Activation of MEF2 by muscle activity is mediated through a calcineurin-dependent pathway

Abstract

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 transgenic mice of a MEF2-dependent reporter gene (desMEF2-lacZ). This response is accompanied by transformation of specialized myo®ber subtypes, and is blocked either by cyclosporin A, a speci®c 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 myo®bers acquire specialized contractile and metabolic properties as a function of changing patterns of muscle contraction.

Possible role for avPGC‐1α in the control of expression of fiber type, along with avUCP and avANT mRNAs in the skeletal muscles of cold‐exposed chickens

“…This latter observation suggests that cold exposure influences fiber phenotype via signals other than PGC-1a. In this regard, the fiber type conversion shown here is similar to what has been observed with calcineurin [31] and PGC-1a [2], transgenics and exercise [32]. The results of the Northern blot analysis revealed that avUCP and avANT transcript levels concomitantly increased from days 1 to 2, and then decreased slightly over the next 5 days, but remained higher than control values ( Fig.…”

Effect of exercise intensity and AICAR on isoform-specific expressions of murine skeletal muscle PGC-1α mRNA: a role of β2-adrenergic receptor activation

“…It was suggested that transcriptional activation of PGC-1␣-a is induced by the interaction on the MEF2 binding site and CRE sequences on the PGC-1␣-a promoter with regulatory factors such as MEF2, class IIa histone deacetylases (HDACs), ATF2, and CREB (1). AMPK, CaMK, CnA, and p38 MAPK have been reported to modulate these regulatory factors (2,7,9,22,29,34,35,38,44). Modulation of these transcription factors and the regulators by these protein kinases and phosphatase might be involved in high-intensity exercise-induced PGC-1␣-a expression.…”

Key signalling factors and pathways in the molecular determination of skeletal muscle phenotype

“…Calcineurin up-regulates the transcription of MEF2 genes (Wu et al, 2000a). It can also dephosphorylate MEF2 directly and enhance its transactivational activity (Dunn et al, 2001;Wu et al, 2001). Hence members of the MEF2 family are transcriptional targets and protein substrates of calcineurin.…”