Fibrosis in skeletal muscle develops after injury or in response to
chronic kidney disease (CKD), but the origin of cells becoming fibrous tissue and the initiating and sustaining mechanisms causing muscle
fibrosis are unclear. We identified muscle fibro/adipogenic progenitor cells (FAPs) that potentially differentiate into adipose tissues or
fibrosis. We also demonstrated that CKD stimulates
myostatin production in muscle. Therefore, we tested whether CKD induces
myostatin, which stimulates fibrotic differentiation of FAPs leading to
fibrosis in skeletal muscles. We isolated FAPs from mouse muscles and found that
myostatin stimulates their proliferation and conversion into fibrocytes. In vivo, FAPs isolated from EGFP-transgenic mice (FAPs-EGFP) were transplanted into muscles of mice with CKD or into mouse muscles that were treated with
myostatin. CKD or
myostatin stimulated FAPs-EGFP proliferation in muscle and increased α-smooth muscle actin expression in FAP-EGFP cells. When
myostatin was inhibited with a neutralizing
peptibody (a chimeric
peptide-Fc fusion
protein), the FAP proliferation and muscle
fibrosis induced by CKD were both suppressed. Knocking down Smad3 in cultured FAPs interrupted their conversion into fibrocytes, indicating that
myostatin directly converts FAPs into fibrocytes. Thus, counteracting
myostatin may be a strategy for preventing the development of
fibrosis in skeletal muscles of patients with CKD.