UCSF

The MADS domain transcription factor family MEF2 is a critical regulator of a number of diverse developmental programs, including cardiovascular, skeletal muscle, neural crest, vasculature, and bone development. One isoform of MEF2, MEF2C, plays a particularly critical role in the formation of the heart and the differentiation of skeletal muscle. MEF2C is a signal-dependent transcription factor that can function as either an activator or a repressor, depending on cofactor interactions and posttranslational modifications. Recently, an isoform of the SAP domain protein Myocardin, Myocardin-935, has been identified as a potent coactivator of MEF2C activity, yet the targets of MEF2C-Myocardin and the transcriptional mechanisms that control Myocardin coactivation of MEF2C remain unresolved. In chapter 2, we identified a highly conserved transcriptional enhancer from the Ampkα2 gene that is sufficient to direct expression exclusively to the myocardium during development and in adulthood. Ampkα2 encodes a subunit of the 5'-AMP-activated protein kinase (AMPK), an energy-sensing enzyme that maintains cellular energy homeostasis and controls cardiac metabolism by regulating fatty acid oxidation, glycolysis, and glucose uptake. We show that the Ampkα2 myocardial enhancer requires a MEF2C-Myocardin complex for activity in vivo and in vitro, and that this complex regulates Ampkα2 expression through two essential, highly conserved MEF2 sites in the enhancer. In addition to regulating genes in the heart, MEF2C is also a potent transcriptional co-activator of many genes and proteins in skeletal muscle, such as GLUT4 and PGC1α. In chapter 3, we sought to determine the requirement of Mef2c in skeletal muscle by generating a conditional knockout mouse. Using two independent, transgenic Cre lines, we determined that Mef2c is required in skeletal muscle for overall body size. Mice lacking Mef2c also have defective fiber type composition and mild glycogen accumulation, but these impairments do not have an effect on exercise abilities. Lastly, we show that MEF2C may function downstream of insulin receptor signaling through a p38 MAPK signaling pathway in skeletal muscle.