ANALYSIS OF CROSS-BRIDGE MECHANICS

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One long range goal in the study of muscle contraction is to explain the physiological responses of muscle fibers in terms of the kinetics and energetics of the actomyosin interaction. The proposed work will approach this goal by measuring the mechanics of contraction of single, permeable, skeletal muscle fibers under a variety of conditions. These data will be used to refine mathematical models of the complex kinetics and energetics of the contractile interaction. The proposed studies are a continuation of an extensive series of experiments carried out over the last 6 years. Previous work has characterized the effect of ligands on the shortening of fast skeletal fibers, and an extension of this approach to slow muscle and to lengthening of both fast and slow fibers will produce new data defining the interaction of MgATP and other ligands with the contractile proteins. Additional correlations linking muscle physiology to the more well known biochemistry of the acto-S1 interaction will be determined by comparing the response of active fibers and the kinetics of the acto-S1 interaction using a series of different nucleotides modified at either the base of ribose ring. Using recently developed methods that allow studies of fibers at higher temperatures, previous studies performed at 10 degree C will also be extended to more to physiological temperatures where preliminary results show that the response of the fibers to alterations in MgATP or pH may be quite different from those found at the lower temperature. Together the data obtained in eh above studies will lead to a more detailed understanding of the energetics of the cross-ridge states involved in substrate binding or in product release. This may in turn lead to more rational therapies for the control of contraction in the treatment of cardiovascular disorders.