FoxO Transcription Factors Are Critical Regulators of Diabetes-Related Muscle Atrophy

Insulin deficiency and uncontrolled diabetes lead to a catabolic state with decreased muscle strength, contributing to disease-related morbidity. FoxO transcription factors are key mediators of insulin action. To study their role in diabetic muscle wasting, we created mice with musclespecific triple knockout of FoxO1/3/4 and induced diabetes in these M-FoxO-TKO mice with streptozotocin (STZ). Muscle mass and myofiber area were decreased 20-30% in STZ-Diabetes mice due to increased ubiquitinproteasome degradation and autophagy, characterized by increased pULK1 and LC3-II. Both the muscle loss and markers of increased degradation/autophagy were completely prevented in STZ-FoxO-TKO mice. Transcriptomic analyses revealed FoxO-dependent increases in ubiquitin-mediated proteolysis pathways in STZ-Diabetes, including regulation of Fbxo32 (Atrogin1), Trim63 (MuRF1), Bnip3L, and Gabarapl. These same genes were increased 1.4- to 3.3-fold in muscle from type 1 diabetics after shortterm insulin deprivation. Thus, FoxO-regulated genes play a rate-limiting role in increased protein degradation and muscle atrophy in insulin-deficient diabetes.