Differentiation of skeletal myoblast cells to functional myotubes involves highly regulated transcriptional dynamics. The myocyte enhancer factor 2 (MEF2) transcription factors are critical to this process, synergizing with the master regulator MyoD to promote muscle specific gene transcription. MEF2 is extensively regulated by myogenic stimuli, both transcriptionally and post-translationally, but to date there has been little progress in understanding how signals upstream of MEF2 are coordinated to produce a coherent response. In this study, we define a novel interaction between the muscle A-kinase anchoring protein (mAKAP) and MEF2 in skeletal muscle. Discrete domains of MEF2 and mAKAP bind directly. Their interaction was exploited to probe the function of mAKAP-tethered MEF2 during myogenic differentiation. Dominant interference of MEF2/mAKAP binding was sufficient to block MEF2 activation during the early stages of differentiation. Furthermore, extended expression of this disrupting domain effectively blocked myogenic differentiation, halting the formation of myotubes and decreasing expression of several differentiation markers. This study expands our understanding of the regulation of MEF2 in skeletal muscle and identifies the mAKAP scaffold as a facilitator of MEF2 transcription and myogenic differentiation.
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