Role of hypoxia in skeletal muscle fibrosis: Synergism between hypoxia and TGF- β signaling upregulates CCN2/CTGF expression specifically in muscle fibers.

Role of hypoxia in skeletal muscle fibrosis: Synergism between hypoxia and TGF-β signaling upregulates CCN2/CTGF expression specifically in muscle fibers. Matrix Biol. 2019 Oct 24;: Authors: Valle-Tenney R, Rebolledo D, Lipson KE, Brandan E Abstract Several skeletal muscle diseases are characterized by fibrosis, the excessive accumulation of extracellular matrix. Transforming growth factor-β (TGF-β) and connective tissue growth factor (CCN2/CTGF) are two profibrotic factors augmented in fibrotic skeletal muscle, together with signs of reduced vasculature that implies a decrease in oxygen supply. We observed that fibrotic muscles are characterized by the presence of positive nuclei for hypoxia-inducible factor-1α (HIF-1α), a key mediator of the hypoxia response. However, it is not clear how a hypoxic environment could contribute to the fibrotic phenotype in skeletal muscle. We evaluated the role of hypoxia and TGF-β on CCN2 expression in vitro. Fibroblasts, myoblasts and differentiated myotubes were incubated with TGF-β1 under hypoxic conditions. Hypoxia and TGF-β1 induced CCN2 expression synergistically in myotubes but not in fibroblasts or undifferentiated muscle progenitors. This induction requires HIF-1α and the Smad-independent TGF-β signaling pathway. We performed in vivo experiments using pharmacological stabilization of HIF-1α or hypoxia-induced via hindlimb ischemia together with intramuscular injections of TGF-β1...
Source: Matrix Biology - Category: Molecular Biology Authors: Tags: Matrix Biol Source Type: research