EXCITATION CONTRACTION COUPLING IN AGING MUSCLE

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The long term goal of this study is to elucidate the mechanism(s) responsible for the decline in skeletal muscle performance with age and their reversion or retardation with non-pharmacological interventions. Age-related decreases in skeletal muscle mass, strength and quality are termed sarcopenia and may contribute to physical disability and loss of independence. In addition to decreased mass, decreases in muscle contractile force has been reported. Despite the importance of muscle mass and strength in preventing disability, the biological mechanisms responsible for these phenomena are poorly understood. The purpose of this proposal is to determine mechanisms responsible for the decline in skeletal muscle contractility with aging. The hypothesis includes (a) mechanistic and (b) intervention studies. (a) Mechanistic studies. A decrease in dihydropyridine receptors at the tubular sarcolemma in aged skeletal muscle results in a reduced supply of calcium to contractile proteins. The functional consequence of these intracellular changes is a decrease in contractile force. (b) Intervention studies. These alterations can be significantly reversed and delayed by long-term dietary caloric restriction. This hypothesis will be explored using the following specific aims: 1) To determine the amount of DHPR expression in isolated fast-twitch extensor digitorum longus muscle fiber from young (7 months), middle age (14), and old (28) Fisher 344 Brown Norway F1 Hybrids rats (F1 Hybrids rats (F344BNF1/NIA). 2) To assess whether reductions in the sarcoplasmic reticulum calcium release is a result of significant number of calcium release channels (RYRs) uncoupled to DHPRs in older animals. 3) To correlate decline in skeletal muscle contraction properties with alterations in intracellular calcium concentrations. 4) To establish whether alterations in sarcolemmal excitation-contraction coupling associated with aging can be significantly reversed and/or delayed by dietary caloric restriction. The current proposal is a novel characterization of the basic mechanisms underlying skeletal muscle impairment with age, which previously have not been addressed.