Cardiac and skeletal muscles respond to changes in physiological demands by remodeling the architecture of individual myocytes. These responses can result in changes in overall mass of the tissue (hypertrophy versus atrophy) or reprogramming of gene expression to alter specialized metabolic and contractile properties of myocytes. Pathological conditions also provoke remodeling responses in muscle tissues that initially resemble physiological adaptations, but subsequently impair contractile performance, ultimately resulting in clinical deterioration and death. Calcium signaling plays a central role in the regulation of muscle growth and gene expression. We have recently demonstrated that the calcium, calmodulin dependent protein phosphatase calcineurin and calcium, calmodulin-dependent protein kinase (CaMK) couple calcium signals to long-term changes in muscle gene expression. Calcineurin dephosphorylates members of the nuclear factor of activated T cells (NFAT) family of transcription factors, resulting in their translocation to the nucleus where they associate with other transcription factors to activate specific programs of gene expression. In addition, both calcineurin and CaMK activate stimulate the activity of MEF2 transcription factor, which controls numerous muscle-specific and stress-responsive genes. We have shown that CaMK activates MEF2 by relieving the repression imposed by class ll histone deacetylases (HDACs). In the absence of CaMK signaling, class ll HDACs interact with MEF2 and repress MEF2 target genes. Activation of CaMK by agonists or muscle activity, induces the phosphorylation of two conserved sites in class ll HDACs, resulting in their dissociation from MEF2 and export from the nucleus to the cytoplasm, with concomitant activation of MEF2 target genes. HDAC mutants lacking CaMK phosphorylation sites associate irreversibly with MEF2 and permanently silence MEF2-dependent genes. The long-term goal of this project is to understand how calcium signals are relayed to MEF2 and NFAT via calcineurin and CaMK and to develop strategies for modifying cardiac and skeletal muscle gene expression by manipulating these signal transduction pathways.
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