, with significant emphasis on patient-reported outcomes. The AWGC consensus offers a comprehensive definition and user-friendly diagnostic criteria for cachexia, tailored specifically for Asian populations. This consensus is set to stimulate future research and enhance the multidisciplinary approach to managing cachexia. With plans to develop further guidelines for the optimal treatment, prevention, and care of cachexia in Asians, the AWGC criteria are expected to drive research across chronic co-morbidities and cancer in Asia, leading to future refinement of diagnostic criteria.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"1949-1958"},"PeriodicalIF":8.9,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13323","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10527209","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}
Martin Boutière, Cécile Cottet-Rousselle, Céline Coppard, Karine Couturier, Catherine Féart, Morgane Couchet, Christelle Corne, Christophe Moinard, Charlotte Breuillard
Background
Combating malnutrition and cachexia is a core challenge in oncology. To limit muscle mass loss, the use of proteins in cancer is encouraged by experts in the field, but it is still debated due to their antagonist effects. Indeed, a high protein intake could preserve lean body mass but may promote tumour growth, whereas a low-protein diet could reduce tumour size but without addressing cachexia. Here we used a realistic rodent model of cancer and chemotherapy to evaluate the influence of different protein intakes on cachexia, tumour response to chemotherapy and immune system response. The goal is to gain a closer understanding of the effect of protein intake in cancer patients undergoing chemotherapy.
Methods
Female Fischer 344 rats were divided into six groups: five groups (n = 14 per group) with cancer (Ward colon tumour) and chemotherapy were fed with isocaloric diets with 8%, 12%, 16%, 24% or 32% of caloric intake from protein and one healthy control group (n = 8) fed a 16% protein diet, considered as a standard diet. Chemotherapy included two cycles, 1 week apart, each consisting of an injection of CPT-11 (50 mg/kg) followed by 5-fluorouracil (50 mg/kg) the day after. Food intake, body weight, and tumour size were measured daily. On day 9, the rats were euthanized and organs were weighed. Body composition was determined and protein content and protein synthesis (SUnSET method) were measured in the muscle, liver, intestine, and tumour. Immune function was explored by flow cytometry.
Results
Cancer and chemotherapy led to a decrease in body weight characterized by a decrease of both fat mass (−56 ± 3%, P < 0.05) and fat-free mass (−8 ± 1%, P < 0.05). Surprisingly, there was no effect of protein diet on body composition, muscle or tumour parameters (weight, protein content, or protein synthesis) but a high cumulative protein intake was positively associated with a high relative body weight and high fat-free mass. The immune system was impacted by cancer and chemotherapy but not by the different amount of protein intake.
Conclusions
Using a realistic model of cancer and chemotherapy, we demonstrated for the first time that protein intake did not positively or negatively modulate tumour growth. Moreover, our results suggested that a high cumulative protein intake was able to improve moderately nutritional status in chemotherapy treated cancer rodents. Although this
{"title":"Protein intake in cancer: Does it improve nutritional status and/or modify tumour response to chemotherapy?","authors":"Martin Boutière, Cécile Cottet-Rousselle, Céline Coppard, Karine Couturier, Catherine Féart, Morgane Couchet, Christelle Corne, Christophe Moinard, Charlotte Breuillard","doi":"10.1002/jcsm.13276","DOIUrl":"10.1002/jcsm.13276","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Combating malnutrition and cachexia is a core challenge in oncology. To limit muscle mass loss, the use of proteins in cancer is encouraged by experts in the field, but it is still debated due to their antagonist effects. Indeed, a high protein intake could preserve lean body mass but may promote tumour growth, whereas a low-protein diet could reduce tumour size but without addressing cachexia. Here we used a realistic rodent model of cancer and chemotherapy to evaluate the influence of different protein intakes on cachexia, tumour response to chemotherapy and immune system response. The goal is to gain a closer understanding of the effect of protein intake in cancer patients undergoing chemotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Female Fischer 344 rats were divided into six groups: five groups (<i>n</i> = 14 per group) with cancer (Ward colon tumour) and chemotherapy were fed with isocaloric diets with 8%, 12%, 16%, 24% or 32% of caloric intake from protein and one healthy control group (<i>n</i> = 8) fed a 16% protein diet, considered as a standard diet. Chemotherapy included two cycles, 1 week apart, each consisting of an injection of CPT-11 (50 mg/kg) followed by 5-fluorouracil (50 mg/kg) the day after. Food intake, body weight, and tumour size were measured daily. On day 9, the rats were euthanized and organs were weighed. Body composition was determined and protein content and protein synthesis (SUnSET method) were measured in the muscle, liver, intestine, and tumour. Immune function was explored by flow cytometry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Cancer and chemotherapy led to a decrease in body weight characterized by a decrease of both fat mass (−56 ± 3%, <i>P</i> < 0.05) and fat-free mass (−8 ± 1%, <i>P</i> < 0.05). Surprisingly, there was no effect of protein diet on body composition, muscle or tumour parameters (weight, protein content, or protein synthesis) but a high cumulative protein intake was positively associated with a high relative body weight and high fat-free mass. The immune system was impacted by cancer and chemotherapy but not by the different amount of protein intake.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Using a realistic model of cancer and chemotherapy, we demonstrated for the first time that protein intake did not positively or negatively modulate tumour growth. Moreover, our results suggested that a high cumulative protein intake was able to improve moderately nutritional status in chemotherapy treated cancer rodents. Although this","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"2003-2015"},"PeriodicalIF":8.9,"publicationDate":"2023-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13276","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10210385","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}
{"title":"Abstract Proceedings of 7th Cancer Cachexia Conference, 28-30 September 2023, Edinburgh.","authors":"","doi":"10.1002/jcsm.13325","DOIUrl":"10.1002/jcsm.13325","url":null,"abstract":"","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 Suppl 1 ","pages":"3-59"},"PeriodicalIF":8.9,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10518434/pdf/JCSM-14-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41096401","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}
We read with great interest the recent article by Álvaro Casas-Herrero et al. entitled ‘Effects of Vivifrail multicomponent intervention on functional capacity: a multicentre, randomized controlled trial’.1 The article validated that the Vivifrail multicomponent exercise training programme is an effective and safe intervention for improving functional capacity in community dwelling frail/prefrail older patients with MCI or mild dementia, which provides strong evidence for the validation of physical intervention. However, here are some questions I would like to discuss with the authors.
The first question is about the missing data: The dropout rate was as high as 37% in general, especially 48% in the intervention group at the end of the third month. It is not a low level for a randomized controlled trial especially under such a small sample size. In clinical research, missing data often result in biased results and may even completely reverse the research conclusion.2 Therefore, I wonder whether this effect had been taken into account in data processing? Tipping-point3 would be recommended to test the effect of missing data. If it had been used in this study, will the result be reversed at a certain level?
Secondly, as more patients discontinued the study in the intervention group compared with the control group, could you please describe the reasons in detail? If the exercise programme itself is difficult for the old, will the promotion be restricted in the future?
Lastly, is there any differences in the characteristics of missing patients between the control group and the intervention group? It is possible that those who can persist 3 months in the intervention group already have better functional capacity. So the significance of intervention observed in the study might partly resulted from the follow-up bias. Especially on the premise of the small sample and high rate of dropouts, the consistency of results might be affected.
In summary, it is hoped that the above-mentioned issues can be pondered in favour of consolidating the findings of Álvaro Casas-Herrero et al. and can better guide clinical decision making.
