Sharp-1 regulates TGF-β signaling and skeletal muscle regeneration

Abstract

Sharp-1 is a basic helix-loop-helix (bHLH) transcriptional repressor which is involved in a number of cellular processes. Our previous studies have demonstrated that Sharp-1 is a negative regulator of skeletal myogenesis and blocks differentiation of muscle precursor cells by modulating MyoD activity. In order to understand its role in pre- and post-natal myogenesis, we assessed skeletal muscle development, and freeze-injury induced regeneration in Sharp-1 deficient mice. We show that embryonic skeletal muscle development is not impaired in the absence of Sharp-1, but post-natally, the regenerative capacity is compromised. Although the initial phases of injury induced regeneration proceed normally in Sharp-1-/- mice, during late stages, the mutant muscle exhibits necrotic fibers, calcium deposits, and fibrosis. TGF-β expression, as well as pSmad 2/3 levels are sustained in the mutant tissue, and treatment with decorin, a TGF-β blocker improves histo-pathology of Sharp-1-/- injured muscles. In vitro, Sharp-1 associates with Smad3, and its overexpression inhibits TGF-β and Smad3-mediated expression of extracellular matrix genes in myofibroblasts. These results demonstrate that Sharp-1 regulates muscle regenerative capacity, at least in part, by modulation of TGF-β signaling.