Uncontrolled type 2 diabetes is more common among Veterans than the general population and leads to decreased muscle strength and increased muscle fatigue, contributing to impaired recovery from illness and disability. Many other veterans have Type 1 diabetes that contributes to muscle weakness even with reasonable glycemic control. These changes are also seen in aging and both conditions are associated with mitochondrial dysfunction in muscle, but the signals that control mitochondrial metabolism in muscle during diabetes and aging remain incompletely understood. We recently reported that mouse models of streptozotocin (STZ) diabetes or aging cause muscle atrophy and mitochondrial dysfunction, which both depend on FoxO transcription factor activation. FoxO activation in STZ diabetic muscle represses nuclear- encoded mitochondrial gene transcription, particularly OXPHOS complex I subunits, and can be prevented by deletion of FoxOs in muscle. Since inhibition of FoxOs in non-muscle tissues can lead to cancer, defining the muscle-specific FoxO protein interactions that lead to improved muscle mitochondrial function in diabetes or aging are critical to improve the treatment of muscle weakness. We have preliminary data demonstrating that FoxOs and Sin3a corepressors are co-localized on OXPHOS promoters and that FoxO or Sin3a overexpression can repress many complex I subunit genes. The goal of this proposal is to investigate the role of FoxO interacting proteins in muscle mitochondrial function and muscle fatigue in the context of uncontrolled diabetes or aging. To accomplish the goals of this project we propose 2 aims: Aim 1 will determine the contribution of FoxO-Sin3 interactions to repression of Complex I (CI) and mitochondrial dysfunction in diabetes; Aim 2 will determine the molecular interactions with FoxOs that contribute to repression of mitochondrial function and muscle fatigue in aging. Our long-term goals are to understand the role of FoxOs and FoxO-target genes in diabetes-induced defects of mitochondrial energy production in muscle to gain insights into the metabolic changes that can contribute to decreased strength, increased fatigue and ultimately lead to disability which is so common in our Veteran population.