{"title":"Comment on ‘Effects of Vivifrail multicomponent intervention on functional capacity: A multicentre randomized controlled trial’ by Casas-Herrero et al.","authors":"Jin Yan, Tianyi Zhang, Yixin Hu","doi":"10.1002/jcsm.13296","DOIUrl":"10.1002/jcsm.13296","url":null,"abstract":"<p>We read with great interest the recent article by Álvaro Casas-Herrero et al. entitled ‘Effects of Vivifrail multicomponent intervention on functional capacity: a multicentre, randomized controlled trial’.<span><sup>1</sup></span> The article validated that the Vivifrail multicomponent exercise training programme is an effective and safe intervention for improving functional capacity in community dwelling frail/prefrail older patients with MCI or mild dementia, which provides strong evidence for the validation of physical intervention. However, here are some questions I would like to discuss with the authors.</p><p>The first question is about the missing data: The dropout rate was as high as 37% in general, especially 48% in the intervention group at the end of the third month. It is not a low level for a randomized controlled trial especially under such a small sample size. In clinical research, missing data often result in biased results and may even completely reverse the research conclusion.<span><sup>2</sup></span> Therefore, I wonder whether this effect had been taken into account in data processing? Tipping-point<span><sup>3</sup></span> would be recommended to test the effect of missing data. If it had been used in this study, will the result be reversed at a certain level?</p><p>Secondly, as more patients discontinued the study in the intervention group compared with the control group, could you please describe the reasons in detail? If the exercise programme itself is difficult for the old, will the promotion be restricted in the future?</p><p>Lastly, is there any differences in the characteristics of missing patients between the control group and the intervention group? It is possible that those who can persist 3 months in the intervention group already have better functional capacity. So the significance of intervention observed in the study might partly resulted from the follow-up bias. Especially on the premise of the small sample and high rate of dropouts, the consistency of results might be affected.</p><p>In summary, it is hoped that the above-mentioned issues can be pondered in favour of consolidating the findings of Álvaro Casas-Herrero et al. and can better guide clinical decision making.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"2454"},"PeriodicalIF":8.9,"publicationDate":"2023-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13296","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10476951","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 gut microbiome and fecal metabolites have been found to influence sarcopenia, but whether there are potential bacteria that can alleviate sarcopenia has been under-investigated, and the molecular mechanism remains unclear.
Methods
To investigate the relationships between the gut microbiome, fecal metabolites and sarcopenia, subjects were selected from observational multi-ethnic study conducted in Western China. Sarcopenia was diagnosed according to the criteria of the Asian Working Group for Sarcopenia 2014. The gut microbiome was profiled by shotgun metagenomic sequencing. Untargeted metabolomic analysis was performed to analyse the differences in fecal metabolites. We investigated bacterium with the greatest relative abundance difference between healthy individuals and sarcopenia patients, and the differences in metabolites associated with the bacteria, to verify its effects on muscle mass and function in a mouse model.
Results
The study included 283 participants (68.90% females, mean age: 66.66 years old) with and without sarcopenia (141 and 142 participants, respectively) and from the Han (98 participants), Zang (88 participants) and Qiang (97 participants) ethnic groups. This showed an overall reduction (15.03% vs. 20.77%, P = 0.01) of Prevotella copri between the sarcopenia and non-sarcopenia subjects across the three ethnic groups. Functional characterization of the differential bacteria showed enrichment (odds ratio = 15.97, P = 0.0068) in branched chain amino acid (BCAA) metabolism in non-sarcopenia group. A total of 13 BCAA and their derivatives have relatively low levels in sarcopenia. In the in vivo experiment, we found that the blood BCAA level was higher in the mice gavaged with live P. copri (LPC) (P < 0.001). The LPC mice had significantly longer wire and grid hanging time (P < 0.02), longer time on rotor (P = 0.0001) and larger grip strength (P < 0.0001), indicating better muscle function. The weight of gastrocnemius mass and rectus femoris mass (P < 0.05) was higher in LPC mice. The micro-computed tomography showed a larger leg area (P = 0.0031), and a small animal analyser showed a higher lean mass ratio in LPC mice (P = 0.0157), indicating higher muscle mass.
