Impairment of Intrinsic Muscle Excitability in Aging

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Project Summary/Abstract As life expectancy increases in the United States, age-related muscle dysfunction becomes a growing public health concern. Declines in muscle power--the speed of muscle force development--limit mobility and increase susceptibility to injury in older people. Power declines not only impact the quality of life of the individual, but also place additional strain on families and the health care system. For this reason, a more profound understanding of the aging process in skeletal muscle is critical for enabling Americans to remain active and healthy later in life. Electromyography has shown that muscle conduction velocity decreases in older muscles, raising the possibility that slower AP conduction velocity in single muscle fibers contributes to power decline. Since voltage-gated Na+ channels are the principal molecular components of action potential initiation and propagation in single muscle fibers, these channels present as targets to help preserve excitability and power. Indeed, earlier studies have raised the possibility that changes in sarcolemmal/transverse-tubular Na+ channel expression and/or gating properties underlie slowed action potential conduction velocity in aging muscle, but the interpretation of these results has been confounded by the inherent limitations of conventional experimental approaches. In Specific Aim 1, two-electrode voltage-clamp electrophysiology and non-invasive, alternating- field optical action potential recordings will be used to test the hypothesis that altered Na+ channel gating and/or expression underlie early age-dependent slowing of muscle actional potential conduction velocity. In doing so, the applicant will gain expertise in two powerful, state-of-the-art techniques which have not previously been used to investigate the impact of aging on muscle excitability. Alterations in Na+ channel gating and/or expression will be tracked in both standard C57BL/6 and accelerated DBA2/J aging mouse models. Specific Aim 2 will test the hypothesis that caloric restriction, an intervention which attenuates neuromuscular decline, slows age-dependent impairment of action potential conduction velocity in both C57BL/6 and DBA2/J muscle by delaying changes in Na+ channel expression/function. Alterations in Na+ channel isoform expression in both C7BL/6 and DBA2/J muscle will be confirmed with immunoblotting. The performance of the work described in Specific Aims 1 and 2 will thus broaden the applicant’s knowledge of aging biology through the introduction of new aging models and the caloric restriction intervention into his research program. An K02 award will promote the applicant’s development as an aging biologist by providing protected time to: 1) set the foundation for a competitive NIA R01-level grant proposal, 2) build new collaborations with established aging scientists (both on campus and at NIA-Bayview), and 3) to attend events focusing on aging/muscle biology and responsible conduct in research.