Aerobic exercise-induced functional and cellular adaptations in patients with myotonic dystrophy type 1

Abstract

Myotonic dystrophy type 1 (DM1) is the most common adult muscular dystrophy affecting ~1/8000 people worldwide. DM1 is characterized by accelerated skeletal muscle weakness and wasting, myotonia and insulin resistance, ultimately causing impaired function and diminished quality of life. A trinucleotide (CTG) repeat expansion in the 3’ region upstream of the DMPK gene results in dysregulation of several RNA binding proteins (RNABPs) important for muscle health such as MBNL and CUGBP1. Exercise was shown to ameliorate DM1 pathology in mice and to be safe for DM1 patients. This thesis aimed to investigate the muscular adaptations of 12-weeks of aerobic exercise in DM1 patients. Eleven DM1 patients (DM1, 42.6 ± 3 y) were recruited from the Neuromuscular and Neurometabolic clinic at McMaster University and age matched to healthy controls (CON, 42.5 ± 2 y). DM1 and CON performed incremental VO2peak testing, muscle and spirometry functional tests and a skeletal muscle biopsy from the Vastus lateralis. After 12-weeks of training on a cycle ergometer (3x/wk @ ~65 %VO2peak), DM1 patients completed post-testing. Exercise training significantly increased total lean mass (TLM) by ~ 1.6 kg (p<0.05) and fibre cross-sectional area by ~30 % in DM1 patients. Aerobic fitness was enhanced following training from 19.7 ± 1.5 mL/kg/min to 26.0 ± 2.1 mL/kg/min (p<0.05). Furthermore, training improved 6-min walk test, timed up & go, and 5X sit-to-stand scores (p<0.05). Mechanistically, exercise modestly altered expression of RNABPs, and augmented mitochondrial function and protein content. This is the first study to comprehensively investigate the effects of aerobic training on muscle health and function in DM1. Our data provides evidence that exercise training can augment fitness, functional capacity and muscle mass in DM1. Further understanding the influence of exercise on DM1 pathology could outline the efficacy of a simple life intervention and provide insight for future pharmacological discoveries for DM1.