This proposal seeks to test the hypothesis that endurance exercise stimulates the release of circulating factors that improve mitochondrial fitness. CyteGens goal is to identify these endogenous factors and engineer them to treat diseases in which mitochondrial dysfunction is central. These diseases include neurodegenerative and other diseases associated with aging, as well as the rare mitochondrial diseases that arise from inborn errors in genes encoding mitochondrial proteins that affect 1 in 5000 individuals. Currently, no effective treatments are available. To identify factors that improve mitochondrial fitness, CyteGen is using a unique mouse model, created by the PI. This model displays a profound mitochondrial syndrome with reduced life span and premature aging due to impaired exonuclease proofreading activity of POLG, the sole mtDNA polymerase. POLG is highly conserved between mice and humans and over 200 mutations in this polymerase have been associated with human disease, supporting CyteGens contention that mouse discoveries will translate into humans. Endurance exercise of POLG mutant mice reverses the early-onset aging syndrome by overcoming the POLG defect in mitochondrial function. Analyses of tissues in exercised mice suggests that endogenous circulating factors may be responsible. We will test the hypothesis that circulating factors secreted as a result of exercise improve mitochondrial function by collecting plasma from exercised POLG mice and sedentary controls and injecting it into old POLG mice that display reduced mitochondrial function and impaired skeletal muscle and cardiac function. Following a schedule of injections that mimics exercise training, we will examine metabolic capacity, cardiac function, spontaneous activity levels and mitochondrial function. A second aim of this study is to use cell based models to determine the effects of plasma from exercised mice on mitochondrial function of POLG mutant cells. The goal of our studies is to identify circulating factors that reverse mitochondrial dysfunction with suitable properties to support initiation of preclinical studies in preparation for clinical evaluation.
Public Health Relevance Statement: Narrative: Mitochondrial dysfunction is associated with a large number of diseases, including neuromuscular disorders, neurodegenerative disorders such as Parkinsons and Alzheimers diseases, and aging. Despite the central role of mitochondria in many diseases, few treatments are available, and none can stop disease progression. This application proposes to use novel and exciting findings on the role of exercise in inhibiting mitochondrial disease to develop novel therapeutic approaches.
Project Terms: Affect; Age; age related; Aging; Alzheimer's Disease; Automobile Driving; base; Biochemical; Biological Assay; Blood Circulation; Cells; Complement; Data; Defect; Disease; Disease Progression; DNA biosynthesis; early onset; effective therapy; Endogenous Factors; endurance exercise; Engineering; Excision; Exercise; exercise training; Exonuclease; Fractionation; Functional disorder; Funding; Future; Genes; Genomics; Goals; Growth; Health Benefit; heart function; Hereditary Disease; Human; human disease; Impairment; improved; Individual; Injections; Knock-in; Laboratories; Lead; Longevity; Measurement; Mediating; Metabolic; Mitochondria; Mitochondrial Diseases; Mitochondrial DNA; mitochondrial dysfunction; mitochondrial fitness; Mitochondrial Proteins; Modeling; mouse model; Mus; Muscle; Muscle function; mutant; Mutant Strains Mice; Mutation; Myocardium; Nerve Degeneration; Neurodegenerative Disorders; Neuromuscular Diseases; normal aging; novel; novel therapeutic intervention; Parkinson Disease; Phase; phase II trial; Phenotype; Physiological; Plasma; Polymerase; preclinical study; premature; Premature aging syndrome; Preparation; Property; Proteins; Proteomics; Protocols documentation; research clinical testing; Resolution; Respiration; Role; Schedule; sedentary; Skeletal Muscle; small molecule; Syndrome; Testing; Tissues; Translating; Work
