Dynamin-related protein 1 (Drp1) is a key mediator of mitochondrial fission and plays an important role in regulating mitochondrial quality control and function. Recent studies reported that in skeletal muscle Drp1 activity was downregulated following exercise training. Additionally, partial deletion of Drp1 resulted in reduced exercise performance. Altogether, it suggests that Drp1 may play an important role in regulating exercise-training adaptations. OBJECTIVE: To determine the effects of skeletal muscle-specific Drp1 deletion on exercise training adaptations. HYPOTHESIS: Deletion of skeletal muscle Drp1 would compromise exercise-training improvements in mitochondrial quality control machinery, mitochondrial function, and exercise performance. METHODS: Male C57Bl/6J wildtype (WT) and tamoxifen-induced skeletal muscle Drp1 knockout (skmDrp1-/-) mice were sedentary (SED) or performed voluntary wheel running (VWR) for 6 weeks (n=7/group). Grip strength was assessed in all mice using a grip strength meter. Exercise capacity tests were performed on a treadmill set at 5% incline with incremental increased speed of 1 m/min every 3 minutes until mice reached fatigue. Isolated mitochondria from quadriceps muscle were used to measure oxygen consumption rates. Gastrocnemius–soleus complexes were collected and used for measuring protein expression by immunoblotting. RESULTS: Ablation of skeletal muscle Drp1 resulted in reduced exercise capacity (Genotype main effect, P < 0.0001). Importantly, exercise capacity and grip strength were significantly improved in WT/VWR mice (P = 0.0005 and 0.0003), but remained unchanged in skmDrp1-/-/VWR mice, when compared to their respective sedentary counterparts. Consistent with the phenotype data, ablation of skeletal muscle Drp1 resulted in lower mitochondrial respiration (Genotype main effect, P < 0.0001). In addition, mitochondrial state 3 (ADP) and 4 (Oligomycin) respiration were improved in WT/VWR mice in comparison to WT/SED (30% increase and 37% decrease, respectively, P = 0.1207 and 0.0124), but remain unchanged in skmDrp1-/-/VWR mice (Interaction, P = 0.1371 and 0.0042, respectively), demonstrating compromised exercise-training adaptations in mitochondrial function. WT/VWR mice exhibited a trend of decreased phospho-Drp1ser616 (-12%) following exercise training, whereas skmDrp1-/-/VWR mice demonstrated an increase trend (9%) when compared to their sedentary counterparts. Finally, skmDrp1-/- mice displayed reduced mitophagy marker, Parkin expression (Genotype main effect, -45%, P < 0.0001). Exercise training significantly elevated Parkin expression when compared to the sedentary groups (Exercise main effect, P = 0.048), mainly driven by the increase of Parkin in WT mice (21%). CONCLUSION: Our data suggest that ablation of skeletal muscle Drp1 compromises exercise-training improvements in whole-body fitness performance as well as mitochondrial function in skeletal muscle which may, in part, be due to compromised adaptations in phospho-Drp1Ser616 and Parkin-mediated mitophagy. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Berger et al. (Fri,) studied this question.