A requirement of Polo-like kinase 1 in murine embryonic myogenesis and adult muscle regeneration.

Zhihao Jia,Xiaoqi Liu,Yifan Kong,Yaohui Nie,Feng Yue,Timothy P Gavin,Shihuan Kuang,Lijie Gu

doi:10.7554/elife.47097

Abstract

Muscle development and regeneration require delicate cell cycle regulation of embryonic myoblasts and adult muscle satellite cells (MuSCs). Through analysis of the Polo-like kinase (Plk) family cell-cycle regulators in mice, we show that Plk1's expression closely mirrors myoblast dynamics during embryonic and postnatal myogenesis. Cell-specific deletion of Plk1 in embryonic myoblasts leads to depletion of myoblasts, developmental failure and prenatal lethality. Postnatal deletion of Plk1 in MuSCs does not perturb their quiescence but depletes activated MuSCs as they enter the cell cycle, leading to regenerative failure. The Plk1-null MuSCs are arrested at the M-phase, accumulate DNA damage, and apoptose. Mechanistically, Plk1 deletion upregulates p53, and inhibition of p53 promotes survival of the Plk1-null myoblasts. Pharmacological inhibition of Plk1 similarly inhibits proliferation but promotes differentiation of myoblasts in vitro, and blocks muscle regeneration in vivo. These results reveal for the first time an indispensable role of Plk1 in developmental and regenerative myogenesis.

Highlights

Adult skeletal muscle has an efficient regenerative capacity in response to muscle injury or physiological stimuli
We surveyed the mRNA levels of Plk1-4 during differentiation of primary myoblasts isolated from limb muscles
The expression pattern of Plk1 was inversely correlated to the expression of myogenic differentiation makers Myog and eMyhc, which were robustly upregulated during differentiation (Figure 1E)

Summary

Introduction

Adult skeletal muscle has an efficient regenerative capacity in response to muscle injury or physiological stimuli (i.e. intense exercise training). Muscle regeneration relies on a population of muscle resident stem cells, known as muscle satellite cells (MuSCs). These cells are located in a unique niche between the basal lamina and the plasma membrane of myofibers (Mauro, 1961) and remain in a quiescent state until activated by regenerative signals. Jia et al deleted the gene that makes PLK1 only in mouse muscle satellite cells to find out the role this protein plays in controlling the cell cycle in stem cells. PLK1 blockers have been used to stop cancer cells from dividing, but Jia et al.’s findings show that this kind of drug may hamper the ability of muscle to repair damage. We used myogenic cell-specific targeted mutation to show that Plk is absolutely required for mitosis and survival of myogenic cells during muscle development and regeneration in mice

Results

Discussion

Materials and methods

Funding Funder National Institutes of Health