Conclusions
The results indicated that there were lower levels of both P. copri and BCAA in sarcopenia individuals. In viv
{"title":"Prevotella copri alleviates sarcopenia via attenuating muscle mass loss and function decline","authors":"Xiaolei Liu, Jiqiu Wu, Jingyi Tang, Zhigang Xu, Bailing Zhou, Yang Liu, Fengjuan Hu, Gongchang Zhang, Rui Cheng, Xin Xia, Yilong Chen, Hongyu Wu, Daoming Wang, Jirong Yue, Biao Dong, Jingyuan Fu, Haopeng Yu, Birong Dong","doi":"10.1002/jcsm.13313","DOIUrl":"10.1002/jcsm.13313","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The gut microbiome and fecal metabolites have been found to influence sarcopenia, but whether there are potential bacteria that can alleviate sarcopenia has been under-investigated, and the molecular mechanism remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To investigate the relationships between the gut microbiome, fecal metabolites and sarcopenia, subjects were selected from observational multi-ethnic study conducted in Western China. Sarcopenia was diagnosed according to the criteria of the Asian Working Group for Sarcopenia 2014. The gut microbiome was profiled by shotgun metagenomic sequencing. Untargeted metabolomic analysis was performed to analyse the differences in fecal metabolites. We investigated bacterium with the greatest relative abundance difference between healthy individuals and sarcopenia patients, and the differences in metabolites associated with the bacteria, to verify its effects on muscle mass and function in a mouse model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The study included 283 participants (68.90% females, mean age: 66.66 years old) with and without sarcopenia (141 and 142 participants, respectively) and from the Han (98 participants), Zang (88 participants) and Qiang (97 participants) ethnic groups. This showed an overall reduction (15.03% vs. 20.77%, <i>P</i> = 0.01) of <i>Prevotella copri</i> between the sarcopenia and non-sarcopenia subjects across the three ethnic groups. Functional characterization of the differential bacteria showed enrichment (odds ratio = 15.97, <i>P</i> = 0.0068) in branched chain amino acid (BCAA) metabolism in non-sarcopenia group. A total of 13 BCAA and their derivatives have relatively low levels in sarcopenia. In the in vivo experiment, we found that the blood BCAA level was higher in the mice gavaged with live <i>P. copri</i> (LPC) (<i>P</i> < 0.001). The LPC mice had significantly longer wire and grid hanging time (<i>P</i> < 0.02), longer time on rotor (<i>P</i> = 0.0001) and larger grip strength (<i>P</i> < 0.0001), indicating better muscle function. The weight of gastrocnemius mass and rectus femoris mass (<i>P</i> < 0.05) was higher in LPC mice. The micro-computed tomography showed a larger leg area (<i>P</i> = 0.0031), and a small animal analyser showed a higher lean mass ratio in LPC mice (<i>P</i> = 0.0157), indicating higher muscle mass.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The results indicated that there were lower levels of both <i>P. copri</i> and BCAA in sarcopenia individuals. In viv","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"2275-2288"},"PeriodicalIF":8.9,"publicationDate":"2023-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13313","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10565657","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}
Sylvia Saalfeld, Robert Kreher, Georg Hille, Uli Niemann, Mattes Hinnerichs, Osman Öcal, Kerstin Schütte, Christoph J. Zech, Christian Loewe, Otto van Delden, Vincent Vandecaveye, Chris Verslype, Bernhard Gebauer, Christian Sengel, Irene Bargellini, Roberto Iezzi, Thomas Berg, Heinz J. Klümpen, Julia Benckert, Antonio Gasbarrini, Holger Amthauer, Bruno Sangro, Peter Malfertheiner, Bernhard Preim, Jens Ricke, Max Seidensticker, Maciej Pech, Alexey Surov
Background
Parameters of body composition have prognostic potential in patients with oncologic diseases. The aim of the present study was to analyse the prognostic potential of radiomics-based parameters of the skeletal musculature and adipose tissues in patients with advanced hepatocellular carcinoma (HCC).
Methods
Radiomics features were extracted from a cohort of 297 HCC patients as post hoc sub-study of the SORAMIC randomized controlled trial. Patients were treated with selective internal radiation therapy (SIRT) in combination with sorafenib or with sorafenib alone yielding two groups: (1) sorafenib monotherapy (n = 147) and (2) sorafenib and SIRT (n = 150). The main outcome was 1-year survival. Segmentation of muscle tissue and adipose tissue was used to retrieve 881 features. Correlation analysis and feature cleansing yielded 292 features for each patient group and each tissue type. We combined 9 feature selection methods with 10 feature set compositions to build 90 feature sets. We used 11 classifiers to build 990 models. We subdivided the patient groups into a train and validation cohort and a test cohort, that is, one third of the patient groups.
Results
We used the train and validation set to identify the best feature selection and classification model and applied it to the test set for each patient group. Classification yields for patients who underwent sorafenib monotherapy an accuracy of 75.51% and area under the curve (AUC) of 0.7576 (95% confidence interval [CI]: 0.6376–0.8776). For patients who underwent treatment with SIRT and sorafenib, results are accuracy = 78.00% and AUC = 0.8032 (95% CI: 0.6930–0.9134).
Conclusions
Parameters of radiomics-based analysis of the skeletal musculature and adipose tissue predict 1-year survival in patients with advanced HCC. The prognostic value of radiomics-based parameters was higher in patients who were treated with SIRT and sorafenib.
