Joo Won Kim, SukHwan Yun, Min Jeong Park, Eyun Song, Sooyeon Jang, Ahreum Jang, Kyung Mook Choi, Sei Hyun Baik, Hwan-Jin Hwang, Hye Jin Yoo
{"title":"HD6277 通过促进肌生成因子和抑制蛋白分解抑制老年小鼠肌肉萎缩","authors":"Joo Won Kim, SukHwan Yun, Min Jeong Park, Eyun Song, Sooyeon Jang, Ahreum Jang, Kyung Mook Choi, Sei Hyun Baik, Hwan-Jin Hwang, Hye Jin Yoo","doi":"10.1002/jcsm.13805","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>G protein–coupled receptor 40 (GPR40) acts as a modulator of various physiological functions, including glycaemic lowering, anti-inflammation and antioxidative stress, in several tissues. However, the role of GPR40 in skeletal muscles remains unclear.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>To investigate the roles of muscle GPR40, C2C12 myoblasts and myotubes were stimulated with palmitate and HD6277, a GPR40 agonist. Muscle strength and myofiber thickness were measured in obese and aged mice fed HD6277.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>In C2C12 myoblasts, the addition of HD6277 induced phosphorylated Akt levels and expression of the myogenic factors, myogenin (MyoG), myocyte enhancer factor 2C (Mef2c) and myosin heavy chain (MyHC, <i>p</i> < 0.05). These changes resulted in accelerated muscle differentiation from myoblasts to myotubes (MyHC-positive area +56.52%; myotube width +34.08% vs. Veh, <i>p</i> < 0.05). In C2C12 myotubes, a palmitate-mediated decrease in the phosphorylation of forkhead box protein O1A (FOXO1A) and increase in the expression of E3 ubiquitin ligases, atrogin-1 and muscle RING-finger protein 1 (MuRF1) were reversed by HD6277 (<i>p</i> < 0.05). Additionally, HD6277 inhibited palmitate-induced apoptotic events such as the Bcl-2 (Bcl2)-associated X protein (Bax)/Bcl-2 ratio, caspase 3 cleavage and nuclear fragmentation in C2C12 myoblasts and myotubes (<i>p</i> < 0.05). These beneficial HD6277-mediated actions disappeared after the addition of an Akt inhibitor (<i>p</i> < 0.05). Similar to in vitro studies, HD6277 administration in obese and aged mice increased myogenic factors and decreased E3 ubiquitin ligase expression and apoptotic events (<i>p</i> < 0.05). HD6277 increased muscle strength (+9.88% vs. Aged, <i>p</i> < 0.05) and myofiber thickness (+29.01% vs. Aged, <i>p</i> < 0.05) in aging mice but only improved myofiber thickness (+11.84% vs. HFD, <i>p</i> < 0.05) in obese mice.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>HD6277 can increase myogenic factors and reduce E3 ligase-mediated proteolysis to inhibit muscle atrophy in aged mice. Our results suggest that GPR40 agonists may have potential as therapeutic agents for sarcopenia.</p>\n </section>\n </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 2","pages":""},"PeriodicalIF":9.4000,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13805","citationCount":"0","resultStr":"{\"title\":\"HD6277 Suppresses Muscle Atrophy by Promoting Myogenic Factors and Inhibiting Proteolysis in Aged Mice\",\"authors\":\"Joo Won Kim, SukHwan Yun, Min Jeong Park, Eyun Song, Sooyeon Jang, Ahreum Jang, Kyung Mook Choi, Sei Hyun Baik, Hwan-Jin Hwang, Hye Jin Yoo\",\"doi\":\"10.1002/jcsm.13805\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>G protein–coupled receptor 40 (GPR40) acts as a modulator of various physiological functions, including glycaemic lowering, anti-inflammation and antioxidative stress, in several tissues. However, the role of GPR40 in skeletal muscles remains unclear.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>To investigate the roles of muscle GPR40, C2C12 myoblasts and myotubes were stimulated with palmitate and HD6277, a GPR40 agonist. Muscle strength and myofiber thickness were measured in obese and aged mice fed HD6277.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>In C2C12 myoblasts, the addition of HD6277 induced phosphorylated Akt levels and expression of the myogenic factors, myogenin (MyoG), myocyte enhancer factor 2C (Mef2c) and myosin heavy chain (MyHC, <i>p</i> < 0.05). These changes resulted in accelerated muscle differentiation from myoblasts to myotubes (MyHC-positive area +56.52%; myotube width +34.08% vs. Veh, <i>p</i> < 0.05). In C2C12 myotubes, a palmitate-mediated decrease in the phosphorylation of forkhead box protein O1A (FOXO1A) and increase in the expression of E3 ubiquitin ligases, atrogin-1 and muscle RING-finger protein 1 (MuRF1) were reversed by HD6277 (<i>p</i> < 0.05). Additionally, HD6277 inhibited palmitate-induced apoptotic events such as the Bcl-2 (Bcl2)-associated X protein (Bax)/Bcl-2 ratio, caspase 3 cleavage and nuclear fragmentation in C2C12 myoblasts and myotubes (<i>p</i> < 0.05). These beneficial HD6277-mediated actions disappeared after the addition of an Akt inhibitor (<i>p</i> < 0.05). Similar to in vitro studies, HD6277 administration in obese and aged mice increased myogenic factors and decreased E3 ubiquitin ligase expression and apoptotic events (<i>p</i> < 0.05). HD6277 increased muscle strength (+9.88% vs. Aged, <i>p</i> < 0.05) and myofiber thickness (+29.01% vs. Aged, <i>p</i> < 0.05) in aging mice but only improved myofiber thickness (+11.84% vs. HFD, <i>p</i> < 0.05) in obese mice.