Calcium-dependent gene regulation in myocyte hypertrophy and remodeling.

Abstract

Striated myocytes from skeletal and cardiac muscle tissues are excitable cells that utilize calcium to trigger actomyosin cross-bridge formation in the generation ofcontractile force. Myocytes respond to different temporalpatterns of activation and changing workloads by alteringprograms of gene expression that adjust cellular mass, kinetic properties of contractile proteins, and metabolic capacity to match muscle phenotypes to different physiological demands. In disease states, modulation of geneexpression in myocytes as a function of contractile workload may have maladaptive consequences. We have considered the general hypothesis that changes in intracellular calcium resulting from different patterns of contractileactivity not only serve to drive muscle contractions, butalso provide a primary stimulus to activity-dependentchanges in gene expression and muscle phenotype. Accordingly, we have investigated the role of calcium-regulated signaling molecules in controlling transcription ofgenes that are subject to activity-dependent regulation.Using cultured myocytes and transgenic mouse models,we have defined features of signaling cascades that modulate transcription of specific contractile protein isoforms, mitochondrial biogenesis, and myocyte mass.These pathways involve calmodulin-dependent proteinkinases, the calcium-calmodulin-regulated protein phosphatase calcineurin, transcription factors of the MEF-2,NF-AT, and PGC-1 families, and proteins of the MCIP(DSCR1) gene family. Calcium released from discrete intracellular and extracellular pools exerts different effectson the kinetics of activation of specific transcription factors in striated myocytes. These results are reviewed andpresented in the context of a conceptual model for activity-dependent gene regulation in myocytes...