1604-P: Lrrc2 Preserves Mitochondrial ATP Production in Diabetic Muscle and Promotes Adaptations to Exercise

Uncontrolled diabetes impairs muscle strength and mitochondrial metabolism, leading to disabilities. FoxOs are key mediators of insulin signaling and we demonstrated that FoxOs mediate mitochondrial dysfunction in mice with streptozotocin (STZ) diabetes. Unfortunately, knockout of FoxOs in proliferative tissues causes cancer. We aimed to investigate FoxO targets restricted to skeletal muscle in hopes of improving strength in diabetic conditions without carcinogenic effects. RNA-seq from STZ mice with/without FoxO1/3/4 triple knockout showed LRRC2 (Leucine rich repeating containing 2) is a striated-muscle specific FoxO target that is transiently increased in diabetic muscle. The function of LRRC2 is unknown, but gene expression databases show LRRC2 is restricted to muscle and heart. Adenoviral overexpression of LRRC2 in C2C12 cells localized to mitochondria and showed increase mRNA levels of biogenesis marker PGC1α, and antioxidant genes SOD2 and Gpx3. To determine LRRC2’s effect on exercise tolerance and mitochondrial bioenergetics in vivo, we created muscle specific LRRC2 knockout (LKO) mice and rendered them diabetic with STZ. Diabetic LKO mice had the poorest performance on treadmill exercise to exhaustion, and female LKO mice showed impaired exercise training with free wheel running when compared to controls. Interestingly, soleus muscles from LKO mice were 17% larger than their controls, whereas extensor digitorum longus (EDL) were 25% smaller in the diabetic LKO mice, indicating divergent effects on oxidative vs. glycolytic muscle. Soleus permeabilized fibers showed 20% decreased ATP production in diabetic LKO compared to controls that was uncoupled from respiration with glutamate/malate. Mitochondria from quad/gastroc of LKO mice showed increased H2O2 production compared to controls.

In conclusion, Lrrc2 is a novel FoxO target that helps preserve mitochondrial function and exercise tolerance in a type 1 diabetes mouse model.