Robert Sanders Williams

The Williams lab seeks to discover fundamental mechanisms of cell regulation pertinent to human health and disease, and to develop technologies that are applicable to clinical medicine. Recent progress has included the characterization of novel proteins and pathways that modulate proliferation and differentiation of myogenic stem cells, hypertrophic growth of the heart, mitochondrial biogenesis and fiber type-specific gene expression in skeletal muscles.

A particularly successful line of recent investigation has focused on calcium-dependent gene regulation in myocyte hypertrophy and remodeling.
Striated myocytes from skeletal and cardiac muscle tissues are excitable cells that utilize calcium to trigger actomyosin cross-bridge formation in the generation of contractile force. Myocytes respond to different temporal patterns of activation and changing workloads by altering programs 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 gene expression 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 contractile activity serve not only to drive muscle contractions, but provide a primary stimulus to activity-dependent changes in gene expression and muscle phenotype. Accordingly, we have investigated the role of calcium-regulated signaling molecules in controlling transcription of genes 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 protein kinases, 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 effects on the kinetics of activation of specific transcription factors in striated myocytes. Our findings support a conceptual model for activity-dependent gene regulation in myocytes.