TY - JOUR
T1 - Requirement of MEF2A, C, and D for skeletal muscle regeneration
AU - Liu, Ning
AU - Nelson, Benjamin R.
AU - Bezprozvannaya, Svetlana
AU - Shelton, John M.
AU - Richardson, James A.
AU - Bassel-Duby, Rhonda
AU - Olson, Eric N.
PY - 2014/3/18
Y1 - 2014/3/18
N2 - 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.
AB - 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.
KW - Myogenesis
KW - Myogenic regulatory factor
KW - Myotube
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U2 - 10.1073/pnas.1401732111
DO - 10.1073/pnas.1401732111
M3 - Article
C2 - 24591619
AN - SCOPUS:84896521456
SN - 0027-8424
VL - 111
SP - 4109
EP - 4114
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 11
ER -