Age-related decreases in skeletal muscle mass, strength and quality (contractile properties, fiber type composition, etc.), are termed sarcopenia and may contribute to physical disability and loss of independence. The long term goal of this study is to elucidate molecular and cellular mechanism(s) underlying sarcopenia. Despite the importance of muscle mass and strength in preventing disability, the biological mechanisms responsible for these phenomena are poorly understood. Although a large volume of literature demonstrates that muscle strength declines with aging, a central issue remains unresolved. Does muscle atrophy alone account for the decreased contractile force with age?. We have proposed that alterations in intracellular calcium activation are an important component of the differences in muscle strength between adult and aged muscles. Currently, there is only limited information available on the regulation of intracellular calcium levels in skeletal muscle of aged animals. The purpose of this proposal is to determine mechanisms responsible for the decline in skeletal muscle contractility with aging. The molecule that transduces sarcolemma voltage into changes in myoplasmic calcium concentrations is the dihydropyridine receptor (DHPR). As a result of mechanical coupling of dihydropyridine receptors to calcium release channels (ryanodine receptors, RYRs), intracellular calcium levels increase stimulating muscle contraction. The working hypothesis of this proposal is that an increase in DHPR- unlinked RYR1 accounts for a fraction of the decline in skeletal muscle force with aging. DHPR-RYR1 uncoupling at the T tubule-sarcoplasmic reticulum triadic junction results in an absolute reduction in sarcoplasmic reticulum calcium release in response to sarcolemmal depolarization and consequently in a reduced contraction strength in aged skeletal muscle.
The specific aims are: 1) To determine whether the decline in single skeletal muscle contractility is associated with alterations in sarcoplasmic reticulum calcium release in single fast- twitch extensor digitorum longus (EDL) muscle fibers from young (8 months), middle age (18), and old (28) Fisher 344 Brown Norway F1 Hybrid rats (F344BNF1/Nia). 2) To assess whether reductions in the sarcoplasmic reticulum calcium release with age result from an increased number of DHPR-unlinked RYR1. 3) To determine the number of DHPR and RYR1 expression in EDL T-tubule and sarcoplasmic reticulum membranes and the receptors affinity constants for high-affinity ligands in the three age groups. 4) To define whether changes in DHPR and/or RYR1 expression results from DNA transcription/translation alterations.
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