Preventing Skeletal and Cardiac Muscle Aging by Restoring Mitochondrial Function

通过恢复线粒体防止骨骼肌和心肌衰老 功能 摘要 衰老伴随着缓慢渐进和不可逆转的结构变化以及两者的功能衰退 心脏和骨骼肌结合在一起会导致老年人运动不耐受和虚弱。这个 养老院安置和住院率的增加使肌肉功能随着年龄的增长而丧失 日益严重的公共卫生危机给社会带来了生活质量和经济代价。尽管如此，还是有 很少有治疗方案可以逆转老年人的骨骼或心肌变性，这在很大程度上是由于 对这些功能障碍背后的机制缺乏了解。我们之前的工作是 证明使用线粒体靶向多肽SS-31治疗可以改善骨骼和心脏 肌肉性能，线粒体功能，并减少氧化还原压力。这些令人惊讶的结果表明 线粒体功能障碍随着年龄的增长是一个比之前认为的更动态的过程，而且可以 通过晚年治疗来逆转，以提高健康寿命。最近的数据表明，SS-31不是一种 传统抗氧化剂通过清除活性氧物种。相反，SS-31似乎与 线粒体心磷脂改善线粒体电子传递系统(ETS)功能并降低 线粒体氧化应激。我们建议短期治疗后改善的ETS功能减少 氧化还原和能量应激，改善衰老心脏和骨骼肌的功能和应激反应。 通过长期治疗，这种改进的应激信号恢复了线粒体和组织结构，导致 肌肉表现的进一步改善。这项提议将定义氧化还原和能源依赖 SS-31治疗逆转心肌和骨骼肌能量障碍的信号机制 晚年(目标1)，以及这些变化随后使心脏和心脏恢复活力的机制 改善性能的骨骼肌结构(目标2)。最终目标3将测试是否减少 从中年开始治疗小鼠线粒体氧化应激可以保持肌肉健康和 锻炼耐力。我们相信，对心脏和骨骼肌的联合研究将提供关键 洞察他们的功能障碍如何对增强的能量学做出反应的异同 和氧化还原信号，以及两者的改进将如何结合起来提高健康寿命和锻炼 宽容。最终的结果将是对这一新的改进范式的机制基础的新见解 肌肉健康，有可能直接移植到老年人身上。

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.