Ca Sparks in Muscle Aging and Dystrophy

肌肉老化和营养不良中的钙火花

• 批准号: 7877944
• 负责人: Jianjie Ma
• 金额: $ 42.28万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7877944
• 关键词: Ablation; Address; Adolescent; Adult; Age; Aging; Belief; Biochemical; Cells; Chronic; Confocal Microscopy; Coupling; Defect; Disease; Doctor of Philosophy; Event; Fiber; Functional disorder; Generations; Genetic; Health; Heart failure; Image; Knowledge; Laboratories; Lead; Link; Measures; Membrane; Membrane Proteins; Methods; Molecular; Monitor; Muscle; Muscle Cells; Muscle Contraction; Muscle Fibers; Muscle function; Muscular Dystrophies; Myocardium; Nature; Neonatal; Nerve Degeneration; Pathologic; Peripheral; Phospholipase C; Physiological; Plastics; Process; Proteins; Proteomics; Regulation; Research Personnel; Role; Ryanodine Receptor Calcium Release Channel; Ryanodine Receptors; Sarcoplasmic Reticulum; Signal Transduction; Skeletal Muscle; Stress; Striated Muscles; Structural Protein; Synaptophysin; Testing; Transgenic Organisms; Triad Acrylic Resin; age related; aged; genetic regulatory protein; interest; junctophilin; muscle aging; muscle stress; numb protein; overexpression; programs; research study; response; therapeutic target

DESCRIPTION (provided by applicant): Ca sparks are the elementary units of Ca-induced Ca release (CICR) in striated muscle cells revealed as localized Ca release events from sarcoplasmic reticulum (SR) by confocal microscopy. While Ca sparks are well defined in cardiac muscle, there has been a general belief that these localized Ca release events are rare in intact adult mammalian skeletal muscle. As a result of the intrinsic difficulties in monitoring Ca spark activity in intact mammalian muscle, the cellular and molecular mechanisms underlying the regulation of CICR in muscle function and the adaptive changes of CICR in muscle aging and dystrophy remain largely unexplored. Recently, we discovered that stress generated by membrane deformation induces a robust Ca spark response spatially confined in close proximity to the sarcolemmal membrane in healthy young mammalian muscles. These induced Ca sparks are repeatable and reversible in young muscle fibers, but become transient and static in aged skeletal muscle. In dystrophic muscle with fragile membrane integrity, induced Ca sparks are irreversible and penetrate from the periphery to the fiber interior. Thus, uncontrolled Ca spark activity could potentially lead to partial depletion of the SR Ca store, triggering increased store- operated Ca entry (SOCE) and providing a dystrophic signal in mammalian skeletal muscle. We hypothesize that Ca sparks can be used as a measure of the plastic nature of CICR in muscle health, aging and dystrophy. Experiments proposed in this project shall focus on addressing the following fundamental questions regarding the physiological function of Ca sparks in skeletal muscle: First, what are the cellular factors that are responsible for the peripheral distribution and the plasticity of Ca sparks in young, healthy skeletal muscle? Second, is there dynamic bi-directional coupling between Ca sparks and SOCE, and does alteration of this coupling produce muscle dysfunction? Third, how do triad-junction resident proteins influence Ca spark function in health, aging and disease? As defects in control of CICR have been linked to numerous pathologic states, including heart failure and neurodegenerative conditions, we hope knowledge gained from our studies will not only help establish the physiological function of stress-induced Ca sparks in skeletal muscle fibers, they may also point to potential therapeutic targets in excitable cells where dysfunction of CICR has been observed.

描述(申请人提供)：钙火花是横纹肌肉细胞钙诱导钙释放(CICR)的基本单位，通过共聚焦显微镜显示为肌浆网(SR)的局部钙释放事件。虽然钙火花在心肌中有很好的定义，但人们普遍认为，这种局部的钙释放事件在完整的成年哺乳动物骨骼肌中很少见。由于监测完整哺乳动物肌肉中钙火花活性的内在困难，CICR调节肌肉功能的细胞和分子机制以及CICR在肌肉衰老和营养不良中的适应性变化在很大程度上尚不清楚。最近，我们发现，在健康的年轻哺乳动物肌肉中，由膜变形产生的应力在空间上诱导了一种强大的钙火花反应，该反应局限在靠近肌膜的地方。在年轻的肌肉纤维中，这些诱导的钙火花是可重复和可逆的，但在老年骨骼肌中，这些诱导的钙火花变得短暂和静态。在膜完整性脆弱的营养不良肌肉中，诱导的钙火花是不可逆的，并从外周渗透到纤维内部。因此，不受控制的钙火花活动可能会导致SR钙库的部分耗尽，触发更多的库操作钙进入(SOCE)，并在哺乳动物骨骼肌中提供营养不良的信号。我们假设，钙火花可以用来衡量CICR在肌肉健康、衰老和营养不良方面的可塑性。本项目中提出的实验将重点解决以下关于骨骼肌中钙火花的生理功能的基本问题：第一，在年轻、健康的骨骼肌中，哪些细胞因素负责钙火花的外周分布和可塑性？第二，钙火花和SOCE之间是否存在动态的双向耦合，这种耦合的改变是否会导致肌肉功能障碍？第三，三联体驻留蛋白在健康、衰老和疾病中如何影响钙火花功能？由于CICR的控制缺陷与许多病理状态有关，包括心力衰竭和神经退行性疾病，我们希望从我们的研究中获得的知识不仅将有助于建立应激诱导骨骼肌纤维中钙火花的生理功能，还可能指向已观察到CICR功能障碍的可兴奋细胞的潜在治疗靶点。