PROJECT 2 - Kyn-AhR interactions modulating muscle-bone crosstalk with aging

Aging is associated with a loss of muscle mass in the form of sarcopenia and a loss of bone mass and density in the form of osteoporosis. Muscle and bone loss with age are, in turn, underlying factors contributing to 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 and bone loss with aging is a poor understanding of the molecular and cellular mechanisms underlying age-related musculoskeletal dysfunction. Our goal is to address this problem by providing critical, new information on the molecular and cellular mechanisms that control these processes, and thereby improve scientific knowledge, technical capability, and eventually clinical practice. Our central hypothesis is that age-associated accumulation of the tryptophan (Trp) metabolite kynurenine (Kyn), a by-product of Trp degradation by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), plays a key role in healthspan regulation by modulating skeletal muscle function and muscle-bone crosstalk. Kyn is now recognized as an agonist of the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that has recently been highlighted as playing a key role in regulating organismal aging and lifespan. Our preliminary data provide a strong rationale for this hypothesis and indicate that 1) Kyn increases significantly with age in human subjects and is positively correlated with measures of frailty, 2) Kyn induces muscle atrophy and inflammation in vivo and increases accumulation of muscle reactive oxygen species in vitro, 3) AhR activation increases significantly with aging in skeletal muscle, 4) AhR inhibition reduces Kyn-induced ROS production and senescence in vitro, and 5) pharmacological inhibition of either IDO1 or AhR increases muscle fiber size in aged mice. These findings suggest that elevated oxidative stress and inflammation in skeletal muscle by Kyn-mediated AhR activation are factors that impair musculoskeletal function and healthspan with aging. Aim 1 will test the hypothesis that inhibiting IDO1 activity in skeletal muscle can improve muscle and bone function with aging. Aim 2 tests the hypothesis that inhibiting AhR in skeletal muscle can improve muscle and bone function with aging. Our expected outcomes include 1) defining the respective role(s) of IDO1 and AhR in skeletal muscle with aging so that they can be targeted therapeutically, and 2) characterizing muscle-bone crosstalk in the context of altered Kyn-AhR interactions to better understand the cellular and molecular processes related to impaired muscle and bone function with aging.