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.

项目总结/摘要 肌肉减少症是在衰老过程中骨骼肌质量的进行性损失，是导致虚弱的主要因素， 使人衰弱的损伤、丧失独立性和老年人生活质量下降。不幸的是肌肉减少症 尽管采取了诸如增加体力活动和改善饮食等干预措施。在肌肉减少症期间， 在由肌肉质量损失（萎缩）和降低的肌肉比力（即， 每单位横截面积的肌肉力量）。越来越多的人认为，肌肉无力是伴随着 肌肉减少症，而不是肌肉大小本身的损失，作为残疾的主要贡献者。我们最近发现， 骨骼肌产生收缩力的要素依赖于钙库操纵的钙内流（SOCE）， 这种能力在老化的骨骼肌中丧失。这种改变的SOCE直接与降低的 mitsugumin 29（MG 29），属于突触素（SYPL 2）家族的肌肉特异性蛋白，其含有 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。MG 29是 对于横小管（TT）系统和有效SOCE的正确形成至关重要。这导致了 降低了衰老肌肉中MG 29的表达，并在肌肉减少症中发展出肌肉功能障碍。骨骼肌 来自年轻的mg 29-/-小鼠的细胞与来自老年野生型（WT）小鼠的细胞相似，因为它们表现出特异性降低， 收缩力、SOCE降低、SR中Ca释放减少、MG 29含量降低并改变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mg 29-/-小鼠中，使得该模型 适用于这一研究领域。在这个建议中，我们特别假设MG 29是适当的TT所必需的。 SOCE在骨骼肌中通过特定蛋白质结构域的作用发挥作用。降低MG 29 正常老化肌肉中的Ca 2+含量导致SOCE缺陷，这导致了 收缩性和年龄相关的肌肉力量损失，不包括肌肉萎缩。我们将检验这一假设 通过两个具体的目的，将：a）检查MG 29在骨骼肌中功能的机制基础，B）建立 MG 29如何适应老化和E-C耦合的多模态方面的更广泛背景，以及c）提供 对治疗肌肉减少症的转化价值。目的1将阐明MG 29对SOCE、SR-Ca 通过使用MG 29 cDNA或RNAi构建体的电穿孔来改变衰老骨骼肌的肌松和收缩性， MG 29的表达，同时评估SOCE功能、SR-Ca释放、收缩力和基因表达 程度.在目标2中，我们使用一种新的小鼠模型，由分子生物学和生物化学方法支持，以解决 负责MG 29在脂质处理中的功能机制的蛋白基序，以建立分子机制 MG 29在骨骼肌中的SOCE调节以及这些机制如何在衰老中改变。

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
• 作者: Bulgart, Hannah R.;Goncalves, Isabella;Weisleder, Noah
• 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