title: Requirement of MEF2A, C, and D for skeletal muscle regeneration.
abstract: Regeneration of adult skeletal muscle following injury occurs through the activation of satellite cells, an injury-sensitive muscle stem cell population that proliferates, differentiates, and fuses with injured myofibers. Members of the myocyte enhancer factor 2 (MEF2) family of transcription factors play essential roles in muscle differentiation during embryogenesis, but their potential contributions to adult muscle regeneration have not been systematically explored. To investigate the potential involvement of MEF2 factors in muscle regeneration, we conditionally deleted the Mef2a, c, and d genes, singly and in combination, within satellite cells in mice, using tamoxifen-inducible Cre recombinase under control of the satellite cell-specific Pax7 promoter. We show that deletion of individual Mef2 genes has no effect on muscle regeneration in response to cardiotoxin injury. However, combined deletion of the Mef2a, c, and d genes results in a blockade to regeneration. Satellite cell-derived myoblasts lacking MEF2A, C, and D proliferate normally in culture, but cannot differentiate. The absence of MEF2A, C, and D in satellite cells is associated with aberrant expression of a broad collection of known and unique protein-coding and long noncoding RNA genes. These findings reveal essential and redundant roles of MEF2A, C, and D in satellite cell differentiation and identify a MEF2-dependent transcriptome associated with skeletal muscle regeneration.
authors.affiliation: Departments of Molecular Biology, Internal Medicine, and Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Nelson
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bezprozvannaya
authors.forename: John M
authors.initials: JM
authors.lastname: Shelton
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics*; D007150:Immunohistochemistry; D064326:MEF2 Transcription Factors / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000254:growth & development*; D060888:Real-Time Polymerase Chain Reaction; D012038:Regeneration / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism*
chemical_list: D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; C578041:Mef2c protein, mouse; C578044:Mef2d protein, mouse
keywords: myogenesis; myogenic regulatory factor; myotube