{"title":"Prognostic role of radiomics-based body composition analysis for the 1-year survival for hepatocellular carcinoma patients","authors":"Sylvia Saalfeld, Robert Kreher, Georg Hille, Uli Niemann, Mattes Hinnerichs, Osman Öcal, Kerstin Schütte, Christoph J. Zech, Christian Loewe, Otto van Delden, Vincent Vandecaveye, Chris Verslype, Bernhard Gebauer, Christian Sengel, Irene Bargellini, Roberto Iezzi, Thomas Berg, Heinz J. Klümpen, Julia Benckert, Antonio Gasbarrini, Holger Amthauer, Bruno Sangro, Peter Malfertheiner, Bernhard Preim, Jens Ricke, Max Seidensticker, Maciej Pech, Alexey Surov","doi":"10.1002/jcsm.13315","DOIUrl":"10.1002/jcsm.13315","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Parameters of body composition have prognostic potential in patients with oncologic diseases. The aim of the present study was to analyse the prognostic potential of radiomics-based parameters of the skeletal musculature and adipose tissues in patients with advanced hepatocellular carcinoma (HCC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Radiomics features were extracted from a cohort of 297 HCC patients as post hoc sub-study of the SORAMIC randomized controlled trial. Patients were treated with selective internal radiation therapy (SIRT) in combination with sorafenib or with sorafenib alone yielding two groups: (1) sorafenib monotherapy (<i>n</i> = 147) and (2) sorafenib and SIRT (<i>n</i> = 150). The main outcome was 1-year survival. Segmentation of muscle tissue and adipose tissue was used to retrieve 881 features. Correlation analysis and feature cleansing yielded 292 features for each patient group and each tissue type. We combined 9 feature selection methods with 10 feature set compositions to build 90 feature sets. We used 11 classifiers to build 990 models. We subdivided the patient groups into a train and validation cohort and a test cohort, that is, one third of the patient groups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We used the train and validation set to identify the best feature selection and classification model and applied it to the test set for each patient group. Classification yields for patients who underwent sorafenib monotherapy an accuracy of 75.51% and area under the curve (AUC) of 0.7576 (95% confidence interval [CI]: 0.6376–0.8776). For patients who underwent treatment with SIRT and sorafenib, results are accuracy = 78.00% and AUC = 0.8032 (95% CI: 0.6930–0.9134).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Parameters of radiomics-based analysis of the skeletal musculature and adipose tissue predict 1-year survival in patients with advanced HCC. The prognostic value of radiomics-based parameters was higher in patients who were treated with SIRT and sorafenib.</p>\u0000 </section>\u0000 </div>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"2301-2309"},"PeriodicalIF":8.9,"publicationDate":"2023-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13315","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10021294","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}
Khawaja M. Talha, Ambarish Pandey, Marat Fudim, Javed Butler, Stefan D. Anker, Muhammad Shahzeb Khan
At least half of all patients with heart failure (HF) are affected by frailty, a syndrome that limits an individual ability to recover from acute stressors. While frailty affects up to 90% of patients with HF with preserved ejection fraction, it is also seen in ~30–60% of patients with HF with reduced ejection fraction, with ~26% higher prevalence in women compared with men. The relationship between frailty and HF is bidirectional, with both conditions exacerbating the other. Frailty is further complicated by a higher prevalence of sarcopenia (by ~20%) in HF patients compared with patients without HF, which negatively affects outcomes. Several frailty assessment methods have been employed historically including the Fried frailty phenotype and Rockwood Clinical Frailty Scale to classify HF patients based on the severity of frailty; however, a validated HF-specific frailty assessment tool does not currently exist. Frailty in HF is associated with a poor prognosis with a 1.5-fold to 2-fold higher risk of all-cause death and hospitalizations compared to non-frail patients. Frailty is also highly prevalent in patients with worsening HF, affecting >50% of patients hospitalized for HF. Such patients with multiple readmissions for decompensated HF have markedly poor outcomes compared to younger, non-frail cohorts, and it is hypothesized that it may be due to major physical and functional limitations that limit recovery from an acute episode of worsening HF, a care aspect that has not been addressed in HF guidelines. Frail patients are thought to confer less benefit from therapeutic interventions due to an increased risk of perceived harm, resulting in lower adherence to HF interventions, which may worsen outcomes. Multiple studies report that <40% of frail patients are on guideline-directed medical therapy for HF, of which most are on suboptimal doses of these medications. There is a lack of evidence generated from randomized trials in this incredibly vulnerable population, and most current practice is governed by post hoc analyses of trials, observational registry-based data and providers' clinical judgement. The current body of evidence suggests that the treatment effect of most guideline-based interventions, including medications, cardiac rehabilitation and device therapy, is consistent across all age groups and frailty subgroups and, in some cases, may be amplified in the older, more frail population. In this review, we discuss the characteristics, assessment tools, impact on prognosis and impact on therapeutic interventions of frailty in patients with HF.
