The Role of Intermediate Filaments in Skeletal Muscle Injury and Disease

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DESCRIPTION (provided by applicant): Skeletal muscle strains, particularly from lengthening ("eccentric") contractions, account for a majority of all sports-related injuries and are characterized by an immediate loss of the ability to produce force. Structural damage alone does not account for the amount of impairment, and there is still not a clear understanding of underlying mechanisms involved and to what extent they can be affected by therapeutic interventions. Damage to the sarcolemma and associated cytoskeletal proteins, including structural proteins of the sarcolemma and intermediate filaments (IPs), is involved, however. The significance of cytoskeletal proteins to the health of skeletal muscle is underscored by the fact that genetic defects in one or more of these proteins cause muscular dystrophies or myopathies in humans. The purpose of the proposed research is to examine the role that IPs cytokeratin 19 (K19) play in skeletal muscle. Experiments are proposed to determine how their absence in muscle affects sarcolemmal organization, membrane stability, sarcolemmal and sarcoplasmic reticulum calcium flux, and contractile function. The proposed research will use an animal model to test the general hypothesis that these IPs play an integral part in the organization of the cytoskeleton, normal calcium homeostasis, and ultimately, muscle function and resistance to injury. The hypothesis will be tested using functional, morphological, and biochemical methods, with both intact muscles and isolated single myofibers. Two specific aims will be addressed: To study the muscle physiology, membrane structure, and susceptibility to injury in animals lacking cytokeratin 19, and To determine whether the reduced specific force and mild myopathy secondary to the persistent absence of IPs is associated with alterations in the myofiber Ca2+ handling. The results from these studies should be helpful in understanding the effects of chronic muscular diseases as well as of acute muscle injuries. They should also elucidate some of the shared cellular and molecular mechanisms of muscle disease and of muscle injury, treatment, and recovery.