HD6277 Suppresses Muscle Atrophy by Promoting Myogenic Factors and Inhibiting Proteolysis in Aged Mice
ABSTRACT 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 r...
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Wiley
2025-04-01
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| Series: | Journal of Cachexia, Sarcopenia and Muscle |
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| Online Access: | https://doi.org/10.1002/jcsm.13805 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Joo Won Kim |
| collection | DOAJ |
| description | ABSTRACT 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. |
| format | Article |
| id | doaj-art-29ee691e6c7844bcbc4a564f1e24be20 |
| institution | OA Journals |
| issn | 2190-5991 2190-6009 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
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| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj-art-29ee691e6c7844bcbc4a564f1e24be202025-08-20T02:35:37ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092025-04-01162n/an/a10.1002/jcsm.13805HD6277 Suppresses Muscle Atrophy by Promoting Myogenic Factors and Inhibiting Proteolysis in Aged MiceJoo Won Kim0SukHwan Yun1Min Jeong Park2Eyun Song3Sooyeon Jang4Ahreum Jang5Kyung Mook Choi6Sei Hyun Baik7Hwan‐Jin Hwang8Hye Jin Yoo9BK21 Graduate Program, Department of Biomedical Sciences Korea University College of Medicine Seoul Republic of KoreaBK21 Graduate Program, Department of Biomedical Sciences Korea University College of Medicine Seoul Republic of KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine Korea University College of Medicine Seoul Republic of KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine Korea University College of Medicine Seoul Republic of KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine Korea University College of Medicine Seoul Republic of KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine Korea University College of Medicine Seoul Republic of KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine Korea University College of Medicine Seoul Republic of KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine Korea University College of Medicine Seoul Republic of KoreaBK21 Graduate Program, Department of Biomedical Sciences Korea University College of Medicine Seoul Republic of KoreaDivision of Endocrinology and Metabolism, Department of Internal Medicine Korea University College of Medicine Seoul Republic of KoreaABSTRACT 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.https://doi.org/10.1002/jcsm.13805GPR40muscle atrophymyoblastmyogenic factorsmyotubesarcopenia |
| spellingShingle | 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 HD6277 Suppresses Muscle Atrophy by Promoting Myogenic Factors and Inhibiting Proteolysis in Aged Mice Journal of Cachexia, Sarcopenia and Muscle GPR40 muscle atrophy myoblast myogenic factors myotube sarcopenia |
| title | HD6277 Suppresses Muscle Atrophy by Promoting Myogenic Factors and Inhibiting Proteolysis in Aged Mice |
| title_full | HD6277 Suppresses Muscle Atrophy by Promoting Myogenic Factors and Inhibiting Proteolysis in Aged Mice |
| title_fullStr | HD6277 Suppresses Muscle Atrophy by Promoting Myogenic Factors and Inhibiting Proteolysis in Aged Mice |
| title_full_unstemmed | HD6277 Suppresses Muscle Atrophy by Promoting Myogenic Factors and Inhibiting Proteolysis in Aged Mice |
| title_short | HD6277 Suppresses Muscle Atrophy by Promoting Myogenic Factors and Inhibiting Proteolysis in Aged Mice |
| title_sort | hd6277 suppresses muscle atrophy by promoting myogenic factors and inhibiting proteolysis in aged mice |
| topic | GPR40 muscle atrophy myoblast myogenic factors myotube sarcopenia |
| url | https://doi.org/10.1002/jcsm.13805 |
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