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusion</h3>\\n \\n <p>HD6277 can increase myogenic factors and reduce E3 ligase-mediated proteolysis to inhibit muscle atrophy in aged mice. Our results suggest that GPR40 agonists may have potential as therapeutic agents for sarcopenia.</p>\\n </section>\\n </div>\",\"PeriodicalId\":48911,\"journal\":{\"name\":\"Journal of Cachexia Sarcopenia and Muscle\",\"volume\":\"16 2\",\"pages\":\"\"},\"PeriodicalIF\":9.4000,\"publicationDate\":\"2025-04-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13805\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Cachexia Sarcopenia and Muscle\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/jcsm.13805\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GERIATRICS & GERONTOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Cachexia Sarcopenia and Muscle","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jcsm.13805","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GERIATRICS & GERONTOLOGY","Score":null,"Total":0}
HD6277 Suppresses Muscle Atrophy by Promoting Myogenic Factors and Inhibiting Proteolysis in Aged Mice
Background
G protein–coupled receptor 40 (GPR40) acts as a modulator of various physiological functions, including glycaemic lowering, anti-inflammation and antioxidative stress, in several tissues. However, the role of GPR40 in skeletal muscles remains unclear.
Methods
To investigate the roles of muscle GPR40, C2C12 myoblasts and myotubes were stimulated with palmitate and HD6277, a GPR40 agonist. Muscle strength and myofiber thickness were measured in obese and aged mice fed HD6277.
Results
In C2C12 myoblasts, the addition of HD6277 induced phosphorylated Akt levels and expression of the myogenic factors, myogenin (MyoG), myocyte enhancer factor 2C (Mef2c) and myosin heavy chain (MyHC, p < 0.05). These changes resulted in accelerated muscle differentiation from myoblasts to myotubes (MyHC-positive area +56.52%; myotube width +34.08% vs. Veh, p < 0.05). In C2C12 myotubes, a palmitate-mediated decrease in the phosphorylation of forkhead box protein O1A (FOXO1A) and increase in the expression of E3 ubiquitin ligases, atrogin-1 and muscle RING-finger protein 1 (MuRF1) were reversed by HD6277 (p < 0.05). Additionally, HD6277 inhibited palmitate-induced apoptotic events such as the Bcl-2 (Bcl2)-associated X protein (Bax)/Bcl-2 ratio, caspase 3 cleavage and nuclear fragmentation in C2C12 myoblasts and myotubes (p < 0.05). These beneficial HD6277-mediated actions disappeared after the addition of an Akt inhibitor (p < 0.05). Similar to in vitro studies, HD6277 administration in obese and aged mice increased myogenic factors and decreased E3 ubiquitin ligase expression and apoptotic events (p < 0.05). HD6277 increased muscle strength (+9.88% vs. Aged, p < 0.05) and myofiber thickness (+29.01% vs. Aged, p < 0.05) in aging mice but only improved myofiber thickness (+11.84% vs. HFD, p < 0.05) in obese mice.
Conclusion
HD6277 can increase myogenic factors and reduce E3 ligase-mediated proteolysis to inhibit muscle atrophy in aged mice. Our results suggest that GPR40 agonists may have potential as therapeutic agents for sarcopenia.
期刊介绍：
The Journal of Cachexia, Sarcopenia and Muscle is a peer-reviewed international journal dedicated to publishing materials related to cachexia and sarcopenia, as well as body composition and its physiological and pathophysiological changes across the lifespan and in response to various illnesses from all fields of life sciences. The journal aims to provide a reliable resource for professionals interested in related research or involved in the clinical care of affected patients, such as those suffering from AIDS, cancer, chronic heart failure, chronic lung disease, liver cirrhosis, chronic kidney failure, rheumatoid arthritis, or sepsis.
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