Abstract
Quiescent satellite cells are myogenic progenitors that enable regeneration of skeletal muscle. One of the early events of satellite cell activation following myotrauma is the induction of the myogenic regulatory factor MyoD, which eventually induces terminal differentiation and muscle function gene expression. The purpose of this study was to elucidate the mechanism by which MyoD is induced during activation of satellite cells in mouse muscle undergoing regeneration. We show that Six1, a transcription factor essential for embryonic myogenesis, also regulates MyoD expression in muscle progenitor cells. Six1 knock-down by RNA interference leads to decreased expression of MyoD in myoblasts. Chromatin immunoprecipitation assays reveal that Six1 binds the Core Enhancer Region of MyoD. Further, transcriptional reporter assays demonstrate that Core Enhancer Region reporter gene activity in myoblasts and in regenerating muscle depends on the expression of Six1 and on Six1 binding sites. Finally, we provide evidence indicating that Six1 is required for the proper chromatin structure at the Core Enhancer Region, as well as for MyoD binding at its own enhancer. Together, our results reveal that MyoD expression in satellite cells depends on Six1, supporting the idea that Six1 plays an important role in adult myogenesis, in addition to its role in embryonic muscle formation.
Highlights
Skeletal muscle is a plastic organ that can regenerate itself after injury
Six1 is Expressed in Satellite Cells of Regenerating Muscle To study the function of Six1 during adult muscle regeneration, and to address the question whether it is involved in the regulation of MyoD expression, we started by determining the profile of Six1 and MyoD protein expression in the TA muscle of adult mice at various time points following injury
We have shown that Six1 is expressed in satellite cells of adult muscle in regeneration, and that its expression and function are consistent with its role in regulating MyoD expression: the Six1 protein is detected in activated satellite cells, and its expression coincides with the presence of MyoD
Summary
Skeletal muscle is a plastic organ that can regenerate itself after injury This property relies on the presence of resident adult stem cells termed satellite cells (reviewed in [1]). Muscle injury leads to the activation of satellite cells: they are released from their anatomic position, initiate several rounds of cell division, and eventually undergo myogenic differentiation to create new muscle mass [2]. The messenger RNA for the myogenic regulatory factor (MRF) Myf transcription factor is expressed by most quiescent satellite cells, the Myf protein itself is absent from these cells [8,9]. Satellite cells initiate their terminal differentiation: MyoD activates the expression of the MRF myogenin, as well as a host of muscle function genes, and the cells undergo fusion and exit the cell cycle
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