SS peptides: improve mitochondrial and skeletal muscle function with age

SS肽：随着年龄的增长改善线粒体和骨骼肌功能

• 批准号: 8554758
• 负责人: David J. Marcinek
• 金额: $ 21.29万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8554758
• 关键词: Acute; Age; Aging; Antioxidants; Cell Aging; Cell Energetics; Cells; Clinical; Comorbidity; Data; Development; Disease; Disuse Atrophy; Elderly; Exercise; Exercise Tolerance; Fiber; Functional disorder; Growth; Health; Health Care Costs; Histology; Homeostasis; Hour; Human; In Situ; Individual; Intervention; Laboratories; Lead; Link; Maintenance; Measures; Metabolic; Metabolic syndrome; Mitochondria; Mitochondrial Myopathies; Mus; Muscle; Muscle Fatigue; Muscle Mitochondria; Muscle function; Muscular Atrophy; Myopathy; Optics; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Oxygen Consumption; Peptides; Performance; Phase II Clinical Trials; Play; Population; Positioning Attribute; Production; Public Health; Quality of life; Reactive Oxygen Species; Respiration; Role; Signal Transduction; Skeletal Muscle; Societies; Spectrum Analysis; Testing; Tissues; Translations; United States; age related; aged; economic cost; human subject; improved; in vivo; innovation; insight; meetings; mitochondrial dysfunction; muscle aging; muscle strength; novel; novel strategies; oxidative damage; public health relevance; research study; sarcopenia; successful intervention; tool; treatment strategy

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.

描述（由申请人提供）：尚无药物治疗可在老年肌肉中实际逆转功能障碍并恢复体内的线粒体能量。在初步实验中，我们发现用线粒体靶向肽SS-31进行单一治疗可逆转线粒体缺陷并改善老年小鼠的骨骼肌功能。线粒体由于它们在连接ATP产生，活性氧的产生和细胞信号传导中的重要作用而位于细胞衰老的中心。在骨骼肌中，线粒体在满足肌肉功能，生长和维护的能源需求方面起着至关重要的作用。因此，线粒体功能的受损会导致肌肉功能不佳，运动不耐受和老年人的生活质量差。有许多研究测试抗氧化剂治疗是否会延迟与年龄和疾病的线粒体功能障碍。相比之下，我们通过针对线粒体ATP产生而独立于反应性氧物种清除的线粒体ATP产生来测试一种逆转线粒体缺陷并改善肌肉功能的创新策略。我们检验了以下假设：SS-31治疗将线粒体功能障碍逆转将减少肌肉减少症并提高老年小鼠的运动耐受性。测试干预措施以逆转线粒体功能障碍的主要局限性之一是无法在体内测量线粒体能量。我们通过在实验室中开发的新的NMR和光谱工具来克服这一局限性，以研究小鼠骨骼肌中的体内线粒体能量。我们提出了一项独特的综合研究，该研究将体内线粒体功能的改进与改善的骨骼肌功能和全身运动的表现联系起来。 AIM 1测试SS-31是否通过增加线粒体ATP的产生来逆转线粒体缺陷并独立于老年骨骼肌的ROS清除ROS的产生。 AIM 2测试是否改善老年小鼠的线粒体功能是否会降低肌肉减少症，改善骨骼肌肉性能并提高运动耐受性。该提案测试了一种新的策略，以逆转老年组织中线粒体功能障碍，这将代表一种新的范式，用于开发干预措施，以改善老年人的骨骼肌肉功能和生活质量。