Novel small molecules for the treatment of sarcopenia

Aging is associated with a loss of muscle mass in the form of sarcopeniaand sarcopenia with its associated weakness contributes directly to the incidence of falls and fractures in the elderlyThese fractures are very costly both in terms of financial burden and quality of lifeA 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 dysfunctionOur goal is to address this problem by providing criticalnew information on small molecule therapeutics that may attenuate muscle loss with agingand thereby improve scientific knowledgetechnical capabilityand eventually clinical practiceOur central hypothesis is that the conversion of the amino acid tryptophan to kynurenine by the enzyme IDOis a key factor in age related loss of muscle mass and strength with agingOur preliminary data provide a strong rationale for this hypothesisand indicate thatcirculating kynurenine levels increase with age in both mice and humanskynurenine treatment of isolated muscle cells increases levels of reactive oxygen specieskynurenine treatment of young mice induces muscle atrophy and decreases muscle strengthtreatment of aged mice with the IDOinhibitormethyl D tryptophanIndoximodincreases muscle mass and muscle fiber sizeandIDOknockout mice show a significant increase in muscle fiber size compared to wild type miceAimwill determine the effects of Indoximod on kynurenine production by primary human skeletal muscle cellsvascular smooth muscle cells and vascular endothelial cells in vitroAimwill identify the optimal IDO inhibitor in vitro and in vivoThe impact of this project will be the development of IDO inhibitors as a new class of molecules to prevent and treat sarcopeniaIn the future this knowledge may be critical in the diagnosistreatment and management of vulnerable patient populations debilitated by the vast array of ageinduced pathologies Aging is associated with a loss of muscle mass in the form of sarcopeniaand sarcopenia with its associated weakness contributes directly to the incidence of falls and fractures in the elderlyThis project will identify small molecule inhibitors of the IDO pathway as a novel therapeutic approach to prevent age related muscle atrophy