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

描述(申请人提供)：目前尚无药物治疗方法可在体内逆转衰老肌肉中的功能障碍和恢复线粒体能量。在初步实验中，我们发现线粒体靶向多肽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。线粒体位于细胞衰老的中心，因为它们在连接ATP产生、活性氧产生和细胞信号转导方面起着重要作用。在骨骼肌中，线粒体在满足肌肉功能、生长和维持所需的能量需求方面起着至关重要的作用。因此，随着年龄的增长，线粒体功能受损会导致老年人肌肉功能下降，运动耐受性下降，生活质量下降。已经有许多研究测试抗氧化剂治疗是否会随着年龄和疾病的增加而延缓线粒体功能障碍。相反，我们测试了一种创新的策略，通过靶向线粒体ATP的产生而不依赖于活性氧物种的清除来逆转线粒体缺陷和改善肌肉功能。我们验证了这样一种假设，即用SS-31治疗逆转线粒体功能障碍将减少老年小鼠的骨骼肌减少并提高运动耐量。测试逆转线粒体功能障碍的干预措施的主要限制之一是无法在体内测量线粒体能量学。我们通过实验室开发的新的核磁共振和光学光谱工具克服了这一限制，在体内研究了小鼠骨骼肌中的线粒体能量学。我们提出了一项独特的综合性研究，将体内和体外线粒体功能的改善与骨骼肌功能和全身运动能力的改善联系起来。目的1检测SS-31是否通过增加线粒体ATP的产生和减少ROS的产生而逆转线粒体的缺陷，而不依赖于ROS对衰老骨骼肌的清除。目的2检测改善老年小鼠线粒体功能是否能减少骨骼肌萎缩，改善骨骼肌运动能力，提高运动耐量。这项建议测试了一种逆转老年组织线粒体功能障碍的新策略，这将代表开发干预措施以改善老年人骨骼肌功能和生活质量的新范式。 公共卫生相关性：骨骼肌功能随年龄的丧失(骨质疏松症)在生活质量和公共卫生保健成本的损失方面对社会都有重大影响，但目前还没有成功的药物干预措施来减少骨质疏松症。这项建议测试了一种新型的MT靶向肽SS-31是否代表了一种创新的策略，通过逆转与年龄相关的线粒体能量学下降来减少骨骼减少和提高随年龄增长的运动耐量。该项目的结果不仅对改善老年人的生活质量有深远的影响，而且对那些患有线粒体肌病的人也有深远的影响。

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.