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.

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.