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)：这项提案旨在建立北卡罗来纳州维克森林大学健康科学的Pi 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，专注于衰老的骨骼肌。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。FIRCA项目通过探索(1)二氢吡啶受体(DHPR)11亚基和21a亚基相互作用的替代途径，以及(2)21上调是否导致11a随年龄下降而导致11a下调，从而扩展和丰富了父母赠款。具体地说，我们的目标是确定持续表达DHPR11S或阻止21a内源性过度表达是否可以改善电压门控SR钙离子释放，从而改善衰老骨骼肌的比力。我们将研究那些在父母资助中研究的替代机制，并使用创新的分子工具，不仅对这个项目，而且对骨骼肌生理学和病理学领域都是如此。FIRCA提案的具体目的是：目的1.确定持续的DHPR 21a过表达是否通过与参与受体介导的内吞作用的GTP酶Dynamin结合而导致DHPR11亚单位的表达减少。这个系统是否在骨骼肌中起作用，尤其是21a亚基内源性过度表达和11亚基下调的衰老肌肉，目前尚不清楚。过度表达病毒介导的21a亚单位将回答21a是否导致幼鼠肌肉和发育不良和2-缺失的肌肉细胞中DHPR11亚单位下调。我们还将确定DHPR11亚单位的长期、均匀表达是否能阻止21a介导的衰老小鼠的内吞作用。目的2.确定肌肉IGF-1的过表达是否能阻止衰老骨骼肌中21a的过度表达，从而阻止21a依赖的11个亚单位的下调和兴奋-收缩解偶联(ECU)。这些实验将验证IGF-1在DHPR 21a亚单位表达和ECU随年龄增长中发挥主要作用的假设。针对骨骼肌的转基因和IGF-1病毒载体的使用将使我们能够研究IGF-1和11/21a表达之间的关系。 公共卫生相关性：据报道，在包括人类在内的几种哺乳动物中，与年龄相关的绝对和特定肌肉收缩力量下降。发展中国家阿根廷2005年的全国人口普查显示，65岁或以上的人口占总人口的10.1%，与美国的12.1%相似。这两个国家的老年中心的激增证明，越来越多的老年人面临失去或失去独立的风险，他们越来越有必要支持他们。尽管肌肉力量在预防老年人残疾方面很重要，但人们对其生物机制只有部分了解。FIRCA的这项提案旨在建立北卡罗来纳州维克森林大学健康科学的Pi 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，以阐明导致骨骼肌性能随年龄下降的细胞和分子机制。