MOLECULAR PHYSIOLOGY OF RESPIRATORY MUSCLES

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DESCRIPTION (Adapted from the applicant's abstract): Despite recent advances, current knowledge of respiratory muscle development, aging and disease remains incomplete. For example, the molecular and functional properties of muscle stem cells are not worked out, mechanisms of muscle injury and aging are not fully understood, and the role of apoptosis in muscle cell death remains unclear. The proposed experiments are designed to extend knowledge in these key areas of muscle molecular physiology. Under Aims 1 and 2, the investigators will determine whether targeted alterations of cell death pathways can inhibit either the myofiber death that occurs in disease or the muscle phenotype changes that occur during aging. Apoptotic nuclei are found in dystrophic muscles, but the importance of apoptosis in dystrophic myofiber death is unclear. Muscle fibers are also lost by unknown mechanisms during aging. By analyzing dystrophic or aged myofibers that overexpress Bcl-2 or lack Bax, the investigators will determine if inhibition of apoptosis will inhibit dystrophic myofiber death or age-related changes in muscle phenotype. The results could potentially lead to therapies of myofiber death in disease and aging based on alteration of cell death pathways. Under Aims 3 and 4, the investigators will determine if the small subset of Sca-1+ and Bcl-2+ muscle cells have the properties of muscle stem cells and how Bcl-2 may function to regulate apoptosis and cell cycle progression in muscle cells. Sca-1 and Bcl-2 are expressed by a limited subset of mononuclear muscle cells, and these cells are at an early stage of myogenesis. The investigators will purify Sca-2+ cells (with anti-Sca-1 immunobeads) and Bcl-2+ cells that have been modified to express selectable markers (with immunobeads or FACS) and they will determine how the functions of these rare early myogenic cells differ from the functions of the more numerous myoblasts that are at a later stage of myogenesis. The identification and characterization of muscle stem cells is central to increasing the understanding of myogenesis.