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 (p57 kip2 ), 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.
Bibliographical noteFunding Information:
We thank Frédéric Auradé for scientific discussions. FR Laboratory is supported by funding from: Association Franc¸aise contre les Myopathies (AFM) via TRANSLAMUSCLE (PROJECT 19507), Labex REVIVE (ANR-10-LABX-73), Fondation pour la Recherche Médicale (FRM; Grant DEQ20130326526), MYOGRAD network (GK1631), Agence Nationale pour la Recherche (ANR) grant Bone-muscle-repair (ANR-13-BSV1-0011-02), BMP-Myomass (ANR-12-BSV1-0038-04), Satnet (ANR-15-CE13-0011-01), and RHU CARMMA (ANR-15-RHUS-0003). AA Laboratory is supported by funding from the NIH R01 (1R01AR062142) and NIH R21 (1R21AR070319). No funding sources were involved in study design, data collection and interpretation, or the decision to submit the work for publication. We wish to acknowledge Adeline Henry and Aurélie Guguin (Plateforme de Cytométrie en flux, Institut Mondor de Recherche Biomédicale), Bénédicte Hoareau (Flow Cytometry Core CyPS, Pierre and Marie Curie University), Serban Morosan, and the animal care facility (Centre d’Expérimentation Fonctionnelle, School of Medicine Pierre et Marie Curie).
© Mademtzoglou et al.