Skeletal muscle atrophy results from insufficient nutrition, aging, certain medications, and a wide range of medical illnesses including cancer, diabetes mellitus, heart or renal failure, and acute or chronic infections. It is linked to increased disability, morbidity, as well as mortality, afflicts millions of Americans, and accounts for tens of billions of dollars in annual healthcare costs. Moreover, veterans are projected to have an increased prevalence of muscle atrophy compared to the general population because of military service-related injuries and medical conditions as well as their older age. Yet, there are no currently approved medical therapies for muscle atrophy, and the molecular determinants that control muscle mass remain incompletely defined. Using conditional genetic engineering, we have identified a surprising new role for the B cell lymphoma 6 (BCL6) transcriptional repressor to maintain muscle mass. Herein, we propose to comprehensively dissect the function of BCL6 in muscle and its epigenomic regulation. In Aim 1, we will test the impact of BCL6 on muscle protein synthesis and degradation, muscle mass, myofiber specification and metabolism, strength, and whole body energy homeostasis. In Aim 2, we will define the genome-wide gene regulatory network for BCL6 and its epigenomic, molecular, and biochemical mechanisms for controlling proteostasis. Together, these studies will reveal new molecular insights and a potential therapeutic pathway to reduce the burden of skeletal muscle loss.