Impairment of Intrinsic Muscle Excitability in Aging

衰老过程中内在肌肉兴奋性的损害

• 批准号: 10300291
• 负责人: Roger Alan Bannister
• 金额: $ 14.05万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2022-03-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300291
• 关键词: Action Potentials; Affect; Aging; American; Applications Grants; Attenuated; Biological Markers; Biology; Biology of Aging; Caloric Restriction; Collaborations; Data; Development; Dietary Intervention; Electrodes; Electromyography; Electrophysiology (science); Energy Intake; Event; Family; Family health status; Fiber; Foundations; Functional disorder; Generations; Goals; Health; Healthcare Systems; Hip Fractures; Hospitalization; Human; Immunoblotting; Impairment; Independent Scientist Award; Individual; Inflammation; Injury; Intervention; Investigation; Knowledge; Life; Life Expectancy; Link; Mental Depression; Methods; Modeling; Molecular; Mus; Muscle; Muscle Fibers; Muscle Mitochondria; Muscle Weakness; Muscular Atrophy; Nature; Optics; Performance; Performance at work; Population; Predisposition; Process; Property; Protein Isoforms; Public Health; Quality of life; Research; Research Proposals; Rodent; Sarcolemma; Scientist; Skeletal Muscle; Speed; Stress; Techniques; Testing; Time; Training; Tubular formation; United States; age related; age-related muscle weakness; aged; career development; falls; flexor digitorum brevis; frailty; insight; mouse model; muscle aging; neuromuscular; novel; patch clamp; preservation; prevent; programs; proteostasis; virtual; voltage; voltage clamp

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.

项目总结/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--限制了机动性， 老年人容易受伤。权力的下降不仅影响个人的生活质量， 也给家庭和医疗保健系统带来额外的压力。因此，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至关重要， 在以后的生活中保持健康。肌电图显示，肌肉传导速度在老年肌肉中降低， 增加了单个肌纤维中AP传导速度较慢导致功率下降的可能性。 由于电压门控Na+通道是动作电位起始的主要分子组成部分， 在单个肌肉纤维中传播，这些通道作为目标存在，以帮助保持兴奋性和动力。 事实上，早期的研究已经提出了肌膜/横管Na+通道的变化可能与肌膜/横管Na+通道的变化有关。 表达和/或门控特性是衰老肌肉中动作电位传导速度减慢的基础，但 这些结果的解释已经被传统实验的固有局限性所混淆。 接近。在特定目标1中，双电极电压钳电生理学和非侵入性，交替- 场光学动作电位记录将用于检验改变Na+通道门控的假设， 和/或表达是早期年龄依赖性的肌电电位传导速度减慢的基础。在 这样做，申请人将获得两个强大的，国家的最先进的技术，以前没有专业知识 用于研究衰老对肌肉兴奋性的影响。Na+通道门控和/或 将在标准C57 BL/6和加速DBA 2/J老化小鼠模型中追踪表达。具体 目标2将检验热量限制这一假设，热量限制是一种减弱神经肌肉衰退的干预措施， 减缓C57 BL/6和DBA 2/J肌肉中动作电位传导速度的年龄依赖性损伤 通过延迟Na+通道表达/功能的变化。两种细胞中Na+通道亚型表达的改变 C7 BL/6和DBA 2/J肌肉将采用免疫印迹法进行确认。所述工作的执行情况 因此，具体目标1和2将通过介绍以下内容拓宽申请人的衰老生物学知识： 新的衰老模型和热量限制干预纳入他的研究计划。K 02奖将促进 申请人的发展作为一个老化的生物学家通过提供保护的时间：1）奠定了基础， 具有竞争力的NIA R 01级拨款提案，2）与成熟的老龄化科学家建立新的合作关系（无论是在 校园和NIA-Bayview），以及3）参加专注于衰老/肌肉生物学和负责任的 进行研究。