3053-LB: Loss of Miro1 Improves Whole-Body and Skeletal Muscle Insulin Sensitivity in Mice with Obesity and Hyperglycemia

Introduction and Objective: Imbalanced skeletal muscle mitochondrial dynamics contribute to the onset and progression of type 2 diabetes (T2D) by mechanisms that remain incompletely understood. Here, we examined the role of Mitochondrial Rho GTPase 1 (Miro1), an outer mitochondrial membrane enzyme, in regulating skeletal muscle insulin action and glucose homeostasis in T2D. Methods: Male mice with skeletal muscle deletion of Miro1 (Miro1SkM-/-) and floxed controls (Miro1fl/fl) were housed at thermoneutrality and maintained on a 60% high-fat diet for 16 wks. Body weight and food intake were measured weekly. Fasting glucose and insulin were measured after 12 wks to determine HOMA-IR. Whole-body glucose clearance was evaluated by insulin tolerance testing after 14 wks. Peripheral insulin sensitivity was determined by hyperinsulinemic-euglycemic clamp after 16 wks of diet in a separate cohort that underwent dual carotid artery and jugular vein catheterization surgery. Muscle tissue was collected from mice with and without a bolus of 14C-2-deoxyglucose to determine skeletal muscle glucose uptake and evaluate insulin signaling. Results: Body weight and food intake were similar in Miro1SkM-/- mice relative to Miro1fl/fl. Fasting glucose, insulin, and HOMA-IR were lower in Miro1SkM-/- mice, and whole-body glucose clearance in response to intraperitoneal insulin injection were improved in Miro1SkM-/- mice. Miro1SkM-/- mice had higher steady-state glucose disposal rates and increased skeletal muscle uptake of 14C-2-deoxyglucose. Miro1SkM-/- mice had increased AKT and AS160 signaling and GLUT4 in skeletal muscle after insulin exposure ex vivo. Conclusion: Skeletal muscle-specific Miro1 deletion improves insulin signaling and glucose uptake, suggesting Miro1 acts as a negative regulator of skeletal muscle insulin action. These findings support a mechanistic role of mitochondrial dynamics in maintaining skeletal muscle insulin sensitivity and indicate therapeutic potential for targeting Miro1 to treat T2D. Disclosure E. Heintz: None. A.L. Taylor: None. E.R. Zunica: None. J. Slone: None. C. Axelrod: None. J.P. Kirwan: Consultant; Current; Eli Lilly and Company. Research Support; Current; Eli Lilly and Company. Advisory Panel; Ended; Novo Nordisk.