Role of Calcium Channels in Aging Skeletal Muscle

钙通道在骨骼肌衰老中的作用

基本信息

批准号：
7764524
负责人：
Osvaldo Delbono
金额：
$ 6.27万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7764524
关键词：
Age Aging Applications Grants 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 Ryanodine Receptors 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

项目摘要

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）：该提案旨在北卡罗来纳州维克森林大学健康科学学院的 PI 博士 Osvaldo Delbono 和阿根廷拉普拉塔国立大学的 Claudia Hereqz 博士之间建立合作关系，作为 R01AG013934- 的延伸12（PI：O. Delbono），重点关注衰老的骨骼肌。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衰老而下降的细胞和分子机制。该 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 上调是否会导致 11a 随着衰老而下调，从而扩展并丰富了母基金。具体来说，我们的目标是确定 DHPR11S 的持续表达或防止 21a 内源性过度表达是否可以改善电压门控 SR Ca2+ 释放，从而改善衰老骨骼肌中的比力。我们将研究父母资助中研究的替代机制，并使用创新的分子工具，不仅适用于该项目，而且适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. 确定持续的 DHPR 21a 过度表达是否会通过与动力蛋白（一种参与受体介导的内吞作用的 GTP 酶）相关而导致 DHPR11 亚基表达减少。该系统是否在骨骼肌中发挥作用，特别是在21a亚基内源性过度表达而11亚基下调的衰老肌肉中，尚不清楚。病毒介导的 21a 亚基的过度表达将回答 21a 是否会导致幼鼠肌肉以及基因缺陷和 2-null 肌细胞中 DHPR11 亚基的下调。我们还将确定 DHPR11 亚基的长期均匀表达是否会阻止衰老小鼠中 21a 介导的内吞作用。目标 2. 确定肌肉 IGF-1 过度表达是否会阻止年龄依赖性 21a 过度表达，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偶联 (ECU)。这些实验将检验 IGF-1 在 DHPR 21a 亚基表达和 ECU 随衰老过程中发挥重要作用的假设。使用针对骨骼肌的转基因和 IGF-1 病毒载体将使我们能够检查 IGF-1 和 11/21a 表达之间的关系。公共卫生相关性：据报道，包括人类在内的几种哺乳动物物种的绝对和特定肌肉收缩力与年龄相关的下降。发展中国家阿根廷2005年的全国人口普查显示，65岁以上人口占总人口的10.1%，与美国的12.1%相近。两国老年中心的激增证明，越来越需要支持不断增长的面临或已经失去独立风险的老年人口。尽管肌肉力量对于预防老年人残疾很重要，但其生物学机制尚不为人所知。该 FIRCA 提案旨在建立北卡罗来纳州维克森林大学健康科学学院 PI 博士 Osvaldo Delbono 与阿根廷拉普拉塔国立大学 Claudia Hereqz 博士之间的合作，以阐明导致骨骼肌衰退的细胞和分子机制性能随老化。