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Catalpol, an iridoid glycoside, improves skeletal muscle function by enhancing myogenesis; it has potential to treat DMD. We demonstrate the positive effects of catalpol in dystrophic skeletal muscle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>mdx<\/jats:italic> (loss of dystrophin) mice (<jats:italic>n<\/jats:italic>\u00a0=\u00a018 per group) were treated with catalpol (200\u00a0mg\/kg) for six consecutive weeks. Serum analysis, skeletal muscle performance and histology, muscle contractile function, and gene and protein expression were performed. Molecular docking and ligand\u2013target interactions, RNA interference, immunofluorescence, and plasmids transfection were utilized to explore the protective mechanism in DMD by which catalpol binding with transforming growth factor\u2010\u03b2\u2013activated kinase 1 (TAK1) in skeletal muscle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Six weeks of catalpol treatment improved whole\u2010body muscle health in <jats:italic>mdx<\/jats:italic> mice, which was characterized by reduced plasma creatine kinase (<jats:italic>n<\/jats:italic>\u00a0=\u00a018, \u221235.1%, <jats:italic>P\u00a0&lt;<\/jats:italic>\u00a00.05) and lactic dehydrogenase (<jats:italic>n<\/jats:italic>\u00a0=\u00a018, \u221210.3%, <jats:italic>P\u00a0&lt;<\/jats:italic>\u00a00.05) activity. These effects were accompanied by enhanced grip strength (<jats:italic>n<\/jats:italic>\u00a0=\u00a018, +25.4%, <jats:italic>P\u00a0&lt;<\/jats:italic>\u00a00.05) and reduced fibrosis (<jats:italic>n<\/jats:italic>\u00a0=\u00a018, \u221229.0% for hydroxyproline content, <jats:italic>P\u00a0&lt;<\/jats:italic>\u00a00.05). Moreover, catalpol treatment protected against muscle fatigue and promoted muscle recovery in the tibialis anterior (TA) and diaphragm (DIA) muscles (<jats:italic>n<\/jats:italic>\u00a0=\u00a06, +69.8%, <jats:italic>P\u00a0&lt;<\/jats:italic>\u00a00.05 and\u00a0+\u00a074.8%, <jats:italic>P\u00a0&lt;<\/jats:italic>\u00a00.001, respectively), which was accompanied by enhanced differentiation in primary myoblasts from DMD patients (<jats:italic>n<\/jats:italic>\u00a0=\u00a06, male, mean age: 4.7\u00a0\u00b1\u00a01.9\u00a0years) and <jats:italic>mdx<\/jats:italic> mice. In addition, catalpol eliminated p\u2010TAK1 overexpression in <jats:italic>mdx<\/jats:italic> mice (<jats:italic>n<\/jats:italic>\u00a0=\u00a012, \u221221.3%, <jats:italic>P\u00a0&lt;<\/jats:italic>\u00a00.05) and primary myoblasts. The catalpol\u2010induced reduction in fibrosis and increased myoblast differentiation resulted from the inhibition of TAK1 phosphorylation, leading to reduced myoblast trans\u2010differentiation into myofibroblasts. Catalpol inhibited the phosphorylation of TAK1 by binding to TAK1, possibly at Asp\u2010206, Thr\u2010208, Asn\u2010211, Glu\u2010297, Lys\u2010294, and Tyr\u2010293.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings show that catalpol and TAK1 inhibitors substantially improve whole\u2010body muscle health and the function of dystrophic skeletal muscles and may provide a novel therapy for DMD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12581","type":"journal-article","created":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T04:54:47Z","timestamp":1598936087000},"page":"1306-1320","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["A potential therapeutic effect of catalpol in Duchenne muscular dystrophy revealed by binding with TAK1"],"prefix":"10.1002","volume":"11","author":[{"given":"Dengqiu","family":"Xu","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University  Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neurology Children's Hospital of Fudan University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingwei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University  Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sijia","family":"Li","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University  Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeren","family":"Sun","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Drug Screening China Pharmaceutical University  Nanjing 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