The Ubiquitin-Proteasome System Is Indispensable for the Maintenance of Muscle Stem Cells

Abstract

Summary: Adult muscle stem cells (satellite cells) are required for adult skeletal muscle regeneration. A proper balance between quiescence, proliferation, and differentiation is essential for the maintenance of the satellite cell pool and their regenerative function. Although the ubiquitin-proteasome is required for most protein degradation in mammalian cells, how its dysfunction affects tissue stem cells remains unclear. Here, we investigated the function of the proteasome in satellite cells using mice lacking the crucial proteasomal component, Rpt3. Ablation of Rpt3 in satellite cells decreased proteasome activity. Proteasome dysfunction in Rpt3-deficient satellite cells impaired their ability to proliferate, survive and differentiate, resulting in defective muscle regeneration. We found that inactivation of proteasomal activity induced proliferation defects and apoptosis in satellite cells. Mechanistically, insufficient proteasomal activity upregulated the p53 pathway, which caused cell-cycle arrest. Our findings delineate a critical function of the proteasome system in maintaining satellite cells in adult muscle. : It is not clear how proteasome insufficiency affects tissue stem cells. Kitajima et al. demonstrate that the proteasome system is indispensable for the maintenance of muscle stem cells. Proteasome dysfunction in Rpt3-deficient satellite cells impairs their ability to proliferate, survive and differentiate, resulting in defective muscle regeneration. Keywords: muscle stem cells, muscle satellite cells, skeletal muscle, muscle regeneration, proteasome dysfunction, Rpt3, p53, proliferation defect, differentiation defect, proteolysis