| First Author | Valle-Tenney R | Year | 2020 |
| Journal | Matrix Biol | Volume | 87 |
| Pages | 48-65 | PubMed ID | 31669521 |
| Mgi Jnum | J:298040 | Mgi Id | MGI:6478769 |
| Doi | 10.1016/j.matbio.2019.09.003 | Citation | Valle-Tenney R, et al. (2020) Role of hypoxia in skeletal muscle fibrosis: Synergism between hypoxia and TGF-beta signaling upregulates CCN2/CTGF expression specifically in muscle fibers. Matrix Biol 87:48-65 |
| abstractText | Several skeletal muscle diseases are characterized by fibrosis, the excessive accumulation of extracellular matrix. Transforming growth factor-beta (TGF-beta) 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-1alpha (HIF-1alpha), 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-beta on CCN2 expression in vitro. Fibroblasts, myoblasts and differentiated myotubes were incubated with TGF-beta1 under hypoxic conditions. Hypoxia and TGF-beta1 induced CCN2 expression synergistically in myotubes but not in fibroblasts or undifferentiated muscle progenitors. This induction requires HIF-1alpha and the Smad-independent TGF-beta signaling pathway. We performed in vivo experiments using pharmacological stabilization of HIF-1alpha or hypoxia-induced via hindlimb ischemia together with intramuscular injections of TGF-beta1, and we found increased CCN2 expression. These observations suggest that hypoxic signaling together with TGF-beta signaling, which are both characteristics of a fibrotic skeletal muscle environment, induce the expression of CCN2 in skeletal muscle fibers and myotubes. |
