MECHANISMS OF MUSCLE AGING--ANALYSIS AND INTERVENTION

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The goals of this unit are to establish the fate of muscle fiber types marked at different stages of muscle development and senescence, and to modulate fiber type by selective precursor cell ablation. Fiber type if an essential determinant of muscle function, and changes in fiber composition represent a major component in the muscle degeneration associated both with aging and with neuromuscular diseases. The physiological ramifications of fiber composition have been extensively studied in numerous systems, and fiber specific genes have been identified. Nevertheless, the fate of individual fiber types, both in the developing embryo and in senescent or degenerating muscle, remains.obscure. We propose to exploit several newly developed technologies to address these questions. We will use a novel transgenic approach using an avian retrovirus-based cell marking strategy to perform lineage analysis on fiber precursors in transgenic mouse muscle. We will modify the cre/lox binary transgenic system to permanently mark different fiber types in senescent muscle, so that their fate can be followed throughout the life span of the animal. Finally, we will assess the effect of perturbing muscle fiber composition by selective ablation of different fiber types, using virally delivered recombinase to activate marker or toxin genes in transgenic mouse muscles. These experiments will clarify important unresolved issues in skeletal muscle function; namely, the identity and fate of fibers involved in age-related atrophy.