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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)., Introduction Myotonic dystrophy type 1 (DM1) is the most commonly diagnosed muscular dystrophy among adults and the second most prevalent of all muscular dystrophies (1). It is a progressive neuromuscular [...]

In Ontario, Canada, wait times for magnetic resonance imaging (MRI) scans continue to exceed provincial targets. We sought to determine the incidence of inappropriate hip MRI scan referrals, based on accepted indications for hip MRI. We developed an algorithm to appraise each MRI referral based on a prescan patient questionnaire and the interpretation of the MRI by a musculoskeletal radiologist. After reviewing 84 patient questionnaires, we considered 32.1% of MRI referrals to be inappropriate; 25.9% of the inappropriate MRI referrals were ordered as a preoperative test for potential hip arthroscopy despite the patients showing severe osteoarthritis. Having no prior radiographic examination was the most common reason for inappropriate referrals, regardless of pathology (48.1%). With limited MRI scanner time available in Ontario, it is essential that guidelines and training be improved on the indications for hip MRI to reduce the wait times for these specialized tests., Despite ongoing efforts and multiple government interventions, wait times for magnetic resonance imaging (MRI) continue to lag behind the provincial standard. Most recent reports suggest that the average Canadian in [...]

Aim: Myotonic dystrophy type 1 (DM1) is the second most common muscular dystrophy after Duchenne and is the most prevalent muscular dystrophy in adults. DM1 patients that participate in aerobic exercise training experience several physiological benefits concomitant with improved muscle mitochondrial function without alterations in typical DM1‐specific disease mechanisms, which suggests that correcting organelle health is key to ameliorate the DM1 pathology. However, our understanding of the molecular mechanisms of mitochondrial turnover and dynamics in DM1 skeletal muscle is lacking. Methods: Skeletal muscle tissue was sampled from healthy and DM1 mice under sedentary conditions and at several recovery time points following an exhaustive treadmill run. Results: We demonstrate that DM1 patients exhibit an imbalance in the transcriptional apparatus for mitochondrial turnover and dynamics in skeletal muscle. Additionally, DM1 mice displayed elevated expression of autophagy and mitophagy regulators. A single dose of exercise successfully enhanced canonical exercise molecular pathways and skeletal muscle mitochondrial biogenesis despite failing to alter the cellular pathology in DM1 mice. However, treadmill running stimulated coordinated organelle fusion and fission signaling, as well as improved alternative splicing of Optic atrophy 1. Exercise also evoked autophagy and mitophagy pathways in DM1 skeletal muscle resulting in the normalized expression of autophagy‐ and lysosome‐related machinery responsible for the clearance of dysfunctional organelles. Conclusion: Collectively, our data indicate that mitochondrial dynamics and turnover processes in DM1 skeletal muscle are initiated with a single dose of exercise, which may underlie the adaptive benefits previously documented in DM1 mice and patients. [ABSTRACT FROM AUTHOR]

