Aerobic exercise elicits clinical adaptations in myotonic dystrophy type 1 patients independently of pathophysiological changes

Abstract

Background Myotonic dystrophy type 1 (DM1) is a complex life-limiting neuromuscular disorder characterized by severe skeletal muscle atrophy, weakness, and cardiorespiratory defects. Exercised DM1 mice exhibit numerous physiological benefits that are underpinned by reduced CUG foci and improved alternative splicing. However, the efficacy of physical activity in patients is unknown. Methods Eleven genetically diagnosed DM1 patients were recruited to examine the extent to which 12 weeks of cycling can recuperate clinical and physiological metrics. Furthermore, we studied the underlying molecular mechanisms through which exercise elicits benefits in skeletal muscle of DM1 patients. RESULTS DM1 was associated with impaired muscle function, fitness, and lung capacity. Cycling evoked several clinical, physical, and metabolic advantages in DM1 patients. We highlight that exercise-induced molecular and cellular alterations in patients do not conform with previously published data in murine models and propose a significant role of mitochondrial function in DM1 pathology. Finally, we discovered a subset of small nucleolar RNAs (snoRNAs) that correlated to indicators of disease severity. Conclusion With no available cures, our data support the efficacy of exercise as a primary intervention to partially mitigate the clinical progression of DM1. Additionally, we provide evidence for the involvement of snoRNAs and other noncoding RNAs in DM1 pathophysiology. Trial registration This trial was approved by the HiREB committee (no. 7901) and registered under ClinicalTrials.gov (NCT04187482). Funding Neil and Leanne Petroff. Canadian Institutes of Health Research Foundation (no. 143325).

Benefits of aerobic exercise in myotonic dystrophy type 1

“…Unexpectedly, this intervention also caused substantial downregulation of the transgene mRNA via accelerated turnover ( 16 ). It is noteworthy, however, that Mikhail and colleagues observed no downregulation of DMPK mRNA following exercise, which may reflect differences of DMPK regulation or the difficulty of forcing nuclear export when the repeat tract is extremely long ( 14 ).…”

“…Reporting in this issue of the JCI , Mikhail and colleagues test the translation of this finding in patients with DM1, and show that exercise is indeed beneficial, but not in ways predicted by studies in transgenic mice ( Figure 1 and ref. 14 ). The authors examined the effects of supervised aerobic exercise on a cycle ergometer in 11 participants with DM1.…”

“…If the benefits of exercise in DM1 patients do not involve reduction of RNA toxicity, then what is the mechanism? Mikhail et al present evidence that RNA toxicity, though not improved by exercise, does not block normal adaptations of muscle to aerobic training ( 14 ). In line with previous work ( 17 , 18 ), Mikhail and colleagues found that mitochondrial function was impaired at baseline in DM1 muscle.…”

“…Although large well-controlled studies are lacking, the report by Mikhail et al ( 14 ) adds to the existing evidence that limb muscles in DM1 can respond favorably to resistance and endurance exercise ( 21 ). Certainly, it is premature to conclude that exercise in DM1 is uniformly safe, especially considering the heterogeneity of the disease.…”

“…Certainly, it is premature to conclude that exercise in DM1 is uniformly safe, especially considering the heterogeneity of the disease. However, the authors tested for signs of aggravated muscle damage, assessing muscle histology and serum creatine kinase, and found none ( 14 ). An unresolved question is whether the pre-exercise reduction of mitochondrial function and aerobic capacity represents a primary effect of the disease process or whether these changes result mainly from severe deconditioning in a disease in which fatigue, limited mobility, daytime hypersomnolence, muscle pain, and other factors often conspire to produce a sedentary lifestyle.…”