Impairment of Intrinsic Muscle Excitability in Aging

项目摘要/摘要 随着美国人预期寿命的增加，与年龄相关的肌肉功能障碍成为越来越多的公众 健康问题。肌肉力量的下降--肌肉力量发展的速度--限制了活动和增加 老年人对伤害的易感性。权力的衰退不仅会影响个人的生活质量，而且 这也给家庭和医疗保健系统带来了额外的压力。出于这个原因，一个更深刻的 了解骨骼肌的衰老过程对于使美国人保持活力和 晚年身体健康。肌电图示老年肌肉的肌肉传导速度减慢， 增加了单个肌纤维AP传导速度较慢导致功率下降的可能性。 由于电压门控钠离子通道是动作电位起始和 在单个肌肉纤维中传播，这些通道作为靶点存在，以帮助保持兴奋性和能量。 事实上，早期的研究已经提出了肌膜/横管Na+通道变化的可能性 表达和/或门控特性导致衰老肌肉的动作电位传导速度减慢，但 这些结果的解释被传统实验的固有局限性所混淆。 接近了。在具体目标1中，双电极电压钳电生理和无创、交流. 现场光学动作电位记录将被用来检验改变Na+通道门控的假设 和/或表达是早期肌肉动作电位传导速度随年龄增长减慢的基础。在……里面 这样做，申请者将获得两项强大的、最先进的技术方面的专业知识，这是以前没有的 用于研究衰老对肌肉兴奋性的影响。钠离子通道门控和/或改变 将跟踪在标准C57BL/6和加速DBA2/J衰老小鼠模型中的表达。特定的 目标2将检验这样一个假设，即卡路里限制，一种减缓神经肌肉衰退的干预措施， 延缓C57BL/6和DBA2/J肌肉动作电位传导速度的增龄性损害 通过延缓Na+通道表达/功能的改变。两者Na+通道异构体表达的变化 C7BL/6和DBA2/J肌肉将通过免疫印迹进行确认。中所述工作的执行情况 因此，具体目标1和2将通过以下方式拓宽申请人对衰老生物学的认识 新的衰老模型和卡路里限制干预了他的研究计划。K02奖将促进 申请人作为老年生物学家的发展，通过提供受保护的时间来：1)为 竞争性的NIA R01级别拨款建议，2)与成熟的老年科学家建立新的合作伙伴关系(两者都在 校园和NIA-Bay view)，以及3)参加关注衰老/肌肉生物学和负责任的活动 研究中的行为。

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.