Lipid hydroperoxides in sarcopenia and muscle wasting: mechanisms and intervention

脂质氢过氧化物在肌肉减少症和肌肉萎缩中的作用：机制和干预

• 批准号: 10366483
• 负责人: Jacob Levi Brown
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366483
• 关键词: Age; Age-Months; Age-Years; Aging; Animal Genetics; Animal Model; Arachidonate 15-Lipoxygenase; Arachidonic Acids; Atrophic; Attenuated; Body Composition; Cessation of life; Communication; Data; Denervation; Development; Diabetes Mellitus; Eicosanoids; Electron Transport; Enzymes; Fiber; Fracture; Functional disorder; Generations; Genetic; Goals; Hand Strength; Health; Health Expenditures; Hindlimb; Hydrogen Peroxide; Intervention; Knockout Mice; Lead; Lipid Peroxidation; Lipid Peroxides; Lipids; Maintenance; Malnutrition; Measures; Mediator of activation protein; Membrane; Mental Depression; Mentors; Mitochondria; Modeling; Morphology; Motor Neurons; Movement; Mus; Muscle; Muscle Fibers; Muscle Proteins; Muscle denervation procedure; Muscle function; Muscular Atrophy; Neuromuscular Junction; Oxidative Stress; Patients; Pharmacology; Phospholipase A2; Phospholipids; Population; Prevalence; Production; Protein Biosynthesis; Proteins; Psyche structure; Quality of life; Research Technics; Risk; Running; Scientist; Secondary to; Skeletal Muscle; Structure; Superoxides; Syndrome; Testing; Training; Veterans; adverse outcome; age related; age-related muscle loss; aged; catalase; design; effective intervention; effective therapy; experimental study; falls; gene therapy; glutathione peroxidase; healthspan; improved; meetings; mitochondrial dysfunction; mouse model; muscle aging; muscle degeneration; muscle form; muscle strength; nerve supply; novel; overexpression; oxidation; physically handicapped; protein biomarkers; protein degradation; reduced muscle mass; response; sarcopenia; skeletal muscle wasting; stable isotope; symposium; therapeutic target; therapy design

SIGNIFICANCE TO VETERANS HEALTH: Two-thirds of all veterans are 55 years of age or older. Sarcopenia is a syndrome that effects approximately 25% of the U.S. population over the age of 70 characterized by progressive loss of skeletal muscle mass and strength with an increased risk of adverse outcomes such as physical disability, poor quality of life and even death. Further, the development of sarcopenia may lead to secondary health conditions such as disuse, malnutrition, falls, fractures and diabetes. In addition to the physical ailments that accompany patients that suffer from sarcopenia, sarcopenia contributes to over $18.5 billion dollars of total health care expenditures. The prevalence of sarcopenia is higher in subjects presenting another health condition than in healthy subjects including mental conditions such as depression that are common among veterans. There are currently no effective treatments for sarcopenia because underlying mechanisms are not fully elucidated. OBJECTIVES: The objective of this study is to test if denervation induced generation of lipid hydroperoxides (LOOHs), through the enzyme 12/15-Lipoxygenase (12/15-Lox) or through direct oxidation of lipids, leads to neuromuscular junction (NMJ) disruption and mitochondrial dysfunction that initiates muscle atrophy, muscle protein breakdown, and weakness. RESEARCH PLAN: In Specific Aim 1, I will test the effect of reducing LOOHs via treatment with the LOOH scavenger liproxstatin-1 on mitochondrial function, NMJ structure and function, protein turnover, and maintenance of muscle mass and function in aged mice. In Specific Aim 2, I will test the effect of muscle specific genetic deletion of 12/15-Lox, an enzyme that generates eicosanoids and oxylipins, on the maintenance of muscle mass and function in aged mice. Finally, in Specific Aim 3, I will test the effect of muscle specific overexpression of glutathione peroxidase 4 (GPx4), an enzyme that reduces LOOHs within membranes, on the maintenance of muscle mass and function in aged mice. We will use a combination of pharmacological approaches, genetic mouse models, and novel research techniques to test the central hypothesis. ANTICIPATED OUTCOMES: All of my Specific Aims focus on reducing skeletal muscle LOOHs (either enzymatically generated or direct oxidation of lipids) in response to age-related denervation. I hypothesize that my interventions will ameliorate skeletal muscle atrophy and dysfunction in hindlimb muscle from aged mice by reducing lipid peroxidation, improving mitochondrial function, reducing rates of protein degradation, and maintaining NMJ integrity. My preliminary data clearly shows that LOOH generation is elevated in aged muscle, and that LOOH generation is strongly correlated to muscle mass loss in models of denervation atrophy. For skeletal muscle mass loss to occur, rates of protein degradation have to be greater than rates of protein synthesis. Therefore, my interventions have to reduce rates of protein degradation and/or increase rates of protein synthesis in denervated muscle. There are multiple lines of evidence that shows mitochondrial health is important for the maintenance of skeletal muscle mass and function. My preliminary data shows that overexpression of GPx4 in a model of accelerated sarcopenia improves mitochondrial function, which may reduce muscle mass loss. Therefore, we hypothesize that reducing LOOHs in muscle will improve mitochondrial function in aged mice. Finally, denervation can propagate oxidative stress and NMJ disruption in surrounding fibers. We predict that reducing LOOHs in muscle will slow NMJ degradation of the surrounding fibers. TRAINING PLAN: My short-term goals are to delineate the mechanisms of LOOH driven sarcopenia and receive training in oxidative stress, aging, the use of stable isotopes, using genetic animal models, and scientific communication. I will receive this training through a combination of meetings with my mentoring team, conferences, presentation, formal courses, and performing experiments. The training plan I have outlined will allow me to achieve my long-term goal of becoming an independent VA scientist.

