Abstract Aging is associated with reduced muscle mass (sarcopenia) and poor bone quality (osteoporosis) which together increase the incidence of falls and bone fractures. It is widely appreciated that aging triggers systemic oxidative stress which can impair bone and muscle stem cell survival and differentiation; yet, the basic mechanisms underlying these age- associated degenerative changes are not well understood. Our preliminary studies demonstrate that (1) levels of reactive oxygen species (ROS) increase significantly in muscle and bone tissues with aging, 2) arginase inhibitor treatment prevents oxidative stress-dependent elevation of atrophy-associated myokines (e.g., myostatin), premature cell senescence and supports myotube formation, 3) arginase inhibition prevents loss of membrane proteins Caveolin 3 (CAV3) and Dysferlin (DYSF) in differentiating myotube, 4) arginase inhibition enhances the expression of osteogenic genes (RUNX2) in bone marrow stromal cells (BMSCs). Based on our new and published findings, our central hypothesis is that elevated levels of ARG1 in bone and muscle cells cause uncoupling of nitric oxide synthesis (NOS), reducing NO formation and further increasing the burden of ROS formation and resulting in imbalanced bone and muscle homeostasis. Furthermore, blocking ARG1 activity or expression can prevent or reduce bone and muscle loss. This hypothesis will be tested with three independent but related aims. Specific Aim 1: Test the hypothesis that inhibition of arginase or lack of expression in muscle and bone can effectively prevent or reduce age dependent muscle and bone loss. We will use muscle- and bone-specific (BMSCs, and osteoblast) ARG1 knockout mice to examine the role of ARG1 in age-dependent loss in musculoskeletal function. Specific Aim 2: Test the hypothesis that age-related increases in arginase activity directly impact key cellular events in muscle and bone anabolism and catabolism. We will use primary human and mouse myoblast and bone cells (BMSC) to test this hypothesis. Specific Aim 3: Determine the molecular mechanisms by which ARG1 modulates muscle and bone homeostasis. We will test the hypothesis that dysregulation of ARG1 affects (a) nitric oxide-follistatin axis in muscle, (b) affects muscle repair/remodeling by altering membrane proteins (CAV3, DYSF) expression in muscles and (c) nitric oxide-RUNX2 axis in bone progenitor cells. Our application will facilitate the successful preclinical translation of ARG1 inhibition as a novel therapeutic strategy for age- related muscle and bone loss.