Cellular localization of the cell cycle inhibitor Cdkn1c controls growth arrest of adult skeletal muscle stem cells.

Despoina Mademtzoglou,Frederic Relaix,Philippos Mourikis,Matthew J Borok,Yusaku Kodaka,Sonia Alonso-Martin,Yoko Asakura,Atsushi Asakura,Amrudha Mohan

doi:10.7554/elife.33337

Abstract

Adult skeletal muscle maintenance and regeneration depend on efficient muscle stem cell (MuSC) functions. The mechanisms coordinating cell cycle with activation, renewal, and differentiation of MuSCs remain poorly understood. Here, we investigated how adult MuSCs are regulated by CDKN1c (p57kip2), a cyclin-dependent kinase inhibitor, using mouse molecular genetics. In the absence of CDKN1c, skeletal muscle repair is severely impaired after injury. We show that CDKN1c is not expressed in quiescent MuSCs, while being induced in activated and proliferating myoblasts and maintained in differentiating myogenic cells. In agreement, isolated Cdkn1c-deficient primary myoblasts display differentiation defects and increased proliferation. We further show that the subcellular localization of CDKN1c is dynamic; while CDKN1c is initially localized to the cytoplasm of activated/proliferating myoblasts, progressive nuclear translocation leads to growth arrest during differentiation. We propose that CDKN1c activity is restricted to differentiating myoblasts by regulated cyto-nuclear relocalization, coordinating the balance between proliferation and growth arrest.

Highlights

Tissue regeneration is of vital importance for restoring tissue structure and function following damage
The number of PAX7+ muscle stem cell (MuSC) on freshly isolated myofibers of Extensor digitorum longus (EDLs) was increased in Cdkn1c mutant mice compared to the controls (Figure 1F–G)
Regenerative adult myogenesis is crucial for recovery from injuries, but can be compromised by degenerative or disease states that affect the functional capacity of skeletal muscle stem cells (MuSC)

Summary

Introduction

Tissue regeneration is of vital importance for restoring tissue structure and function following damage. Once stimulated by homeostatic demand or damage, adult MuSCs exit quiescence, re-enter the cell cycle, and provide differentiated progeny for muscle repair, while a subpopulation self-renews to preserve the quiescent pool Members of the Cip/Kip family have been shown to inhibit proliferation and promote differentiation in embryonic muscle or in myoblasts in vitro, their involvement in postnatal MuSC cell cycle regulation is less well documented (Halevy et al, 1995; Reynaud et al, 1999; Zhang et al, 1999; Messina et al, 2005; Chakkalakal et al, 2014; Zalc et al, 2014). Our results suggest that muscle stem cells require Cdkn1c activity for the dynamic control of growth arrest during adult myogenesis

Results

Discussion

Materials and methods