{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T22:01:48Z","timestamp":1790892108988,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,11,2]],"date-time":"2021-11-02T00:00:00Z","timestamp":1635811200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Skeletal muscle atrophy is a severe condition that involves loss of muscle mass and quality. Drug intake can also cause muscle atrophy. Biguanide metformin is the first\u2010line and most widely prescribed anti\u2010diabetic drug for patients with type 2 diabetes. The molecular mechanism of metformin in muscle is unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Myostatin expression was investigated at the protein and transcript levels after metformin administration. To investigate the pathways associated with myostatin signalling, we used real\u2010time polymerase chain reaction, immunoblotting, luciferase assay, chromatin immunoprecipitation assay, co\u2010immunoprecipitation, immunofluorescence, primary culture, and confocal microscopy. Serum analysis, physical performance, and immunohistochemistry were performed using our <jats:italic>in vivo<\/jats:italic> model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Metformin induced the expression of myostatin, a key molecule that regulates muscle volume and triggers the phosphorylation of AMPK. AMPK alpha2 knockdown in the background of metformin treatment reduced the myostatin expression of C2C12 myotubes (\u221249.86\u00a0\u00b1\u00a012.03%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) and resulted in increased myotube diameter compared with metformin (+46.62\u00a0\u00b1\u00a00.88%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). Metformin induced the interaction between AMPK and FoxO3a, a key transcription factor of myostatin. Metformin also altered the histone deacetylase activity in muscle cells (&gt;3.12\u2010fold\u00a0\u00b1\u00a00.13, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). The interaction between HDAC6 and FoxO3a induced after metformin treatment. Confocal microscopy revealed that metformin increased the nuclear localization of FoxO3a (&gt;3.3\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). Chromatin immunoprecipitation revealed that metformin induced the binding of FoxO3a to the myostatin promoter. The transcript\u2010level expression of myostatin was higher in the gastrocnemius (GC) muscles of metformin\u2010treated wild\u2010type (WT) (+68.9\u00a0\u00b1\u00a010.01%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and db\/db mice (+55.84\u00a0\u00b1\u00a06.62%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) than that in the GC of controls (<jats:italic>n<\/jats:italic>\u00a0=\u00a04 per group). Average fibre cross\u2010sectional area data also showed that the metformin\u2010treated C57BL\/6J (WT) (\u221231.74\u00a0\u00b1\u00a00.75%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and C57BLKS\/J\u2010db\/db (\u221218.11\u00a0\u00b1\u00a00.94%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) mice had decreased fibre size of GC compared to the controls. The serum myoglobin level was significantly decreased in metformin\u2010treated WT mice (\u221266.6\u00a0\u00b1\u00a09.03%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results demonstrate that metformin treatment impairs muscle function through the regulation of myostatin in skeletal muscle cells via AMPK\u2010FoxO3a\u2010HDAC6 axis. The muscle\u2010wasting effect of metformin is more evident in WT than in db\/db mice, indicating that more complicated mechanisms may be involved in metformin\u2010mediated muscular dysfunction.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12833","type":"journal-article","created":{"date-parts":[[2021,11,2]],"date-time":"2021-11-02T07:02:32Z","timestamp":1635836552000},"page":"605-620","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":94,"title":["Metformin induces muscle atrophy by transcriptional regulation of myostatin via HDAC6 and FoxO3a"],"prefix":"10.1002","volume":"13","author":[{"given":"Min Ju","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Anatomy Korea University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Wook","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Anatomy Korea University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Ok","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Anatomy Korea University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hae","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Anatomy Korea University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Jeong","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Anatomy Korea University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Anatomy Korea University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joo Yeon","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Anatomy Korea University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang Woo","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Anatomy Korea University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pu Reum","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Anatomy Korea University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun Hwa","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Anatomy Korea University College of Medicine  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeon Soo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Anatomy Korea University 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