Duchenne Muscular Dystrophy (DMD) is an X-linked severe muscle-wasting disease that exhibits metabolic disorders. Mitochondrial dysfunction is a pathological feature preceding muscle-wasting. Dynamin related protein 1 (Drp1) is a key mediator of mitochondrial fission reported to have excessive activity in mouse models of DMD. However, it remains unknown whether inhibiting skeletal muscle Drp1 improves skeletal muscle function and glycemic control in DMD. Therefore, we aim to assess the role of Drp1 in regulating skeletal muscle function and whole-body glycemic control in a mouse model of DMD.
Methods: We generated dystrophin-deficient mice with inducible skeletal muscle-specific Drp1 knockout by crossing male tamoxifen-inducible skeletal muscle specific Drp1flox/flox mice with female D2-mdx mice. Tamoxifen was given to all animals at 7-weeks-old for 5 days. Grip Strength Testing (GST), Hangwire Impulse (HI) and Glucose Tolerance Testing (GTT) were assessed at 2-, 6-, 10-, and 14-weeks post Drp1 knockout. Skeletal muscle was collected one week after final testing with isolated mitochondria being used for respirometry.
Results: There was no difference in body or muscle tissue weight between groups. Grip strength was significantly higher 6 to 14 weeks post partial Drp1 ablation in comparison to wildtype (WT) mdx counterparts (16.9% (p=0.012), 10.8% (p=0.035), and 16.0% (p=0.006)). Consistently, HI was markedly improved post Drp1 ablation when compared to the WT mdx counterparts (144.1% (p=0.052), 80.4% (p=0.0003), and 62.6% (p=0.061)). Furthermore, whole-body glucose tolerance, assessed by GTT Incremental Area under the Curve was improved 10- and 14-weeks post partial Drp1 ablation when compared to WT mdx counterparts (–27.2% and -25.5%, p=0.110 and 0.037). Mitochondrial basal respiration was significantly higher in partial Drp1 knockout mdx mice in comparison to WT mdx counterparts (+108%, p=0.003).
Conclusion: Partial ablation of skeletal muscle-specific Drp1 induces improvements in mitochondrial respiration, skeletal muscle function and glycemic control in a mouse model of DMD.