Stk24 promotes early myogenic differentiation through p38 MAPK and Limk2/Cofilin2

Abstract

Myogenic differentiation is a complex and highly orchestrated process that involves many molecules and pathways. With intensive studies, both in vivo and in vitro, in the past decades by many groups, we have gained a good knowledge about the molecular mechanisms that regulate myogenic differentiation. However, gaps still exist. In our current study, we aimed to identify key kinases that are involved in myogenic differentiation. In an RNAi-based screening for protein kinases involved in C2C12 myoblast differentiation, we identified Stk24 (also called Mst3), a member of the mammalian Ste20 family, as one of the key regulators required for myoblast differentiation. When Stk24 was knocked down in cell culture models or in zebrafish, the myogenic differentiation was suppressed. To explore the role of Stk24 in vivo, we generated a Stk24 knockout (KO) mouse strain by CRISPR/Cas9. The Stk24-null mice had fewer quiescent muscle satellite cells (MuSC) than the wild-type control. Consistently, the Stk24 KO mice displayed delayed muscle regeneration compared to the wild-type mice. When we isolated and examined Stk24-null MuSC in culture, they also showed defective myogenic differentiation with relatively normal proliferation. Mechanistically, we found that key pro-differentiation factors like MyoD, MEF2A and MEF2C were downregulated in Stk24-null myoblasts during differentiation. The differentiation delay was partially mediated by the decreased activity of p38 MAPK, a key MAPK required for myogenic differentiation. Furthermore, we also demonstrated that Stk24 promotes the myogenic differentiation through the Limk2/Cofilin2 axis to facilitate the formation of F-actin that is involved in cytoskeletal change during myogenesis. Collectively, my research data reveal that Stk24 promotes myogenic differentiation, both in cell culture and in vivo, through the p38 MAPK pathway and the Limk2-Cofilin2 axis.

Date of Award	2019
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology