Aerobic exercise elicits clinical adaptations in myotonic dystrophy type 1 patients independently of pathophysiological changes
Andrew I Mikhail, Peter L Nagy, Katherine Manta, Nicholas Rouse, Alexander Manta, Sean Y Ng, Michael F Nagy, Paul Smith, Jian-Qiang Lu, Joshua P Nederveen, Vladimir Ljubicic, Mark A Tarnopolsky, Andrew I Mikhail, Peter L Nagy, Katherine Manta, Nicholas Rouse, Alexander Manta, Sean Y Ng, Michael F Nagy, Paul Smith, Jian-Qiang Lu, Joshua P Nederveen, Vladimir Ljubicic, Mark A Tarnopolsky
Abstract
BackgroundMyotonic 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.MethodsEleven 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.RESULTSDM1 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.ConclusionWith 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 registrationThis trial was approved by the HiREB committee (no. 7901) and registered under ClinicalTrials.gov (NCT04187482).FundingNeil and Leanne Petroff. Canadian Institutes of Health Research Foundation (no. 143325).
Keywords: Cell Biology; Mitochondria; Muscle Biology; Neuromuscular disease; RNA processing.
Conflict of interest statement
Conflict of interest: MAT is the founder, CEO, and CSO of Exerkine Corp. PLN is the founder, owner, and CMO of Praxis Genomics.
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