Current Research:
We are interested in understanding how muscle contraction is regulated by the multimeric troponin complex in striated muscle. Troponin is located within the thin filament and it is known to be critical for regulating Ca2+-activated contraction in striated muscle. An important focus of current research efforts in this area of muscle biology is to better understand how molecular interactions among troponin subunits act to regulate muscle contraction. The inhibitory troponin subunit, troponin I (TnI), plays a critical role in this process by inhibiting tension development until Ca2+ binds to regulatory sites on the Ca2+ binding subunit, troponin C. Recent advances in molecular biology have allowed us to further define the role of TnI in Ca2+-activated contraction in the intact myofilament of adult cardiac myocytes. Using viral-mediated gene transfer into adult cardiac myocytes, we have examined the effects of two different TnI isoforms on tension development and found that different isoforms of TnI strongly influence myofilament Ca2+sensitivity and pH sensitivity. More recently, the domains within TnI which influence these myofilament functions have been investigated by making chimeras of the two isoforms. This approach has the potential to provide a better understanding of functional TnI domains and the important interactions among thin filament proteins that are necessary for the regulation of muscle contraction. Ultimately, the knowledge gained from these studies may lead to an improved understanding of pathophysiological conditions in the heart and to better treatment of these conditions.
Representative publications:
Braz JC, Gregory K, Pathak, A Zhao, W Sahin B Klevitsky R, Kimball TF, Lorenz JN, Nairn AC, Liggett SB, Bodi I, Wang S, Schwartz A, Lakatta EG, DePaoli-Roach AA, Robbins J, Hewett TE, Bibb JA, Westfall MV, Kranias EG, Molkentin JD. "PKC-Alpha Regulates Cardiac Contractility and Propensity Toward Heart Failure." Nat. Med, 10:248-254, 2004.
Metzger, JM and MV Westfall. Covalent and non-covalent modification of thin filament action: the essential role of troponin in cardiac muscle regulation. Circ. Res. 94:146-158, 2004.
MV Westfall, Borton, AR. "Role of Troponin I Phosphorylation in Protein Kinase C-Mediated Enhanced Contractile Performance of Rat Myocytes." J. Biol. Chem, 278:33694-33700, 2003.
Westfall, M.V., Albayya, F.P., and Metzger, J.M. "Functional Analysis of Troponin I Regulatory Domains in the Intact Myofilament of Adult Single Cardiac Myocytes." J Biol Chem, 274: 22508-22516, 1999.
Westfall, M.V., Rust, E.M., Albayya, F., and Metzger, J.M. "Adenovirus-Mediated Myofilament Gene Transfer into Adult Cardiac Myocytes." Methods Cell Biol, 52: 307-322, 1998.
Westfall, M.V., Rust, E.M., and Metzger, J.M. "Slow Skeletal Troponin I Gene Transfer, Expression and Myofilament Incorporation Enhances Adult Cardiac Myocyte Contractile Function." Proc. Natl. Acad. Sci, 94:5444-5449, 1997.
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