{"title":"Frailty and heart failure: State-of-the-art review","authors":"Khawaja M. Talha, Ambarish Pandey, Marat Fudim, Javed Butler, Stefan D. Anker, Muhammad Shahzeb Khan","doi":"10.1002/jcsm.13306","DOIUrl":"10.1002/jcsm.13306","url":null,"abstract":"<p>At least half of all patients with heart failure (HF) are affected by frailty, a syndrome that limits an individual ability to recover from acute stressors. While frailty affects up to 90% of patients with HF with preserved ejection fraction, it is also seen in ~30–60% of patients with HF with reduced ejection fraction, with ~26% higher prevalence in women compared with men. The relationship between frailty and HF is bidirectional, with both conditions exacerbating the other. Frailty is further complicated by a higher prevalence of sarcopenia (by ~20%) in HF patients compared with patients without HF, which negatively affects outcomes. Several frailty assessment methods have been employed historically including the Fried frailty phenotype and Rockwood Clinical Frailty Scale to classify HF patients based on the severity of frailty; however, a validated HF-specific frailty assessment tool does not currently exist. Frailty in HF is associated with a poor prognosis with a 1.5-fold to 2-fold higher risk of all-cause death and hospitalizations compared to non-frail patients. Frailty is also highly prevalent in patients with worsening HF, affecting >50% of patients hospitalized for HF. Such patients with multiple readmissions for decompensated HF have markedly poor outcomes compared to younger, non-frail cohorts, and it is hypothesized that it may be due to major physical and functional limitations that limit recovery from an acute episode of worsening HF, a care aspect that has not been addressed in HF guidelines. Frail patients are thought to confer less benefit from therapeutic interventions due to an increased risk of perceived harm, resulting in lower adherence to HF interventions, which may worsen outcomes. Multiple studies report that <40% of frail patients are on guideline-directed medical therapy for HF, of which most are on suboptimal doses of these medications. There is a lack of evidence generated from randomized trials in this incredibly vulnerable population, and most current practice is governed by post hoc analyses of trials, observational registry-based data and providers' clinical judgement. The current body of evidence suggests that the treatment effect of most guideline-based interventions, including medications, cardiac rehabilitation and device therapy, is consistent across all age groups and frailty subgroups and, in some cases, may be amplified in the older, more frail population. In this review, we discuss the characteristics, assessment tools, impact on prognosis and impact on therapeutic interventions of frailty in patients with HF.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"1959-1972"},"PeriodicalIF":8.9,"publicationDate":"2023-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13306","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10367805","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}
Myostatin, encoded by the MSTN gene comprising 3 exons, is a potent negative regulator of skeletal muscle growth. Although a variety of myostatin inhibitors have been invented for increasing muscle mass in muscle wasting diseases, no effective inhibitor is currently available for clinical use. Myostatin isoforms in several animals have been reported to inhibit myostatin, but an isoform has never been identified for the human MSTN gene, a conserved gene among animals. Here, a splice variant of the human MSTN gene was explored.
Methods
Transcripts and proteins were analysed by reverse transcription-PCR amplification and western blotting, respectively. Proteins were expressed from expression plasmid. Myostatin signalling was assayed by the SMAD-responsive luciferase activity. Cell proliferation was assayed by the Cell Counting Kit-8 (CCK-8) assay and cell counting. Cell cycle was analysed by the FastFUCCI system.
