Skeletal Muscle Adaptations to Exercise in a Pre‐clinical Model of Myotonic Dystrophy Type 1

Myotonic dystrophy type I (DM1) is the second most common muscular dystrophy (MD), and most prevalent adult form of MD. Caused by a CTG microsatellite repeat expansion in the 3′ untranslated region (UTR) of the DMPK gene, muscle weakness, wasting, myotonia, and insulin resistance most prominently characterize DM1. Recent studies investigating the therapeutic efficacy of exercise training in DM1 patients demonstrate that chronic physical activity can elicit some functional benefits. Enhancing our understanding of exercise‐induced alterations in DM1 biology may assist in the discovery of effective lifestyle and/or pharmacological interventions to mitigate DM1. Thus, the purpose of this investigation was to examine exercise‐induced skeletal muscle plasticity in a pre‐clinical model of DM1. Three groups of mice (3–6 months old, n = 10–14/group) were utilized: i) sedentary human skeletal actin‐long repeat (HSA‐LR) mice (SED‐DM1), ii) HSA‐LR mice with volitional access to a home cage running wheel for 6–8 weeks (EX‐DM1), and iii) sedentary wild‐type mice (WT). HSA‐LR animals are engineered to possess a CTG expansion of ~250 repeats in the 3′ UTR of the HSA gene. These mice best recapitulate the myopathy characteristic of the human disorder, and thus serve as the most heavily employed pre‐clinical model of DM1. EX‐DM1 animals ran 5.6 km/day, which is similar to the running volume of healthy, WT mice previously reported in the literature. Utilizing the pen test to examine muscular endurance and motor performance, the WT group exhibited a significantly higher score, as compared to SED‐DM1 mice. The pen test score was normalized in the EX‐DM1 group. EX‐DM1 mice also demonstrated rescued forelimb grip strength, which was 24% lower (p < 0.05) in the SED‐DM1 animals versus the WT group. Direct, in situ stimulation of the plantar flexor muscle group revealed that chronic exercise normalized the aberrant force‐frequency relationship observed between WT and SED‐DM1 groups. Furthermore, EX‐DM1 animals demonstrated a tendency for enhanced fatigue resistance relative to WT and SED‐DM1 mice during repetitive, electrical stimulation‐evoked muscle contractile activity in situ. Finally, preliminary results suggest that chronic exercise can diminish the severity of myotonic discharges observed in the muscle of DM1 mice. Collectively, our data suggest that chronic physical activity elicits numerous favorable adaptations in DM1 biology. Examination of the underlying molecular mechanisms driving this beneficial muscle remodelling is warranted. Support or Funding Information Natural Science and Engineering Research Council of Canada (NSERC)

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