NEURAL TRANSGENIC OVEREXPRESSION OF IGF-1 AND SARCOPENIA

Wake Forest University Health Sciences, Winston-Salem NC

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Abstract

DESCRIPTION (provided by applicant): This pilot project will investigate neural control of sarcopenia. Results from these studies will provide the foundation for a full research proposal (R01) application. The long-term goal of this study is to elucidate the cellular and molecular mechanism(s) that are responsible for the decline in skeletal muscle performance with age. Age-related decreases in skeletal muscle mass, strength, and quality (contractile properties, fiber type, composition, etc.) are termed sarcopenia. This composite condition contributes to physical disability and loss of independence. In addition to muscle atrophy, a decline in muscle contractile force with age has been reported in several mammalian species, including humans. Despite the importance of muscle strength in preventing disability, the biological mechanisms responsible for these phenomena are poorly understood. This pilot project is designed to investigate the role of neural influence on age-related excitation--contraction uncoupling and alterations in muscle fiber type composition. The results of this study will provide the basis for a larger project, which will focus on counteracting the neural-dependent structural and functional decline that occurs in skeletal muscle in conjunction with the aging process. We hypothesize that transgenic neural overexpression of IGF-1 prevents excitation-contraction uncoupling and loss in type IIB fibers, consequently decreasing age-related skeletal muscle force. This hypothesis will be assessed using the following specific aims: 1. To test whether IGF-1 expression in the spinal cord prevents loss of type IIB fibers in muscles from aging C57BL/6 mice. Muscle fiber denervation will be studied using a technique developed in our laboratory to identify a newly expressed tetrodotoxin-resistant Na* channel population in denervated whole muscle and in single fibers. Fiber type composition will be measured using monoclonal antibodies against myosin heavy chain isoforms in transgenic and wild type young and old mice. 2. To test whether overexpression of IGF-1 in spinal cord prevents excitation-contraction-uncoupling in single intact muscle fibers from aging mice. The decline in specific force is associated with decreases in peak intracellular calcium concentration in single intact fast- and slow-twitch muscle fibers. Age-related decreases in intracellular calcium influx have been demonstrated in single-contracting and patchclamped muscle fibers. In this project, we will examine whether this process is under neural control and whether the expression of hIGF-1 in spinal cord neurons restores excitation-contraction coupling.