Effects Of Skeletal Muscle Drp1 Knockout On Exercise Training-induced Whole-body Adaptations

Exercise training provides a myriad of whole-body benefits including improved metabolic health and exercise capacity. Mitochondria remodeling plays a central role in exercise training-induced whole-body adaptations. Dynamin-Related Protein 1 (Drp1) is the main regulator for mitochondrial fission. Recent studies have reported that Drp1 (Ser616) phosphorylation was upregulated in skeletal muscle following acute exercise and Drp1 ablation in skeletal muscle led to reduced maximal running capacity, suggesting it may play an important role in exercise training-induced adaptation. PURPOSE: To determine the effects of skeletal muscle Drp1 partial ablation in regulating whole body glucose homeostasis and exercise capacity following exercise training in mice. METHODS: C57Bl/6 J wildtype (WT) and tamoxifen-induced skeletal muscle-specific Drp1 partial knockout (mDrp1+/-) mice were used for this study. Mice were randomly assigned to either sedentary (SED) or 4-week voluntary wheel running (VWR) group (n = 6-8/group). Intraperitoneal glucose tolerance testing (0.1 mg/g bodyweight) and treadmill exercise capacity (0% grade, incremental speed until exhaustion) were performed during the last week of training. Blood lactate concentration was measured before and immediately after exercise capacity test. Two-way ANOVA was used when comparing groups. RESULTS: There was no difference in body weight among groups. Although not statistically significant, the blood glucose incremental area under the curve (AUC) showed a trending reduction in the WT mice after exercise training (WT/SED 8656.8 ± 847 vs. WT/VWR 6825.9 ± 927.0) but not in the mDrp1+/-/VWR mice (mDrp1+/-/SED 6426.9.3 ± 1006.5 vs. mDrp1+/-/VWR 7750.6 ± 1556.6). In addition, the change of blood lactate concentration after exercise capacity test was significantly lower in VWR mice compared to SED mice, regardless of genotype (VWR 0.7 ± 0.1 mmol ·L-1, SED 1.3 ± 0.2 mmol ·L-1, main effect of VWR, P = 0.013). There was no difference in exercise capacity between WT and mDrp1+/- mice at baseline or after exercise training. CONCLUSION: Our data suggest that skeletal muscle Drp1 may play an important role in exercise training-induced improvement in whole-body glucose tolerance. Supported by: National Institute of Health (R15DK131512)