Voluntary wheel running complements microdystrophin gene therapy to improve muscle function in mdx mice

Abstract

We tested the hypothesis that voluntary wheel running would complement microdystrophin gene therapy to improve muscle function in young mdx mice, a model of Duchenne muscular dystrophy. mdx mice injected with a single dose of AAV9-CK8-microdystrophin or vehicle at age 7 weeks were assigned to three groups: mdxRGT (run, gene therapy), mdxGT (no run, gene therapy), or mdx (no run, no gene therapy). Wild-type (WT) mice were assigned to WTR (run) and WT (no run) groups. WTR and mdxRGT performed voluntary wheel running for 21 weeks; remaining groups were cage active. Robust expression of microdystrophin occurred in heart and limb muscles of treated mice. mdxRGT versus mdxGT mice showed increased microdystrophin in quadriceps but decreased levels in diaphragm. mdx final treadmill fatigue time was depressed compared to all groups, improved in mdxGT, and highest in mdxRGT. Both weekly running distance (km) and final treadmill fatigue time for mdxRGT and WTR were similar. Remarkably, mdxRGT diaphragm power was only rescued to 60% of WT, suggesting a negative impact of running. However, potential changes in fiber type distribution in mdxRGT diaphragms could indicate an adaptation to trade power for endurance. Post-treatment in vivo maximal plantar flexor torque relative to baseline values was greater for mdxGT and mdxRGT versus all other groups. Mitochondrial respiration rates from red quadriceps fibers were significantly improved in mdxGT animals, but the greatest bioenergetic benefit was observed in the mdxRGT group. Additional assessments revealed partial to full functional restoration in mdxGT and mdxRGT muscles relative to WT. These data demonstrate that voluntary wheel running combined with microdystrophin gene therapy in young mdx mice improved whole-body performance, affected muscle function differentially, mitigated energetic deficits, but also revealed some detrimental effects of exercise. With microdystrophin gene therapy currently in clinical trials, these data may help us understand the potential impact of exercise in treated patients.

Prolonged voluntary wheel running reveals unique adaptations in mdx mice treated with microdystrophin constructs ± the nNOS-binding site

“…Further, in the diaphragm, GT2 can result in a high degree of force production when prolonged endurance exercise is applied but the addition of running to animals treated with this construct decreases mitochondrial respiration. These findings demonstrate that prolonged (52 weeks) voluntary wheel running and a microdystrophin construct structure with or without the nNOS binding site in mdx mice will sustain the functional benefits we reported for microdystrophin combined with short-term (21 weeks) voluntary wheel running in mdx mice (Hamm et al, 2021). Our findings further demonstrate that prolonged voluntary wheel running complemented the functional improvements provided by both microdystrophin constructs but also revealed the unique benefits of each to dystrophic muscle.…”

Dietary Conjugated Linoleic Acid Reduces Body Weight and Fat in Snord116m+/p− and Snord116m−/p− Mouse Models of Prader–Willi Syndrome

“…The procedures for in vivo muscle testing were recently published [22]. Briefly, at the end of the study, following both running wheel and metabolism measurements, body weight was determined, and mice were anesthetized with isoflurane (VetOne Fluriso, Boise, ID, USA) and placed on the temperature-controlled platform (40 • C) of the contractile apparatus (ASI), as described.…”

“…The mouse tail was taped (M3, St. Paul, MN, USA) loosely to the platform to keep it clear of the foot pedal. In vivo plantarflexor torque-frequency and fatigue assays were determined as described in Hamm et al [22]. Dynamic Muscle Control (DMC) software controlled the timing and frequency of the stimulations and collection of torque.…”

Physiotherapeutic Protocol and ZnO Nanoparticles: A Combined Novel Treatment Program against Bacterial Pyomyositis

“…On the other hand, exercise can be used to build muscular strength and endurance. Hamm et al [ 37 ] proposed that a threshold could be established to guide appropriate exercise prescription for individuals with muscular atrophy. Kimura et al [ 38 ] demonstrated that immobility might minimize the muscle fiber necrosis in instances with muscular dystrophy.…”