SS peptides: a new approach to improve mitochondrial and skeletal muscle function

描述（由申请人提供）：没有药理治疗显示实际上逆转功能障碍并恢复衰老肌肉的线粒体能量。在初步实验中，我们发现线粒体靶向肽SS-31的单一治疗可以逆转线粒体缺陷并改善老年小鼠的骨骼肌功能。线粒体处于细胞衰老的中心，因为它们在连接ATP的产生、活性氧的产生和细胞信号传导方面起着重要作用。在骨骼肌中，线粒体在满足肌肉功能、生长和维持的能量需求方面起着关键作用。因此，随着年龄的增长，线粒体功能受损导致肌肉功能下降，运动不耐受，老年人生活质量下降。许多研究都在测试抗氧化治疗是否会随着年龄和疾病延缓线粒体功能障碍。相反，我们测试了一种创新的策略，通过独立于活性氧清除的线粒体ATP生产来逆转线粒体缺陷和改善肌肉功能。我们验证了用SS-31治疗逆转线粒体功能障碍将减少老年小鼠肌肉减少症和提高运动耐受性的假设。测试干预措施逆转线粒体功能障碍的主要限制之一是无法在体内测量线粒体能量。我们利用实验室开发的新的核磁共振和光谱学工具来研究小鼠骨骼肌的体内线粒体能量学，克服了这一限制。我们提出了一项独特的综合研究，将线粒体在体内和离体功能的改善与骨骼肌功能和全身运动表现的改善联系起来。Aim 1测试SS-31是否通过增加线粒体ATP生成和减少ROS生成而独立于ROS清除来逆转衰老骨骼肌的线粒体缺陷。目的2测试改善老年小鼠线粒体功能是否能减少肌肉减少症，改善骨骼肌性能，增加运动耐量。该建议测试了一种逆转老年组织线粒体功能障碍的新策略，这将为开发改善老年人骨骼肌功能和生活质量的干预措施提供新的范例。

DESCRIPTION (provided by applicant): There is no pharmacologic treatment shown to actually reverse dysfunction and restore mitochondrial energetics in vivo in aged muscle. In preliminary experiments we have found that a single treatment with a mitochondrially targeted peptide, SS-31, REVERSES mitochondrial deficits and improves skeletal muscle function in aged mice. Mitochondria sit at the center of cellular aging due to their important role in connecting ATP production, reactive oxygen species production and cell signaling. In skeletal muscle, mitochondria play a critical role in meeting energy demand for muscle function, growth and maintenance. Thus, impaired mitochondrial function with age leads to poor muscle function, exercise intolerance, and poor quality of life of the elderly. There have been many studies testing whether antioxidant treatment delays mitochondrial dysfunction with age and disease. In contrast, we test an innovative strategy to REVERSE mitochondrial deficits and improve muscle function by targeting mitochondrial ATP production independently of reactive oxygen species scavenging. We test the hypothesis that reversing mitochondrial dysfunction with SS-31 treatment will reduce sarcopenia and improve exercise tolerance in aged mice. One of the main limitations to testing interventions to reverse mitochondrial dysfunction is the inability to measure mitochondrial energetics in vivo. We overcome this limitation with new NMR and optical spectroscopy tools developed in our laboratory to study in vivo mitochondrial energetics in mouse skeletal muscle. We propose a unique integrative study that links improvements in mitochondrial function in vivo and ex vivo with improved skeletal muscle function and whole body exercise performance. Aim 1 tests whether SS-31 reverses mitochondrial deficits by increasing mitochondrial ATP production and reducing ROS production independently of ROS scavenging in aged skeletal muscle. Aim 2 tests whether improving mitochondrial function in aged mice reduces sarcopenia, improves skeletal muscle performance, and increases exercise tolerance. This proposal tests a novel strategy for reversal of mitochondrial dysfunction in aged tissues that would represent a new paradigm for developing interventions to improve skeletal muscle function and quality of life in the elderly. PUBLIC HEALTH RELEVANCE: The loss of skeletal muscle function with age (sarcopenia) has significant impacts on society in terms of both loss of quality of life and public health care costs, yet there are no successful pharmacological interventions to reduce sarcopenia. This proposal tests whether SS-31, a novel mt targeted peptide, represents an innovative strategy to reduce sarcopenia and improve exercise tolerance with age by reversing the age-related decline in mitochondrial energetics. Results from this project will have far reaching implications for improving the quality of life in not only the elderly, but also those suffering from mitochondral myopathies.