This project's long-term goal is to elucidate the cellular and molecular mechanism(s) responsible for the decline in skeletal muscle performance with aging. This project will test two interconnected hypotheses: (1) Age-related decrease in IGF-1 results in DHPR beta1a upregulation, which contributes to DHPR alpha-1 subunit downregulation, decrease in intracellular Ca2+ release, and loss in specific force in fast- and slow- twitch skeletal muscle fibers, and (2) sustained expression of the DHPR prevents ECU in aging skeletal muscle. These hypotheses will be tested using the following specific aims: 1) SR Ca2+ release, measured in the cytosol, is impaired in aging skeletal muscle. One of the pillars of the proposed ECU hypothesis is the decreased SR Ca2+ release in aging skeletal muscle, but only indirect evidence has been gathered to date. New developments allow us to measure the SR Ca2+ release process across ages directly, in the cytosol, in a model-independent manner. 2) Impaired SR Ca2+ release could be associated with changes in SR Ca2+ content or release kinetics. Also fundamental to the ECU hypothesis is the premise that SR Ca2+ release is impaired in aging muscle fibers as a consequence of an increase in uncoupled RyR1 and not a decrease in lumenal Ca2+ available for release. The development of engineered chameleon dyes targeted exclusively to the SR will allow us to measure SR Ca2+ content and the kinetics of SR Ca2+ release in muscle fibers from mice of different ages. 3) Sustained expression of DHPRa1s prevents excitation-contraction uncoupling in aging muscle. We have postulated that increased """"""""orphan"""""""" RyR1 in muscle fibers from aging mice results from downregulation of DHPRa1 subunit expression. Recent progress in in vivo protein expression allows us to test this concept directly by expressing the DHPRa1 subunit in fast- and slow-twitch muscles of different ages and examining its impact on charge movement, a1 subunit expression in subcellular domains, SR Ca2+ release, and single intact muscle fiber force. 4) Age-dependent DHPR ?1a overexpression leads to DHPRa1s subunit downregulation. These experiments aim to demonstrate that IGF-1's decreased influence on muscle with aging leads to increased DHPR ?1a gene transcription. Elevated ?1a subunit in senescent mice alters ?1a-a1 subunit stoichiometry, which leads to DHPRa1 subunit downregulation by activating proteasome-mediated degradation.
A better understanding of the decline in skeletal muscle molecular structure and function will allow more rationale interventions aimed at improving physical performance and independence in the elderly.
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