Preventing Skeletal and Cardiac Muscle Aging by Restoring Mitochondrial Function

通过恢复线粒体功能预防骨骼肌和心肌老化

• 批准号: 9564597
• 负责人: David J. Marcinek
• 金额: $ 81.95万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9564597
• 关键词: Acute; Age; Aging; Antioxidants; Attenuated; Biological Assay; C57BL/6 Mouse; Calcium; Cardiac; Cardiolipins; Congestive Heart Failure; Contractile Proteins; Data; Doxorubicin; EFRAC; Economics; Elderly; Electron Transport; Exercise Tolerance; Extracellular Matrix; Fiber; Fibrosis; Functional disorder; Gene Expression; Health; Heart; Heart failure; Homeostasis; Hospitalization; Human; Hybrids; Inner mitochondrial membrane; Intervention; Kinetics; Left Ventricular Hypertrophy; Measures; Membrane; Mitochondria; Modification; Molecular; Mus; Muscle; Muscle Cells; Muscle function; Muscular Atrophy; Myocardial dysfunction; Myocardium; Nursing Homes; Oxidants; Oxidation-Reduction; Oxidative Stress; Peptides; Performance; Phase II Clinical Trials; Phosphorylation; Post-Translational Protein Processing; Process; Production; Property; Proteins; Proteomics; Public Health; Quality of life; Reactive Oxygen Species; Relaxation; Rodent; Role; Signal Transduction; Skeletal Muscle; Skin; Societies; Stress; Structure; System; Testing; Tissues; Translations; Work; age effect; aged; biological adaptation to stress; catalase; cohort; cost; cytochrome c; economic cost; effective therapy; exercise intolerance; frailty; functional decline; functional disability; improved; improved functioning; in vivo; in vivo magnetic resonance spectroscopy; insight; male; middle age; mitochondrial dysfunction; muscle aging; muscle degeneration; muscular structure; prevent; protein expression; restoration; reuptake; sarcopenia; sex; targeted treatment; time use; treatment duration; young adult

PREVENTING SKELETAL AND CARDIAC MUSCLE AGING BY RESTORING MITOCHONDRIAL FUNCTION SUMMARY Aging is accompanied by slowly progressive and irreversible structural changes and functional declines in both heart and skeletal muscle that combine to contribute to exercise intolerance and frailty in the elderly. The increased rates of nursing home placement and hospitalization make the loss of muscle function with age a growing public health crisis in terms of both quality of life and economic costs to society. Despite this, there are few treatment options to reverse either skeletal or cardiac muscle degeneration in the elderly, due in large part to the poor understanding of the mechanisms that underlie these dysfunctions. Our previous work has demonstrated that treatment with the mitochondrial targeted peptide SS-31 improves skeletal and cardiac muscle performance, mitochondrial function, and reduces redox stress. These surprising results demonstrate that mitochondrial dysfunction with age is a more dynamic process than previously thought and can be reversed by late-life treatment to improve healthspan. Recent data indicates that SS-31 does not act as a traditional antioxidant by scavenging reactive oxygen species. Instead SS-31 appears to interact with mitochondrial cardiolipin to improve mitochondrial electron transport system (ETS) function and reduce mitochondrial oxidative stress. We propose that improved ETS function with short-term treatment reduces redox and energy stress which improves function and stress response of the aged heart and skeletal muscle. With long-term treatment this improved stress signaling restores mitochondrial and tissue structure, leading to further improvements in muscle performance. This proposal will define the redox and energy dependent signaling mechanisms by which SS-31 treatment reverses cardiac and skeletal muscle energetic dysfunction at late age (Aim 1), as well as the mechanisms by which these changes subsequently rejuvenates cardiac and skeletal muscle structure to improve performance (Aim 2). The final Aim 3 will test whether reducing mitochondrial oxidative stress by treating mice beginning in middle age can preserve muscle healthspan and exercise tolerance. We believe that the combined study of both heart and skeletal muscle will provide key insights into similarities and differences in how their functional impairments respond to enhanced energetics and redox signaling and how improvements in both will combine to enhance healthspan and exercise tolerance. The end result will be new insights into the mechanistic basis of this new paradigm for improving muscle health with potential for direct translation to elderly humans.

通过恢复线粒体来防止骨骼和心肌老化 功能 概括 衰老伴随着缓慢进行性和不可逆转的结构变化，两者的功能下降 心脏和骨骼肌结合起来有助于运动中的不宽容和脆弱。这 疗养院安置和住院的率提高使肌肉功能丧失随着年龄的增长 就生活质量和对社会的经济成本而言，公共卫生危机日益增加。尽管如此，还有 很少有治疗选择可以扭转老年人的骨骼或心脏肌肉变性，很大程度上是由于 对这些功能障碍的机制的理解不佳。我们以前的工作有 证明用线粒体靶向肽SS-31进行治疗可改善骨骼和心脏 肌肉性能，线粒体功能并减少氧化还原应激。这些令人惊讶的结果证明了 与年龄相比，与年龄的线粒体功能障碍比以前想象的更具动态的过程 通过晚期治疗逆转以改善健康状态。最近的数据表明SS-31不充当 传统的抗氧化剂通过清除活性氧。而是SS-31似乎与 线粒体心脂蛋白可改善线粒体电子传输系统（ETS）功能并降低 线粒体氧化应激。我们建议改善的ETS功能通过短期治疗减少 氧化还原和能量应力改善了老年心脏和骨骼肌的功能和应力反应。 通过长期处理，这种改善的应力信号传导恢复了线粒体和组织结构，导致 进一步改善肌肉性能。该建议将定义氧化还原和能量依赖性 SS-31处理逆转心脏和骨骼肌肉能量功能障碍的信号传导机制 晚年（AIM 1），以及这些变化随后恢复心脏和心脏的机制 骨骼肌结构以提高性能（AIM 2）。最终目标3将测试是否减少 从中年开始治疗小鼠通过治疗小鼠可以保留肌肉健康范围，并且 运动耐受性。我们认为，心脏和骨骼肌的综合研究将提供关键 洞悉其功能障碍对增强能量学的响应方式的相似性和差异 氧化还原信号传导以及两者的改进将如何结合起来，以增强健康范围和运动 宽容。最终结果将是对这种改进的新范式的机械基础的新见解 肌肉健康，有可能直接转化为老年人。