Historically, much of what has been learned about skeletal muscle contraction has been extrapolated to the study of contraction in heart muscle; however, there is evidence (e.g. reviews by Julian and Moss, Circ. Res., 38:53; Jewell, Circ. Res. 40:221, 1977) clearly suggesting that these extrapolations are not always valid. The objective of the proposed research is to obtain detailed information regarding the mechanism of contraction in heart muscle, and also to obtain insights as to the ways in which this mechanism may differ from that in skeletal muscle. The mechanical properties of these muscles will be determined in order to obtain measures of the extent of interaction and the kinetics of interaction between the primary contractile proteins, actin and myosin. Specifically, the parameters of muscle tension, velocity of shortening, and stiffness, as well as the tension transients in response to abrupt length changes, will be measured in preparations from which the surface membranes have been effectively removed by either chemical treatments or mechanical means. Each of these mechanical parameters will be measured in controlled solutions containing partially or fully activating levels of calcium; varying amounts of free magnesium, a substance required for muscle contraction and which also appears to influence the activation of muscle contraction by calcium; and varied levels of MgATP, which is the energy substrate for contraction. Careful attention will be given in each of these measurements to the control of the average length of the sarcomere, the basic functional unit of muscle, to prevent distortion of the experimental results. Additional experiments will be done in which the protein subunit compositions of the contractile protein myosin, particularly the myosin light chains, and the requlatory protein troponin in these muscle preparations will be experimentally altered in order to determine their possible roles in the regulation of the kinetics and extent of interaction of myosin cross-bridges with the actin-containing thin filaments. The information obtained in the proposed experiments should provide important clues regarding the mechanism of interaction of actin and myosin in heart and other striated muscles. In that this study will further the characterization of normal muscle, the information obtained should suggest possible mechanisms of altered function in diseased muscle.
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