Regulation of Store-Operated Calcium Entry During Muscle Aging

肌肉衰老过程中钙库操纵的钙进入的调节

• 批准号: 10459619
• 负责人: Marco Brotto
• 金额: $ 49.43万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459619
• 关键词: Ablation; Acute; Address; Age; Age-Years; Aging; Amino Acid Motifs; Area; Atrophic; Attenuated; Baltimore; Binding; Binding Proteins; Biochemical; Biophysics; Bypass; Calcium; Cholesterol; Chronic; Complementary DNA; Coupling; Data; Dependovirus; Diet; Drops; Elderly; Electroporation; Elements; Family; Fiber; Functional disorder; Future; Gene Delivery; Gene Expression; Generations; Genes; Health Care Costs; Health Expenditures; Human; Impairment; In Situ; Influentials; Injury; Intervention; Knock-out; Knowledge; Link; Lipid Binding; Lipids; Longitudinal Studies; Maintenance; Mediating; Medical; Membrane; Membrane Proteins; Modeling; Modification; Molecular; Molecular Biology; Molecular Genetics; Morphology; Mus; Muscle; Muscle Development; Muscle Fibers; Muscle Weakness; Muscle function; Muscular Atrophy; Myopathy; Names; Nerve; Persons; Phenotype; Physical activity; Population; Protein Family; Proteins; Public Health; Publishing; Quality of life; RNA Interference; Regulation; Research; Rodent; Role; Ryanodine Receptor Calcium Release Channel; STIM1 gene; Sarcoplasmic Reticulum; Signal Transduction; Skeletal Muscle; Skin; Synaptophysin; Syndrome; System; Technology; Tertiary Protein Structure; Testing; Tissues; Triad Acrylic Resin; Wild Type Mouse; Woman; age related; age-related muscle loss; aged; disability; frailty; improved; improved functioning; in vivo; men; metabolomics; mouse model; multimodality; muscle aging; muscle form; muscle physiology; muscle strength; novel; overexpression; preclinical study; protein oligomer; reduced muscle strength; relating to nervous system; sarcopenia; skeletal muscle wasting; targeted treatment; translational study; uptake

Project Summary/Abstract Sarcopenia is the progressive loss of skeletal muscle mass during aging and is a leading factor contributing to frailty, debilitating injuries, loss of independence, and reduced quality of life in the elderly. Unfortunately, sarcopenia progresses despite interventions such as increased physical activity and improved diet. During sarcopenia, the age-related decreases in muscle strength result from a combination of loss of muscle mass (atrophy) and reduced muscle specific force (i.e., muscle force per unit of cross-sectional area). Increasingly, it is thought that it is the muscle weakness that accompanies sarcopenia, rather than the loss of muscle size per se, as the principal contributor to disability. We recently found that elements of contractile force generation in skeletal muscle are dependent on store-operated Ca2+ entry (SOCE) and that this capacity is lost in aging skeletal muscle. This altered SOCE is directly associated with a reduced content of mitsugumin 29 (MG29), a muscle-specific protein belonging to the synaptophysin (SYPL2) family which contains a MARVEL domain involved in cholesterol binding, lipid handling and formation of oligomers of these proteins. MG29 is essential for the proper formation of the transverse-tubule (TT) system and efficient SOCE. This leads to a link between reduced MG29 expression in aged muscle and the development of muscle dysfunction in sarcopenia. Skeletal muscles from young mg29-/- mice are similar to those from aged wild-type (WT) mice in that they demonstrate decreased specific contractile force, reduced SOCE, reduced Ca release from the SR, reduced content of MG29, and altered TT morphology. Therefore, our data demonstrate that key aspects of skeletal muscle aging are present in mg29-/- mice, making this model applicable for this line of research. In this proposal we specifically hypothesize that MG29 is required for proper TT formation and that SOCE functions in skeletal muscle through the action of specific protein domains. Decreased MG29 content in normal aged muscle leads to defective SOCE, which results in the decreased availability of Ca2+ for contractility and age-related loss of muscle strength not accounted for by muscle atrophy. We will test this hypothesis through two specific aims that will: a) examine the mechanistic basis for MG29 function in skeletal muscle, b) establish how MG29 fits into the broader context of the multi-modal aspects of aging and E-C coupling, and c) provide translational value for the treatment of sarcopenia. Aim 1 will elucidate the contribution of MG29 to SOCE, SR-Ca release and contractility in aged skeletal muscle by using electroporation of MG29 cDNA or RNAi constructs to alter the expression of MG29 and concomitantly evaluate SOCE function, SR-Ca release, contractile force and gene expression levels. In Aim 2 we use a novel mouse model supported by molecular biology and biochemical approaches to resolve the protein motifs responsible for the mechanism of MG29 function in lipid handling to establish the molecular mechanisms of SOCE regulation by MG29 in skeletal muscle and how these mechanisms are altered in aging.

