The long-term goal of this study is to elucidate the cellular and molecular mechanism(s) responsible for the decline in skeletal muscle performance with age. In this project we propose a novel mechanism by which changes in EC coupling, from skeletal to cardiac type, result in the reported decline in specific force in skeletal muscles from senescent mice. This project will test the hypothesis that the expression of DHPR alpha1c subunit in aging muscle results in changes from skeletal- to a combination of skeletal- and cardiac- excitation-contraction coupling in both fast- and slow-twitch muscle fibers. This leads to a greater dependence of muscle contraction on Ca 2+-induced Ca 2+ release, decrease in sarcoplasmic reticulum Ca 2+ release associated with fewer and dysfunctional RyR1, and subsequent decrease in fiber specific force. We also propose that sustained transgenic overexpression of IGF-1 in skeletal muscle prevents age-dependent switching in skeletal to cardiac EC type in muscles from senescent mice. This hypothesis will be assessed using the following specific aims: 1) To demonstrate that the functional expression of DHPR alpha1c subunit in voltage-clamped single fast- and slow-twitch muscle fibers from senescent wild-type (24 months) - compared to young-adult (7 months) and middle-aged (14) C57BL/6 mice or FVB can be prevented by sustained overexpression of IGF- 1 (S1S2 mice)in skeletal muscle. 2) To establish that Ca 2+ influx through the DHPR alpha1c contributes to sarcoplasmic reticulum Ca 2+ release through a Ca2+-induced Ca 2+ release mechanism in fast- and slow-twitch muscle fibers from senescent but not from young-adult and middle-aged mice or age-matched IGF-1 transgenic mice. 3) To determine that the decline in single fast- and slow-twitch muscle fiber specific force in senescent mice is associated with an increased sensitivity to extracellular Ca 2+ in contrast to the absence of influence on muscle fibers from young-adult and middle-aged mice, and that this phenomenon is prevented by sustained overexpression of IGF-1 in muscle. 4) To demonstrate the increase in DHPR alpha1lc subunit gene expression in fast- and slow-twitch muscles from wild type but not IGF-1 transgenic senescent mice.
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