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.

通过恢复线粒体来预防骨骼肌和心肌老化 功能 概括 衰老伴随着两方面缓慢进行且不可逆转的结构变化和功能衰退 心脏和骨骼肌共同导致老年人运动不耐受和虚弱。这 疗养院安置和住院率的增加使得肌肉功能随着年龄的增长而丧失 就生活质量和社会经济成本而言，公共卫生危机日益严重。尽管如此，仍有 很少有治疗方案可以逆转老年人的骨骼或心肌退化，这在很大程度上是由于 对这些功能障碍背后的机制了解甚少。我们之前的工作有 证明用线粒体靶向肽 SS-31 治疗可改善骨骼和心脏功能 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表明 随着年龄的增长，线粒体功能障碍是一个比以前认为的更加动态的过程，并且可以通过 通过晚年治疗来改善健康寿命，可以逆转这种情况。最近的数据表明 SS-31 并不充当 传统的抗氧化剂通过清除活性氧来实现。相反，SS-31 似乎与 线粒体心磷脂可改善线粒体电子传递系统 (ETS) 功能并减少 线粒体氧化应激。我们建议通过短期治疗改善 ETS 功能，从而减少 氧化还原和能量应激可改善衰老心脏和骨骼肌的功能和应激反应。 通过长期治疗，这种改善的应激信号可以恢复线粒体和组织结构，从而导致 进一步提高肌肉性能。该提案将定义氧化还原和能量依赖 SS-31 治疗逆转心脏和骨骼肌能量功能障碍的信号机制 晚年（目标 1），以及这些变化随后使心脏和神经恢复活力的机制 骨骼肌结构以提高表现（目标 2）。最终的Aim 3将测试是否减少 通过从中年开始治疗小鼠来消除线粒体氧化应激可以保持肌肉健康寿命 运动耐力。我们相信，心脏和骨骼肌的综合研究将提供关键 深入了解他们的功能障碍如何应对增强的能量的相似性和差异 和氧化还原信号传导以及两者的改进如何结合起来以增强健康寿命和锻炼 宽容。最终结果将是对这种新范式的机制基础的新见解，以改进 肌肉健康有可能直接影响老年人。