Michael Regnier, Associate Professor & Vice Chair Thrust Area Education |
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Research Interests Contact Information Research Description The rate at which muscles can produce force or shorten is an important factor in the control of movement. These parameters are also important in cardiac contractions where they control the amount and rate of blood pumped by the heart. At the cellular level the rates of muscle force development and shortening are determined by interactions of the proteins actin and myosin, and these interactions are fueled by the hydrolysis of ATP. This thermodynamic process of chemical energy conversion into mechanical work (chemo-mechanical transduction) is controlled by calcium binding to a group of regulatory proteins associated with actin. The mechanisms by which these proteins regulate muscle force and shortening are still poorly understood, however, due to the complex and cooperative interactions that occur during contractions. There is increasing evidence of significant differences between cardiac and skeletal muscle contractile regulation, which likely results from different isoforms of thick and thin filament proteins. Pathologies such as diabetes, hypertrophic cardiomyopathy, hypothyroidism and heart failure, as well as ischemia/reperfusion injury, involve alterations in the contractile and regulatory proteins of myocardium. Changes in protein isoforms resulting from disease or mutation often impair cardiac function during normal activation of the heart or during strenuous activity. A long-term objective of our research is to understand the detailed mechanisms of Ca2+ mediated thin filament (TF) activation and regulation of contraction in striated muscle to provide information in designing effective preventions and therapies to cardiac myopathies. To study these questions we have developed a variety of molecular and cellular techniques. Caged compounds, pharmaceutical agents and mechanical transients are used to study actin-myosin interactions, the calcium binding dynamics of the regulatory proteins and the kinetic relationships between these two processes. We also extract native regulatory proteins from muscle and replace them with regulatory proteins modified by site-directed mutagenesis to determine how protein structure modifies contractile activation and kinetics. Site-directed mutants mimicking those found in cardiomyopathies are used as models for functional deficits with disease. Labeling these proteins with fluorescent tags can give a detailed picture of the relationship between protein structure and function. Mechanical measurements are made from single, isolated cardiac and skeletal muscle cells. An exciting and correlative approach we employ is to make mechanical measurements from isolated contractile and regulatory proteins using sophisticated equipment that allows characterization of force and speed at the nano– and micro-scale. The information gathered from these experiments is used to develop mathematical models of the relationship between protein structures, chemo-mechanical transduction and the regulation of contraction by calcium. This research is important for devising strategies to improve cardiac and muscle performance and to design therapeutic approaches for people with cardiac and neuromuscular diseases. Teaching Activities
Honors and Awards
Selected Publications
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