Results
Reverse transcription-PCR amplification of the full-length MSTN transcript in CRL-2061 rhabdomyosarcoma cells revealed two bands consisting of a thick expected-size product and a thin additional small-size product. Sequencing of the small-size product showed a 963-bp deletion in the 5′ end of exon 3, creating exon 3s, which contained unusual splice acceptor TG dinucleotides. The novel variant was identified in other human cell lines, although it was not identified in skeletal muscle. The 251-amino acid isoform encoded by the novel variant (myostatin-b) was identified in CRL-2061 rhabdomyosarcoma cells. Transfection of a myostatin-b expression plasmid into CRL-2061 and myoblast cells inhibited endogenous myostatin signalling (44%, P < 0.001 and 63%, P < 0.001, respectively). Furthermore, myostatin-b inhibited myostatin signalling induced by recombinant myostatin (68.8%, P < 0.001). In remarkable contrast, myostatin-b did not inhibit the myostatin signalling induced by recombinant growth differentiation factor 11 (9.2%, P = 0.70), transforming growth factor β (+3.1%, P = 0.83) or activin A (+1.1%, P = 0.96). These results indicate the myostatin-specific inhibitory effect of myostatin-b. Notably, the expression of myostatin-b in myoblasts significantly enhanced cell proliferation higher than the mock-transfected cells by the CCK-8 and direct cell counting assays (60%, P < 0.05 and 39%, P < 0.05, respectively). Myostatin-b increased the percentage of S-phase cells significantly higher than that of the mock-transfected cells (53
{"title":"A novel splice variant of the human MSTN gene encodes a myostatin-specific myostatin inhibitor","authors":"Kazuhiro Maeta, Manal Farea, Hisahide Nishio, Masafumi Matsuo","doi":"10.1002/jcsm.13314","DOIUrl":"10.1002/jcsm.13314","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Myostatin, encoded by the <i>MSTN</i> gene comprising 3 exons, is a potent negative regulator of skeletal muscle growth. Although a variety of myostatin inhibitors have been invented for increasing muscle mass in muscle wasting diseases, no effective inhibitor is currently available for clinical use. Myostatin isoforms in several animals have been reported to inhibit myostatin, but an isoform has never been identified for the human <i>MSTN</i> gene, a conserved gene among animals. Here, a splice variant of the human <i>MSTN</i> gene was explored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Transcripts and proteins were analysed by reverse transcription-PCR amplification and western blotting, respectively. Proteins were expressed from expression plasmid. Myostatin signalling was assayed by the SMAD-responsive luciferase activity. Cell proliferation was assayed by the Cell Counting Kit-8 (CCK-8) assay and cell counting. Cell cycle was analysed by the FastFUCCI system.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Reverse transcription-PCR amplification of the full-length <i>MSTN</i> transcript in CRL-2061 rhabdomyosarcoma cells revealed two bands consisting of a thick expected-size product and a thin additional small-size product. Sequencing of the small-size product showed a 963-bp deletion in the 5′ end of exon 3, creating exon 3s, which contained unusual splice acceptor TG dinucleotides. The novel variant was identified in other human cell lines, although it was not identified in skeletal muscle. The 251-amino acid isoform encoded by the novel variant (myostatin-b) was identified in CRL-2061 rhabdomyosarcoma cells. Transfection of a myostatin-b expression plasmid into CRL-2061 and myoblast cells inhibited endogenous myostatin signalling (44%, <i>P</i> < 0.001 and 63%, <i>P</i> < 0.001, respectively). Furthermore, myostatin-b inhibited myostatin signalling induced by recombinant myostatin (68.8%, <i>P</i> < 0.001). In remarkable contrast, myostatin-b did not inhibit the myostatin signalling induced by recombinant growth differentiation factor 11 (9.2%, <i>P</i> = 0.70), transforming growth factor β (+3.1%, <i>P</i> = 0.83) or activin A (+1.1%, <i>P</i> = 0.96). These results indicate the myostatin-specific inhibitory effect of myostatin-b. Notably, the expression of myostatin-b in myoblasts significantly enhanced cell proliferation higher than the mock-transfected cells by the CCK-8 and direct cell counting assays (60%, <i>P</i> < 0.05 and 39%, <i>P</i> < 0.05, respectively). Myostatin-b increased the percentage of S-phase cells significantly higher than that of the mock-transfected cells (53","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 5","pages":"2289-2300"},"PeriodicalIF":8.9,"publicationDate":"2023-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13314","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9997264","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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