A decline in both strength and function in skeletal muscle, plus a restriction of its adaptability is a hallmark of aging in mammals. However, the molecular basis of this muscle senescence is not clear. The loss in muscle mass and a decrease in strength and force output during senescence is accompanied by a selective reduction in muscle fiber size, shifts in fiber composition, and changes in several physiological parameters. The paucity of information concerning muscle aging, as opposed to myogenic development, is due to a lack of data concerning the regulation of muscle fiber types. In addition, only ineffective in vivo systems are available to test gene programs which may affect muscle senescence and which can be perturbed at different stages of the life cycle. One purpose of this program project is to develop suitable experimental systems for identifying the intrinsic properties of senescent muscle which may cause the observed deficits in performance, and to investigate relevant structural and physiological parameters involved in senescence by perturbing gene expression in aging animals. The investigators will define the genetic pathways underlying age-related changes in skeletal muscle, establish transgenic systems for testing molecular models of muscle senescence, and test interventional strategies to reverse or attenuate the cumulative effects of aging on skeletal muscle performance. The four investigators in the program project have a common interest in muscle biology. Their areas of research include skeletal muscle biochemistry, physiology and molecular biology, as well as retrovirology and transgenic technology. In unit 1, Dr. Rosenthal will study the origin of individual muscle fiber types during myogenic development, and will then track their fate in the aging animal. She will use both viral and transgenic approaches to develop models of muscle senescence by ablating specific muscle fibers. In unit 2, Dr. Sweeney will use transgenic methodology to modulate the mechanical damage in muscle by decreasing the levels of oxygen free radicals, and then assess adaptation to functional deficits in targeted fiber types. In unit 3, Dr. Balice-Gordon will study ways to modify senescent muscle atrophy by viral and transgenic delivering selected growth factors and hormone receptors using viral and transgenic delivery systems. In unit 4, Dr. Hughes will establish the molecular mechanisms by which the ski oncogene produces fiber-specific hypertrophy, and use this as a model for the attenuation of muscle senescence. He will use a novel retroviral delivery system. The project also has core facilities to be shared between the laboratories. A transgenic animal and virus core (Core C), under the guidance of Dr. Hughes, is located at the NCI facility at Frederick, Maryland. This facility will streamline the production and analysis of transgenic animals to allow the rapid testing of the in vivo aging models. A morphology and physiology core (Core B), operated by Drs. Kelly and Sweeney at the UP, will provide the structural and fiber type analysis of muscles, which is an essential component of most of the projects. An administrative core (Core A), located at the MGH under the guidance of Dr. Rosenthal, will use the resources at the Cardiovascular Research Center and the MGH-East Animal Facility to plan and implement routine meetings, conference calls and review sessions necessary to coordinate activities at the three research centers, and will coordinate exchange of animals and reagents between the laboratories.
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