Activation of MEF2 by muscle activity is mediated through a calcineurin-dependent pathway.
Gene expression in skeletal muscles of adult vertebrates is altered profoundly by changing patterns of contractile work. Here we observed that the functional activity of MEF2 transcription factors is stimulated by sustained periods of endurance exercise or motor nerve pacing, as assessed by expression in trans genic mice of a MEF2-dependent reporter gene (desMEF2-lacZ). This response is accompanied by transformation of specialized myofiber subtypes, and is blocked either by cyclosporin A, a specific chemical inhibitor of calcineurin, or by forced expression of the endogenous calcineurin inhibitory protein, myocyte-enriched calcineurin interacting protein 1. Calcineurin removes phosphate groups from MEF2, and augments the potency of the transcriptional activation domain of MEF2 fused to a heterologous DNA binding domain. Across a broad range, the enzymatic activity of calcineurin correlates directly with expression of endogenous genes that are transcriptionally activated by muscle contractions. These results delineate a molecular pathway in which calcineurin and MEF2 participate in the adaptive mechanisms by which skeletal myofibers acquire specialized contractile and metabolic properties as a function of changing patterns of muscle contraction.
Wu
H
H
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Rothermel
B
B
Kanatous
S
S
Rosenberg
P
P
Naya
F J
FJ
Shelton
J M
JM
Hutcheson
K A
KA
DiMaio
J M
JM
Olson
E N
EN
Bassel-Duby
R
R
Williams
R S
RS
D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D015151:Immunoblotting; D007700:Kinetics; D064326:MEF2 Transcription Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000378:metabolism; D018006:Myogenic Regulatory Factors; D009211:Myoglobin / Q000096:biosynthesis; D010805:Physical Conditioning, Animal; D005082:Physical Exertion; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D001616:beta-Galactosidase / Q000378:metabolism
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D009211:Myoglobin; D012333:RNA, Messenger; D014157:Transcription Factors; D012313:RNA; D016572:Cyclosporine; D019703:Calcineurin; D001616:beta-Galactosidase