项目概要/摘要 肌肉减少症是衰老过程中骨骼肌质量的逐渐丧失，是导致虚弱的主要因素， 使老年人衰弱、丧失独立性和生活质量下降。不幸的是，肌肉减少症正在进展 尽管采取了增加体力活动和改善饮食等干预措施。在肌肉减少症期间，与年龄相关的减少 肌肉力量的下降是由肌肉质量损失（萎缩）和肌肉比力降低（即， 每单位横截面积的肌肉力量）。越来越多的人认为，伴随而来的是肌肉无力。 肌肉减少症，而不是肌肉尺寸本身的损失，是导致残疾的主要原因。我们最近发现 骨骼肌收缩力产生的要素取决于钙库操纵的 Ca2+ 进入 (SOCE)，并且 衰老的骨骼肌会丧失这种能力。这种改变的 SOCE 与减少的含量直接相关 mitsugumin 29 (MG29)，一种肌肉特异性蛋白，属于突触素 (SYPL2) 家族，包含 MARVEL 结构域参与胆固醇结合、脂质处理和这些蛋白质寡聚体的形成。 MG29是 对于横管（TT）系统的正确形成和有效的 SOCE 至关重要。这导致了之间的联系 减少衰老肌肉中 MG29 的表达以及肌肉减少症中肌肉功能障碍的发展。骨骼肌 来自年轻 mg29-/- 小鼠的结果与来自老年野生型 (WT) 小鼠的结果相似，因为它们表现出特异性降低 收缩力，减少 SOCE，减少 SR 中的 Ca 释放，减少 MG29 含量，并改变 TT 形态。 因此，我们的数据表明，骨骼肌衰老的关键方面存在于 mg29-/- 小鼠中，使得该模型成为可能 适用于这一领域的研究。在此提案中，我们特别假设 MG29 是正确 TT 所必需的 SOCE 通过特定蛋白质结构域的作用在骨骼肌中发挥作用。 MG29 减少 正常老化肌肉中的含量会导致 SOCE 缺陷，从而导致 Ca2+ 的可用性降低 收缩力和与年龄相关的肌肉力量丧失并非由肌肉萎缩引起。我们将检验这个假设 通过两个具体目标：a) 检查 MG29 在骨骼肌中功能的机制基础，b) 建立 MG29 如何适应老化和 E-C 耦合的多模式方面的更广泛背景，以及 c) 提供 治疗肌肉减少症的转化价值。目标 1 将阐明 MG29 对 SOCE、SR-Ca 的贡献 通过使用 MG29 cDNA 或 RNAi 构建体的电穿孔来改变老化骨骼肌的释放和收缩性 MG29 的表达并同时评估 SOCE 功能、SR-Ca 释放、收缩力和基因表达 水平。在目标 2 中，我们使用由分子生物学和生化方法支持的新型小鼠模型来解决 负责 MG29 在脂质处理中发挥作用的机制的蛋白质基序，以建立分子机制 骨骼肌中 MG29 的 SOCE 调节以及这些机制在衰老过程中如何改变。

项目成果

Leveraging Plasma Membrane Repair Therapeutics for Treating Neurodegenerative Diseases.

• DOI: 10.3390/cells12121660
• 发表时间: 2023-06-18
• 期刊: CELLS
• 影响因子: 6
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• 通讯作者: Weisleder, Noah

Investigating genetic drivers of dermatomyositis pathogenesis using meta-analysis.

• DOI: 10.1016/j.heliyon.2020.e04866
• 发表时间: 2020-09
• 期刊: Heliyon
• 影响因子: 4
• 作者: Aljabban J;Syed S;Syed S;Rohr M;Weisleder N;McElhanon KE;Hasan L;Safeer L;Hoffman K;Aljabban N;Mukhtar M;Adapa N;Allarakhia Z;Panahiazar M;Neuhaus I;Kim S;Hadley D;Jarjour W
• 通讯作者: Jarjour W