Aging is associated with a loss of muscle mass in the form of sarcopenia, and sarcopenia with its associated weakness contributes directly to the incidence of falls and fractures in the elderly. These fractures are very costly both in terms of financial burden and quality of life. A critical barrier to progress in correcting the problem of muscle loss with aging is a lack of therapeutics that can prevent or delay age-related musculoskeletal dysfunction. Our goal is to address this problem by providing critical, new information on small molecule therapeutics that may attenuate muscle loss with aging, and thereby improve scientific knowledge, technical capability, and eventually clinical practice. Our central hypothesis is that the conversion of the amino acid tryptophan to kynurenine by the enzyme IDO1 is a key factor in age-related loss of muscle mass and strength with aging. Our preliminary data provide a strong rationale for this hypothesis, and indicate that 1) circulating kynurenine levels increase with age in both mice and humans, 2) kynurenine treatment of isolated muscle cells increases levels of reactive oxygen species, 3) kynurenine treatment of young mice induces muscle atrophy and decreases muscle strength, 4) treatment of aged mice with the IDO1 inhibitor 1-methyl-D-tryptophan (Indoximod) increases muscle mass and muscle fiber size, and 5) IDO1 knockout mice show a significant increase in muscle fiber size compared to wild-type mice. Aim 1 will determine the effects of Indoximod on kynurenine production by primary human skeletal muscle cells, vascular smooth muscle cells and vascular endothelial cells in vitro. Aim 2 will identify the optimal IDO inhibitor in vitro and in vivo. The impact of this project will be the development of IDO inhibitors as a new class of molecules to prevent and treat sarcopenia. In the future this knowledge may be critical in the diagnosis, treatment and management of vulnerable patient populations debilitated by the vast array of age- induced pathologies.
Public Health Relevance Statement: Aging is associated with a loss of muscle mass in the form of sarcopenia, and sarcopenia with its associated weakness contributes directly to the incidence of falls and fractures in the elderly. This project will identify small-molecule inhibitors of the IDO pathway as a novel therapeutic approach to prevent age-related muscle atrophy.
Project Terms: Address; Affect; Age; age related; age-related muscle loss; aged; Aging; Amino Acids; Attenuated; Biological Assay; Blood Vessels; Cell Count; Cells; clinical practice; cost; Data; Development; Diagnosis; Disease Outcome; Dose; Elderly; Enzymes; Exercise; falls; Fatigue; Financial Hardship; Fracture; frailty; Functional disorder; Future; Goals; Human; improved; In Vitro; in vivo; Incidence; inhibitor/antagonist; Knockout Mice; Knowledge; Kynurenine; Measures; Molecular; Molecular Target; Morphology; Mus; Muscle; Muscle Cells; Muscle Fibers; muscle form; muscle strength; Muscular Atrophy; Musculoskeletal; Natural regeneration; novel; novel therapeutic intervention; Outcome; Pathology; Pathway interactions; patient population; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; prevent; Production; Public Health; Quality of life; Reactive Oxygen Species; reduced muscle strength; repaired; Research; research and development; response; Risk; Rodent; sarcopenia; satellite cell; Skeletal Muscle; small hairpin RNA; small molecule; small molecule inhibitor; small molecule therapeutics; Smooth Muscle Myocytes; Therapeutic; Time; Toxicology; Tryptophan; Vascular Endothelial Cell; Vascular Smooth Muscle; Wild Type Mouse; Work