SIGNIFICANCE TO VETERANS HEALTH: Two-thirds of all veterans are 55 years of age or older. Sarcopenia is a syndrome that effects approximately 25% of the U.S. population over the age of 70 characterized by progressive loss of skeletal muscle mass and strength with an increased risk of adverse outcomes such as physical disability, poor quality of life and even death. Further, the development of sarcopenia may lead to secondary health conditions such as disuse, malnutrition, falls, fractures and diabetes. In addition to the physical ailments that accompany patients that suffer from sarcopenia, sarcopenia contributes to over $18.5 billion dollars of total health care expenditures. The prevalence of sarcopenia is higher in subjects presenting another health condition than in healthy subjects including mental conditions such as depression that are common among veterans. There are currently no effective treatments for sarcopenia because underlying mechanisms are not fully elucidated. OBJECTIVES: The objective of this study is to test if denervation induced generation of lipid hydroperoxides (LOOHs), through the enzyme 12/15-Lipoxygenase (12/15-Lox) or through direct oxidation of lipids, leads to neuromuscular junction (NMJ) disruption and mitochondrial dysfunction that initiates muscle atrophy, muscle protein breakdown, and weakness. RESEARCH PLAN: In Specific Aim 1, I will test the effect of reducing LOOHs via treatment with the LOOH scavenger liproxstatin-1 on mitochondrial function, NMJ structure and function, protein turnover, and maintenance of muscle mass and function in aged mice. In Specific Aim 2, I will test the effect of muscle specific genetic deletion of 12/15-Lox, an enzyme that generates eicosanoids and oxylipins, on the maintenance of muscle mass and function in aged mice. Finally, in Specific Aim 3, I will test the effect of muscle specific overexpression of glutathione peroxidase 4 (GPx4), an enzyme that reduces LOOHs within membranes, on the maintenance of muscle mass and function in aged mice. We will use a combination of pharmacological approaches, genetic mouse models, and novel research techniques to test the central hypothesis. ANTICIPATED OUTCOMES: All of my Specific Aims focus on reducing skeletal muscle LOOHs (either enzymatically generated or direct oxidation of lipids) in response to age-related denervation. I hypothesize that my interventions will ameliorate skeletal muscle atrophy and dysfunction in hindlimb muscle from aged mice by reducing lipid peroxidation, improving mitochondrial function, reducing rates of protein degradation, and maintaining NMJ integrity. My preliminary data clearly shows that LOOH generation is elevated in aged muscle, and that LOOH generation is strongly correlated to muscle mass loss in models of denervation atrophy. For skeletal muscle mass loss to occur, rates of protein degradation have to be greater than rates of protein synthesis. Therefore, my interventions have to reduce rates of protein degradation and/or increase rates of protein synthesis in denervated muscle. There are multiple lines of evidence that shows mitochondrial health is important for the maintenance of skeletal muscle mass and function. My preliminary data shows that overexpression of GPx4 in a model of accelerated sarcopenia improves mitochondrial function, which may reduce muscle mass loss. Therefore, we hypothesize that reducing LOOHs in muscle will improve mitochondrial function in aged mice. Finally, denervation can propagate oxidative stress and NMJ disruption in surrounding fibers. We predict that reducing LOOHs in muscle will slow NMJ degradation of the surrounding fibers. TRAINING PLAN: My short-term goals are to delineate the mechanisms of LOOH driven sarcopenia and receive training in oxidative stress, aging, the use of stable isotopes, using genetic animal models, and scientific communication. I will receive this training through a combination of meetings with my mentoring team, conferences, presentation, formal courses, and performing experiments. The training plan I have outlined will allow me to achieve my long-term goal of becoming an independent VA scientist.