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

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

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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 (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.

Original languageEnglish (US)
Article numbere33337
JournaleLife
Volume7
DOIs
StatePublished - Oct 2018

Bibliographical note

Funding 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).

Funding Information:
We thank Frédéric Auradé for scientific discussions. FR Laboratory is supported by funding from: Association Française 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).Association Française contre les Myopathies TRANSLAMUSCLE (PROJECT 19507) Frederic Relaix Labex Revive ANR-10-LABX-73 Frederic Relaix Fondation pour la Recherche Médicale Grant DEQ20130326526 Frederic Relaix MyoGrad Network GK1631 Frederic Relaix Agence Nationale de la Recherche Bone-muscle-repair (ANR-13-BSV1-455 0011-02),BMP-Myomass (ANR-12-BSV1-0038-04), Satnet (ANR-15-CE Frederic Relaix National Institutes of Health NIH R01 (1R01AR062142) and 457 NIH R21 (1R21AR070319) Atsushi Asakura The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Publisher Copyright:
© Mademtzoglou et al.

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