Normal heart function is dependent on the Frank-Starling mechanism of matching stroke volume to venous return to adjust cardiac output with changes in metabolic demand. This mechanism is often diminished in cardiac disease. Our studies have lead us to believe that the steep sarcomere length-dependence of Ca2+ activated force in cardiac muscle (the cellular basis of the Frank-Starling mechanism) results from the properties of cardiac thin filaments and interaction with myosin cross-bridges. These are determined by 1) the isoform specific properties of thin filament regulatory proteins, 2) the unique dependence of Ca2+ binding to cardiac thin filaments in force generation and 3) the effects of length-dependent changes in cross-bridge proximity in thin filament activation. Physiologically, cardiac force sensitivity to [Ca2+] is regulated by altered phosphorylation of contractile proteins, including TF regulatory subunits, myosin regulatory light chains, myosin-binding protein-C and titin. The protein phosphorylation profile of the heart changes during cardiac disease. It was recently demonstrated that depressed force generating capacity in failing hearts was enhanced by interventions that selectively increased cross-bridge access to cardiac thin filaments by stimulating phosphorylation of selected cardiac proteins. In this study we will determine the effect that phosphorylation of specific proteins has on cardiac contractility, in isolation from other potential sites of phosphorylation. We will also determine how phosphorylation effects are altered by FHC mutations of cTnI and how they influence stretch activation of cardiac muscle. Better understanding the molecular mechanism of the sarcomere length dependence of contraction should lead to targeted therapeutics to treat heart disease and failure. Force generation by the heart is modified by adding or removing phosphate groups from contractile proteins during both normal and diseased physiological states. Detailed knowledge of the interactions between the molecular components of the heart's contractile mechanism to be obtained in this study are key to designing ways to compensate for heart failure following an ischemic heart attack, prolonged cardiac failure or genetic disease.
NIH ExPorter
NIH ExPorter