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

Abstract

Sharp-1 is a basic helix-loop-helix (bHLH) transcriptional repressor that is involved in a number of cellular processes. Our previous studies have demonstrated that Sharp-1 is a negative regulator of skeletal myogenesis and it blocks differentiation of muscle precursor cells by modulating the activity of MyoD. 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; however, post-natally, the regenerative capacity is compromised. Although the initial phases of injury-induced regeneration proceed normally in Sharp-1 2/2 mice, during late stages, the mutant muscle exhibits necrotic fibers, calcium deposits and fibrosis. TGF-b expression, as well as levels of phosphorylated Smad2 and Smad3, are sustained in the mutant tissue and treatment with decorin, which blocks TGF-b signaling, improves the histopathology of Sharp-1 2/2 injured muscles. In vitro, Sharp-1 associates with Smad3, and its overexpression inhibits TGF-b-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-b signaling.

Activation of satellite cells and the regeneration of human skeletal muscle are expedited by ingestion of nonsteroidal anti‐inflammatory medication

“…Laminin and collagen IV are major components of the basement membrane, which constitutes one side of the satellite cell niche as well as serving to surround—mechanically support—muscle fibers. The proteoglycan decorin has been shown to play a role in inducing the proliferation of satellite cells (14) and in modulating fibrosis in regenerating muscle (13). Transient fibrosis is often seen during regeneration (28), the removal of which is important for the completion of the restoration process.…”

“…Yet the potential of NSAIDs to influence muscle ECM remodeling is unknown. In the current study, we chose to focus on these same groups of matrix proteins and also to include decorin, which has been shown to play a role in modulating fibrosis (13) as well as in activating satellite cells (14).…”

MicroRNA expression profiles differ between primary myofiber of lean and obese pig breeds

“…Furthermore, DE miRNAs were intensively involved in not only the metabolic pathways such as lipid metabolic process, fatty acid metabolic process, galactose metabolism, cysteine and methionine metabolism but also signaling pathways such as wnt-protein binding, toll-like receptor, mTOR, TGF-β, positive regulation of MAPK cascade signaling pathways ( Fig 6 ). Many studies have reported that the TGF-β family played important roles in skeletal muscle development [ 35 , 36 ]. MAPK signalling pathway is known to be involved in regulation of muscle differentiation by affecting the activities of myogenic transcription factors as well as controlling the expression of structural muscle genes [ 37 ].…”

Therapeutic Effect of Losartan, an Angiotensin II Type 1 Receptor Antagonist, on CCl4-Induced Skeletal Muscle Injury

“…TNF-α pushes cells toward apoptosis, whereas the TGFs appear to direct them towards fibrosis [ 1 ]. TGF-β plays a key role in the fibrogenic response of skeletal muscle after CCl 4 treatment [ 23 , 24 , 25 , 26 ] . We found that not only liver but also skeletal muscle is impaired by chronic CCl 4 intoxication.…”