Skeletal muscle adaptations to chronic exercise in a pre-clinical model of myotonic dystrophy type 1

Abstract

Myotonic dystrophy type 1 (DM1) is the second most common muscular dystrophy and most prevalent adult form. A microsatellite expansion comprised of CTG repetitions in the dystrophia myotonica protein kinase (DMPK) gene, DM1 is characterized by muscle weakness, wasting, and myotonia. The expanded nucleotide sequence of the DMPK mRNA results in the misregulation of important RNA-binding proteins (RNABPs), Muscleblind-like 1 (MBNL1) in particular. MBNL1 becomes trapped in myonuclei within the repeating CUG transcript, which reduces the RNABPs ability to process newly synthesized mRNAs that are important for the maintenance of healthy muscle function. Recent studies with DM1 participants demonstrate that exercise is safe, enjoyable, and elicits benefits in muscle strength and function. However, the molecular mechanisms of exercise adaptation in DM1 are largely unknown. Understanding the cellular processes that drive exercise-induced remodelling may assist in the discovery of effective lifestyle interventions to mitigate DM1. In this thesis, three groups of mice were utilized: i) sedentary DM1 animals (SED-DM1), ii) DM1 mice who volitionally exercised daily on a home cage running wheel (EX-DM1), and iii) sedentary healthy, wild-type mice (WT). EX-DM1 animals ran 5.6 km/day during the 7-week experimental time course, a volume of volitional physical activity that is lower than that observed in WT animals. Post-exercise functional tests demonstrated that chronic exercise significantly improved motor performance, muscle strength and endurance. Electromyography revealed that chronic exercise mitigated myotonia. At the cellular and molecular levels, we found that chronic physical activity attenuated RNA toxicity, liberated MBNL1 from myonuclear sequestration, and selectively normalized the spliceopathy of bridging integrator 1 and muscle-specific chloride channel mRNAs. Collectively, our data indicate that chronic exercise improves DM1 at the molecular, cellular and physiological levels.