Role of Calcium Channels in Aging Skeletal Muscle

钙通道在骨骼肌衰老中的作用

• 批准号: 8207958
• 负责人: Osvaldo Delbono
• 金额: $ 5.56万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207958
• 关键词: Age; Aging; Argentina; Award; Biological; Biology of Aging; Calcium Channel; Censuses; Charge; Collaborations; Country; Cytosol; Developing Countries; Development; Dihydropyridine Receptors; Down-Regulation; Dyes; Dynamin; Elderly; Endocytosis; Engineering; Genetic Transcription; Goals; Growth Factor; Guanosine Triphosphate Phosphohydrolases; Health Sciences; Human; Insulin-Like Growth Factor I; International; Investigation; Kinetics; Lead; Learning; Life; Measures; Mediating; Membrane; Modeling; Molecular; Movement; Mus; Muscle; Muscle Cells; Muscle Fibers; Operating System; Orphan; Parents; Pathology; Pathway interactions; Performance; Physiology; Play; Population; Potassium; Process; Protein Isoforms; Reporting; Research; Risk; Role; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Skeletal Muscle; Techniques; Testing; Time; Transgenic Organisms; United States; Universities; Up-Regulation; Viral; Viral Vector; Work; age related; disability; forest; improved; in vivo; innovation; multicatalytic endopeptidase complex; muscle aging; muscle strength; overexpression; parent grant; prevent; programs; protein expression; public health relevance; receptor mediated endocytosis; research study; senescence; skeletal; tool; voltage

DESCRIPTION (provided by applicant): This proposal aims to establish a collaboration between PI Dr. Osvaldo Delbono at Wake Forest University Health Sciences, NC, and Dr. Claudia Hereqz at the National University of La Plata, Argentina, as an extension of R01AG013934-12 (PI: O. Delbono), which focuses on aging skeletal muscle. This research will be done primarily at the National University of La Plata. This project's long- term goal is to elucidate the cellular and molecular mechanisms responsible for the decline in skeletal muscle performance with aging. This FIRCA project extends and enriches the parent grant by enabling exploration of (1) alternative pathways for dihydropyridine receptor (DHPR)11subunit and 21a subunit interaction and (2) whether 21 upregulation causes 11a downregulation with aging. Specifically, we aim to determine whether sustained expression of DHPR11S or preventing 21a endogenous overexpression improves voltage-gated SR Ca2+ release and, consequently, specific force in aging skeletal muscle. We will investigate alternative mechanisms to those studied in the parent grant and use molecular tools that are innovative, not only for this project, but for the field of skeletal muscle physiology and pathology generally. The specific aims of the FIRCA proposal are: Aim 1. To determine whether sustained DHPR 21a overexpression results in decreased expression of the DHPR11 subunit by association with dynamin, a GTPase involved in receptor- mediated endocytosis. Whether this system operates in skeletal muscle, particularly aging muscle in which the 21a subunit is endogenously over expressed and 11 is down regulated, is not known. Over-expressing the viral-mediated 21a subunit will answer whether 21a leads to downregulation of the DHPR11 subunit in muscles from young mice and dysgenic and 2-null muscle cells. We will also determine whether prolonged, homogeneous expression of the DHPR11 subunit prevents 21a-mediated endocytosis in senescent mice. Aim 2. To determine whether muscle IGF-1 overexpression prevents age-dependent 21a over- expression and, consequently, 21a-dependent 11 subunit downregulation and excitation-contraction uncoupling (ECU) in aging skeletal muscle. These experiments will test the hypothesis that IGF-1 plays a major role in DHPR 21a subunit expression and ECU with aging. The use of transgenic and IGF-1 viral vectors targeted to skeletal muscle will allow us to examine the relationship between IGF-1 and 11/21a expression. PUBLIC HEALTH RELEVANCE: The age-related decline in absolute and specific muscle contractile force has been reported in several mammalian species, including humans. The 2005 national census in Argentina, a developing country, showed that those 65 years or older comprise 10.1% of the population, similar to the 12.1% in the United States. The proliferation of geriatric centers in both countries attests to the increasing need to support the growing population of elders who are at risk of losing or have lost their independence. Despite the importance of muscle strength in preventing disability in the elderly, the biological mechanisms responsible are only partially understood. This FIRCA proposal aims to establish collaboration between PI Dr. Osvaldo Delbono at Wake Forest University Health Sciences, NC, and Dr. Claudia Hereqz at the National University of La Plata, Argentina to elucidate the cellular and molecular mechanisms responsible for the decline in skeletal muscle performance with aging.

描述（由申请人提供）：本提案旨在建立北卡罗来纳州威克森林大学健康科学学院的Osvaldo Delbono博士和阿根廷拉普拉塔国立大学的Claudia Hereqz博士之间的合作，作为R01AG013934-12 （PI: O. Delbono）的延伸，重点研究老化的骨骼肌。这项研究将主要在拉普拉塔国立大学进行。该项目的长期目标是阐明骨骼肌性能随年龄增长而下降的细胞和分子机制。本FIRCA项目通过探索(1)二氢吡啶受体（DHPR）11亚基与21a亚基相互作用的替代途径，以及(2)21的上调是否会导致11a随着年龄的增长而下调，扩展并丰富了亲本资助。具体来说，我们的目的是确定持续表达DHPR11S或防止21a内源性过表达是否能改善电压门控SR Ca2+释放，从而改善老化骨骼肌的比力。我们将研究在母体资助下研究的替代机制，并使用创新的分子工具，不仅用于本项目，而且用于骨骼肌生理学和病理学领域。FIRCA提案的具体目标是：目标1。为了确定持续的DHPR 21a过表达是否通过与动力蛋白（一种参与受体介导的内吞作用的GTPase）相关而导致DHPR11亚基表达降低。该系统是否在骨骼肌中起作用尚不清楚，特别是在21a亚基内源性过表达而11亚基下调的老化肌肉中。过表达病毒介导的21a亚基将回答21a是否会导致年轻小鼠肌肉和发育不良和2-null肌肉细胞中DHPR11亚基的下调。我们还将确定DHPR11亚基的长时间均匀表达是否会阻止衰老小鼠21a介导的内吞作用。目标2。确定肌肉IGF-1过表达是否能阻止年龄依赖性21a过表达，从而阻止衰老骨骼肌中21a依赖性11亚基下调和兴奋-收缩解耦（ECU）。这些实验将验证IGF-1在DHPR 21a亚基表达和ECU与衰老的关系中起主要作用的假设。使用靶向骨骼肌的转基因和IGF-1病毒载体将使我们能够检查IGF-1与11/21a表达之间的关系。