Aerobic exercise elicits clinical adaptations in myotonic dystrophy type 1 patients independently of pathophysiological changes
Andrew I. Mikhail, … , Vladimir Ljubicic, Mark A. Tarnopolsky
Andrew I. Mikhail, … , Vladimir Ljubicic, Mark A. Tarnopolsky
Published March 22, 2022
Citation Information: J Clin Invest. 2022;132(10):e156125. https://doi.org/10.1172/JCI156125.
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Clinical Research and Public Health Cell biology Muscle biology

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).

Authors

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

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Figure 7

Exercise training ameliorates mitochondrial deficiency in DM1 patients.

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Exercise training ameliorates mitochondrial deficiency in DM1 patients. ...
Gene expression of all subunits of complex I (A), complex II (B), complex III (C), complex IV (D), and complex V (E) of the mitochondrial electron transport chain expressed as fold change relative to CON and grouped into mitochondrial (left) and nuclear encoded genes (right). (F) Representative Western blot of mitochondrial protein complexes (CI–CV). Full blot was overexpressed and cropped for better visualization of CI. A typical Ponceau stain displayed below demonstrates sample loading. Approximate molecular weights (kDa) shown at right of blots. (G) Graphical representation of CI–CV protein expression. (H) Representative images of succinate dehydrogenase staining. Original magnification, ×20. (I) State 2 complex I (CI) respiration in the presence of pyruvate plus malate (PM). (J) State 3 CI maximal respiration in the presence of PM plus ADP plus glutamate (PMDG). (K) State 3 complex I+II (CI+II) maximal respiration in the presence of PMDG plus succinate (PMDGS). (L) State 3 complex II (CII) maximal respiration in the presence of PMDGS plus rotenone (PMDGSR). (M) Submaximal ADP titration (25, 100, 500, 1000, 2000, 4000, and 8000 μM) curve with PM. Two samples from CON were of poor quality and therefore excluded from the respiration analysis. All respiration experiments were performed in duplicate and averaged for each participant. Data are expressed with bar graphs as mean (A–E) or as box and whisker plots with plus signs representing the mean (G and I–M). n = 9–11. *P < 0.05 versus CON, 1-way ANOVA followed by Bonferroni’s correction; #P < 0.05 versus DM1-PRE, 2-tailed paired t test corrected for multiple comparisons.