Dynamic Phosphorylation of the Myocyte Enhancer Factor 2Cα1 Splice Variant Promotes Skeletal Muscle Regeneration and Hypertrophy.
The transcription factor MEF2C (Myocyte Enhancer Factor 2C) plays an established role in the early steps of myogenic differentiation. However, the involvement of MEF2C in adult myogenesis and in muscle regeneration has not yet been systematically investigated. Alternative splicing of mammalian MEF2C transcripts gives rise to two mutually exclusive protein variants: MEF2Cα2 which exerts a positive control of myogenic differentiation, and MEF2Cα1, in which the α1 domain acts as trans-repressor of the MEF2C pro-differentiation activity itself. However, MEF2Cα1 variants are persistently expressed in differentiating cultured myocytes, suggesting a role in adult myogenesis. We found that overexpression of both MEF2Cα1/α2 proteins in a mouse model of muscle injury promotes muscle regeneration and hypertrophy, with each isoform promoting different stages of myogenesis. Besides the ability of MEF2Cα2 to increase differentiation, we found that overexpressed MEF2Cα1 enhances both proliferation and differentiation of primary myoblasts, and activates the AKT/mTOR/S6K anabolic signaling pathway in newly formed myofibers. The multiple activities of MEF2Cα1 are modulated by phosphorylation of Ser98 and Ser110, two amino acid residues located in the α1 domain of MEF2Cα1. These specific phosphorylations allow the interaction of MEF2Cα1 with the peptidyl-prolyl isomerase PIN1, a regulator of MEF2C functions. Overall, in this study we established a novel regulatory mechanism in which the expression and the phosphorylation of MEF2Cα1 are critically required to sustain the adult myogenesis. The described molecular mechanism will represent a new potential target for the development of therapeutical strategies to treat muscle-wasting diseases. Stem Cells 2017;35:725-738.
Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Modena, Italy.
Fiorenza
F
Baruffaldi
Département de Biologie du Développement et Cellules Souches, Institut Pasteur (CNRS URA 2578), Paris, France.
Didier
D
Montarras
Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Modena, Italy.
Valentina
V
Basile
Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Modena, Italy.
Luca
L
De Feo
Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Modena, Italy.
Sara
S
Badodi
Randall Division of Cell and Molecular Biophysics, King's College London, UK.
Massimo
M
Ganassi
Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Modena, Italy.
Renata
R
Battini
Institute Pasteur-Cenci Bolognetti, DAHFMO-Unit of Histology and Medical Embryology, IIM, Sapienza University, Rome, Italy.|Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
Carmine
C
Nicoletti
Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Modena, Italy.
Carol
C
Imbriano
Institute Pasteur-Cenci Bolognetti, DAHFMO-Unit of Histology and Medical Embryology, IIM, Sapienza University, Rome, Italy.|Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
Antonio
A
Musarò
Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Modena, Italy.
Susanna
S
Molinari
D000375:Aging / Q000378:metabolism; D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D006984:Hypertrophy; D064326:MEF2 Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000473:pathology* / Q000503:physiopathology*; D032446:Myoblasts / Q000378:metabolism; D041681:NIH 3T3 Cells; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D000072417:Protein Domains; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism; D012694:Serine / Q000378:metabolism
D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D012694:Serine; C000606850:Pin1 protein, mouse
Alternative splicing; Differentiation; Hypertrophy; MEF2 transcription factors; Myogenesis; Peptidyl-prolyl isomerase; Phosphorylation; Pin1; Tissue regeneration