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Clinical MedicineIn-Press PreviewCell biologyMuscle biology Open Access | 10.1172/JCI156125
1Department of Kinesiology, McMaster University, Hamilton, Canada
2Department of Neurology, Praxis Genomics, Atlanta, United States of America
3Department of Pediatrics, McMaster University Children's Hospital, Hamilton, Canada
4Pathology and Molecular Medicine/Neuropathology, McMaster University, Hamilton, Canada
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1Department of Kinesiology, McMaster University, Hamilton, Canada
2Department of Neurology, Praxis Genomics, Atlanta, United States of America
3Department of Pediatrics, McMaster University Children's Hospital, Hamilton, Canada
4Pathology and Molecular Medicine/Neuropathology, McMaster University, Hamilton, Canada
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1Department of Kinesiology, McMaster University, Hamilton, Canada
2Department of Neurology, Praxis Genomics, Atlanta, United States of America
3Department of Pediatrics, McMaster University Children's Hospital, Hamilton, Canada
4Pathology and Molecular Medicine/Neuropathology, McMaster University, Hamilton, Canada
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1Department of Kinesiology, McMaster University, Hamilton, Canada
2Department of Neurology, Praxis Genomics, Atlanta, United States of America
3Department of Pediatrics, McMaster University Children's Hospital, Hamilton, Canada
4Pathology and Molecular Medicine/Neuropathology, McMaster University, Hamilton, Canada
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1Department of Kinesiology, McMaster University, Hamilton, Canada
2Department of Neurology, Praxis Genomics, Atlanta, United States of America
3Department of Pediatrics, McMaster University Children's Hospital, Hamilton, Canada
4Pathology and Molecular Medicine/Neuropathology, McMaster University, Hamilton, Canada
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1Department of Kinesiology, McMaster University, Hamilton, Canada
2Department of Neurology, Praxis Genomics, Atlanta, United States of America
3Department of Pediatrics, McMaster University Children's Hospital, Hamilton, Canada
4Pathology and Molecular Medicine/Neuropathology, McMaster University, Hamilton, Canada
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1Department of Kinesiology, McMaster University, Hamilton, Canada
2Department of Neurology, Praxis Genomics, Atlanta, United States of America
3Department of Pediatrics, McMaster University Children's Hospital, Hamilton, Canada
4Pathology and Molecular Medicine/Neuropathology, McMaster University, Hamilton, Canada
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1Department of Kinesiology, McMaster University, Hamilton, Canada
2Department of Neurology, Praxis Genomics, Atlanta, United States of America
3Department of Pediatrics, McMaster University Children's Hospital, Hamilton, Canada
4Pathology and Molecular Medicine/Neuropathology, McMaster University, Hamilton, Canada
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1Department of Kinesiology, McMaster University, Hamilton, Canada
2Department of Neurology, Praxis Genomics, Atlanta, United States of America
3Department of Pediatrics, McMaster University Children's Hospital, Hamilton, Canada
4Pathology and Molecular Medicine/Neuropathology, McMaster University, Hamilton, Canada
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1Department of Kinesiology, McMaster University, Hamilton, Canada
2Department of Neurology, Praxis Genomics, Atlanta, United States of America
3Department of Pediatrics, McMaster University Children's Hospital, Hamilton, Canada
4Pathology and Molecular Medicine/Neuropathology, McMaster University, Hamilton, Canada
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1Department of Kinesiology, McMaster University, Hamilton, Canada
2Department of Neurology, Praxis Genomics, Atlanta, United States of America
3Department of Pediatrics, McMaster University Children's Hospital, Hamilton, Canada
4Pathology and Molecular Medicine/Neuropathology, McMaster University, Hamilton, Canada
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1Department of Kinesiology, McMaster University, Hamilton, Canada
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3Department of Pediatrics, McMaster University Children's Hospital, Hamilton, Canada
4Pathology and Molecular Medicine/Neuropathology, McMaster University, Hamilton, Canada
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Published March 22, 2022 - More info
BACKGROUND. Myotonic dystrophy type 1 (DM1) is a complex life-limiting neuromuscular disorder characterized by severe skeletal muscle atrophy, weakness, and cardio-respiratory 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. Lastly, we discovered a subset of small nucleolar RNAs (snoRNAs) that correlated to indicators of disease severity.
CONCLUSION. With no available cures, our data supports 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 (#7901) and registered under ClinicalTrials.gov (NCT04187482).
FUNDING. This work was primarily supported by Neil and Leanne Petroff. This study was also supported by a Canadian Institutes of Health Research Foundation Grant to MAT (#143325).
View Supplementary table 2 - Individual patient clinical data
View Supplementary table 3 - top 500 differentially expressed genes between DM1-PRE and CON
View Supplementary table 4 - Computed snoRNA score
View Supplementary table 6 - Novel misspliced genes in DM1
View Complete study protocol submitted to local ethics board