Role of cyclin-dependent kinase inhibitors in differentiation of satellite cells

Abstract

Satellite cells are a rare population of stem cells residing in skeletal muscle. They are activated upon injury, enter the cell cycle, and proliferate. These activated satellite cells eventually stop their cell cycle, fuse with each other, and differentiate into multinucleated myotubes for muscle regeneration. Some small proportion of activated satellite cells undergo self-renewal to repopulate the satellite cell pool. For any cell, this transition occurs at the G1 phase, from where the cell can undergo cell cycle arrest, thereby moving towards differentiation, or it can proceed to S-phase and proliferate. The cyclin-dependent kinase inhibitors (CDKI) play a major role in this G1/S transition. In this study, we aim to investigate the roles of CDKIs such as p21, p27, and p57 in the differentiation process of satellite cells. We demonstrate that the overexpression of p21 reduces the Pax7(+)MyoD(-) reserve cell population, a population of in vitro quiescent satellite cells. We also show that the overexpression of p21, p27, and p57 increases the population of Myosin heavy chain (MHC)(+) differentiated cells, thus promoting the cells towards myogenic differentiation. Furthermore, we show that the overexpression of the N-terminal CDK inhibitory domain of p21 shows a higher number of MHC(+) differentiated cells compared with the control cells or C-terminal domain of p21, suggesting that the N-terminal domain of p21 is necessary in pushing the myoblasts towards differentiation. These data help in elucidating the molecular mechanisms involved in the differentiation of satellite cells, which could be used to better understand the muscle regeneration process.