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Transforming growth factor\u2010\u03b21 (TGF\u2010\u03b21) contributes to muscle pathogenesis in elderly people and DMD patients; inhibition of TGF\u2010\u03b21 signalling is a promising therapeutic strategy for muscle\u2010wasting disorders. Hemojuvelin (HJV or Hjv as the murine homologue) is a membrane\u2010bound protein that is highly expressed in skeletal muscle, heart, and liver. In hepatic cells, Hjv acts as a coreceptor for bone morphogenetic protein, a TGF\u2010\u03b2 subfamily member. The aim of this study was to investigate whether Hjv plays an essential role in muscle physiological and pathophysiological processes by acting as a coreceptor for TGF\u2010\u03b21 signalling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Conventional and conditional <jats:italic>Hjv<\/jats:italic> knockout mice as well as <jats:italic>mdx<\/jats:italic> and aged mice transfected with Hjv overexpression vector were used to study the role of Hjv in muscle physiology and pathophysiology. qRT\u2010PCR, western blotting, and immunohistochemistry examinations were conducted to evaluate gene, protein, and structural changes <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>. Exercise endurance was determined using treadmill running test, and muscle force was detected by an isometric transducer. RNA interference, immunoprecipitation, and dual\u2010luciferase reporter assays were utilized to explore the mechanism by which Hjv regulates TGF\u2010\u03b21 signalling in skeletal muscle.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Conventional and conditional <jats:italic>Hjv<\/jats:italic> knockout mice displayed muscle atrophy, fibrosis, reduced running endurance, and muscle force. HJV was significantly down\u2010regulated in the muscles of DMD patients (<jats:italic>n<\/jats:italic>\u00a0=\u00a03, mean age: 11.7\u00a0\u00b1\u00a05.7\u00a0years) and <jats:italic>mdx<\/jats:italic> mice as well as in those of aged humans (<jats:italic>n<\/jats:italic>\u00a0=\u00a010, 20% women, mean age: 75.1\u00a0\u00b1\u00a09.5\u00a0years) and mice. Overexpression of Hjv rescued dystrophic and age\u2010related muscle wasting. Unlike its function in hepatic cells, the bone morphogenetic protein downstream phosphorylated p\u2010Smad1\/5\/8 signalling pathway was unchanged, but TGF\u2010\u03b21, TGF\u2010\u03b2 receptor II (T\u03b2RII), and p\u2010Smad2\/3 expression were increased in <jats:italic>Hjv\u2010<\/jats:italic>deficient muscles. Mechanistically, loss of Hjv promoted activation of Smad3 signalling induced by TGF\u2010\u03b21, whereas Hjv overexpression inhibited TGF\u2010\u03b21\/Smad3 signalling by directly interacting with T\u03b2RII on the muscle membrane.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings identify an unrecognized role of HJV in skeletal muscle by regulating TGF\u2010\u03b21\/Smad3 signalling as a coreceptor for T\u03b2RII. Unlike the TGF\u2010\u03b21\/Smad3 pathway, HJV could be a reliable drug target as its expression is not widespread. Novel therapeutic strategies could potentially be devised to interfere only with the muscle function of HJV to treat DMD and age\u2010related muscle wasting.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12414","type":"journal-article","created":{"date-parts":[[2019,3,19]],"date-time":"2019-03-19T09:09:15Z","timestamp":1552986555000},"page":"557-573","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age\u2010related muscle wasting"],"prefix":"10.1002","volume":"10","author":[{"given":"Peng","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Space Medicine Fundamentals and Application China Astronaut Research and Training Center  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"He","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Space Medicine 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