Cellular and molecular mechanisms of cardiac muscle contraction in health and disease
The major area of research in my lab is understanding the molecular mechanisms that govern the regulation of contractile function in the cardiac sarcomere. In particular, we are focused on unraveling the functional roles of contractile proteins in the modulation of force generation and cross-bridge kinetics in cardiac muscle. We study the functional effects of post-translational modifications of contractile proteins at the level of the myofilaments and in vivo whole organ function, and how genetic defects in these proteins lead to altered cross-bridge function and the development of impaired contractile function in vivo and ultimately dilated and hypertrophic cardiomyopathies. We employ a variety of molecular and biophysical techniques to study cross-bridge function and cardiac muscle mechanics. We utilize knockout and transgenic animal models as well as in vivo gene transfer techniques to study the functional roles of contractile proteins on in vivo cardiac function using echocardiography, pressure-volume catheterization, and magnetic resonance imaging.
Schematic of the cardiac sarcomere
The cardiac sarcomere is composed of a network of contractile and structural proteins that regulate cardiac muscle function. The force and speed of cardiac muscle contraction is a major determinant of in vivo organ function and is modulated by the cyclical interactions of actin and myosin. Regulation of actin and myosin binding is determined by a network of myofilament regulatory proteins and the level of intracellular Ca2+. The troponin complex and tropomyosin are thin filament proteins which govern the availability of actin binding sites, and the essential and regulatory light chains, and myosin binding protein C modulate the position and mechanical properties of myosin.
- Chen Y, A Somji, X Yu & JE Stelzer.Altered in vivo left ventricular torsion and principal strains in hypothyroid rats. Am. J. Physiol. Heart Circ. Physiol. 299:H1577-87, 2010.
- Desjardins CL, Y Chen, AT Coulton, BD Hoit, X Yu & JE Stelzer.Cardiac myosin binding protein C insufficiency leads to early onset of mechanical dysfunction. Circ Cardiovasc Imaging 5:127-36, 2012.
- Coulton AT & JE Stelzer.Cardiac myosin binding protein C and its phosphorylation regulate multiple steps in the cross-bridge cycle of muscle contraction. Biochemistry 51:3292-301, 2012.
- Merkulov S, X Chen, MP Chandler & JE Stelzer.In vivo cardiac myosin binding protein C gene transfer rescues myofilament contractile dysfunction in cardiac myosin binding protein C null mice. Circ Heart Fail 5:635-44, 2012.
- Cheng Y, Wan X, McElfresh TA, Chen X, Gresham KS, Rosenbaum DS, Chandler MP & Stelzer JE. Impaired contractile function due to decreased cardiac myosin binding protein C content in the sarcomere. Am J Physiol Heart Circ Physiol. 305:H52-H65, 2013.