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However, the role of GPR40 in skeletal muscles remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats: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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). These changes resulted in accelerated muscle differentiation from myoblasts to myotubes (MyHC\u2010positive area +56.52%; myotube width +34.08% vs. Veh,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). In C2C12 myotubes, a palmitate\u2010mediated decrease in the phosphorylation of forkhead box protein O1A (FOXO1A) and increase in the expression of E3 ubiquitin ligases, atrogin\u20101 and muscle RING\u2010finger protein 1 (MuRF1) were reversed by HD6277 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Additionally, HD6277 inhibited palmitate\u2010induced apoptotic events such as the Bcl\u20102 (Bcl2)\u2010associated X protein (Bax)\/Bcl\u20102 ratio, caspase 3 cleavage and nuclear fragmentation in C2C12 myoblasts and myotubes (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). These beneficial HD6277\u2010mediated actions disappeared after the addition of an Akt inhibitor (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Similar to in\u00a0vitro studies, HD6277 administration in obese and aged mice increased myogenic factors and decreased E3 ubiquitin ligase expression and apoptotic events (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). HD6277 increased muscle strength (+9.88% vs. Aged,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and myofiber thickness (+29.01% vs. Aged,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) in aging mice but only improved myofiber thickness (+11.84% vs. HFD,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) in obese mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>HD6277 can increase myogenic factors and reduce E3 ligase\u2010mediated proteolysis to inhibit muscle atrophy in aged mice. Our results suggest that GPR40 agonists may have potential as therapeutic agents for sarcopenia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13805","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T04:53:47Z","timestamp":1744692827000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["HD6277 Suppresses Muscle Atrophy by Promoting Myogenic Factors and Inhibiting Proteolysis in Aged Mice"],"prefix":"10.1002","volume":"16","author":[{"given":"Joo\u00a0Won","family":"Kim","sequence":"first","affiliation":[{"name":"BK21 Graduate Program, Department of Biomedical Sciences Korea University College of Medicine  Seoul Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"SukHwan","family":"Yun","sequence":"additional","affiliation":[{"name":"BK21 Graduate Program, Department of Biomedical Sciences Korea University College of Medicine  Seoul 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