Key points: Myotonic dystrophy type 1 (DM1), the second most common muscular dystrophy and most prevalent adult form of muscular dystrophy, is characterized by muscle weakness, wasting and myotonia.A microsatellite repeat expansion mutation results in RNA toxicity and dysregulation of mRNA processing, which are the primary downstream causes of the disorder.Recent studies with DM1 participants demonstrate that exercise is safe, enjoyable and elicits benefits in muscle strength and function; however, the molecular mechanisms of exercise adaptation in DM1 are undefined.Our results demonstrate that 7 weeks of volitional running wheel exercise in a pre‐clinical DM1 mouse model resulted in significantly improved motor performance, muscle strength and endurance, as well as reduced myotonia.At the cellular level, chronic physical activity attenuated RNA toxicity, liberated Muscleblind‐like 1 protein from myonuclear foci and improved mRNA alternative splicing. Myotonic dystrophy type 1 (DM1) is a trinucleotide repeat expansion neuromuscular disorder that is most prominently characterized by skeletal muscle weakness, wasting and myotonia. Chronic physical activity is safe and satisfying, and can elicit functional benefits such as improved strength and endurance in DM1 patients, but the underlying cellular basis of exercise adaptation is undefined. Our purpose was to examine the mechanisms of exercise biology in DM1. Healthy, sedentary wild‐type (SED‐WT) mice, as well as sedentary human skeletal actin‐long repeat animals, a murine model of DM1 myopathy (SED‐DM1), and DM1 mice with volitional access to a running wheel for 7 weeks (EX‐DM1), were utilized. Chronic exercise augmented strength and endurance in vivo and in situ in DM1 mice. These alterations coincided with normalized measures of myopathy, as well as increased mitochondrial content. Electromyography revealed a 70–85% decrease in the duration of myotonic discharges in muscles from EX‐DM1 compared to SED‐DM1 animals. The exercise‐induced enhancements in muscle function corresponded at the molecular level with mitigated spliceopathy, specifically the processing of bridging integrator 1 and muscle‐specific chloride channel (CLC‐1) transcripts. CLC‐1 protein content and sarcolemmal expression were lower in SED‐DM1 versus SED‐WT animals, but they were similar between SED‐WT and EX‐DM1 groups. Chronic exercise also attenuated RNA toxicity, as indicated by reduced (CUG)n foci‐positive myonuclei and sequestered Muscleblind‐like 1 (MBNL1). Our data indicate that chronic exercise‐induced physiological improvements in DM1 occur in concert with mitigated primary downstream disease mechanisms, including RNA toxicity, MBNL1 loss‐of‐function, and alternative mRNA splicing. Key points: Myotonic dystrophy type 1 (DM1), the second most common muscular dystrophy and most prevalent adult form of muscular dystrophy, is characterized by muscle weakness, wasting and myotonia.A microsatellite repeat expansion mutation results in RNA toxicity and dysregulation of mRNA processing, which are the primary downstream causes of the disorder.Recent studies with DM1 participants demonstrate that exercise is safe, enjoyable and elicits benefits in muscle strength and function; however, the molecular mechanisms of exercise adaptation in DM1 are undefined.Our results demonstrate that 7 weeks of volitional running wheel exercise in a pre‐clinical DM1 mouse model resulted in significantly improved motor performance, muscle strength and endurance, as well as reduced myotonia.At the cellular level, chronic physical activity attenuated RNA toxicity, liberated Muscleblind‐like 1 protein from myonuclear foci and improved mRNA alternative splicing. [ABSTRACT FROM AUTHOR]

Neuromuscular disorders (NMDs) are chronic conditions that affect the neuromuscular system. Many NMDs currently have no cure; however, as more effective therapies become available for NMD patients, these individuals will exhibit improved health and/or prolonged lifespans. As a result, persons with NMDs will likely desire to engage in a more diverse variety of activities of daily living, including increased physical activity or exercise. Therefore, there is a need to increase our knowledge of the effects of acute exercise and chronic training on the neuromuscular system in NMD contexts. Here, we discuss the disease mechanisms and exercise biology of Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and myotonic dystrophy type 1 (DM1), which are among the most prevalent NMDs in children and adults. Evidence from clinical and preclinical studies are reviewed, with emphasis on the functional outcomes of exercise, as well as on the putative cellular mechanisms that drive exercise-induced remodelling of the neuromuscular system. Continued investigation of the molecular mechanisms of exercise adaptation in DMD, SMA, and DM1 will assist in enhancing our understanding of the biology of these most prevalent NMDs. This information may also be useful for guiding the development of novel therapeutic targets for future pursuit. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase 1 (PRMT1), PRMT4, and PRMT5 catalyze the methylation of arginine residues on target proteins. Previous work suggests that these enzymes regulate skeletal muscle plasticity. However, the function of PRMTs during disuseinduced muscle remodeling is unknown. The purpose of our study was to determine whether denervation-induced muscle disuse alters PRMT expression and activity in skeletal muscle, as well as to contextualize PRMT biology within the early disuse-evoked events that precede atrophy, which remain largely undefined. Mice were subjected to 6, 12, 24, 72, or 168 h of unilateral hindlimb denervation. Muscle mass decreased by ~30% after 72 or 168 h of neurogenic disuse, depending on muscle fiber type composition. The expression, localization, and activities of PRMT1, PRMT4, and PRMT5 were modified, exhibiting changes in gene expression and activity that were PRMT-specific. Rapid alterations in canonical muscle atrophy signaling such as forkhead box protein O1, muscle RING-finger protein-1, as well as peroxisome proliferator-activated receptor-α coactivator-1α (PGC- 1) content, AMP-activated protein kinase (AMPK) and p38 mitogenactivated protein kinase, were observed before measurable decrements in muscle mass. Denervation-induced modifications in AMPKPRMT1 and PGC-1α-PRMT1 binding revealed a novel, putative PRMT1-AMPK-PGC-1α signaling axis in skeletal muscle. Here, PGC-1α-PRMT1 binding was elevated after 6 h of disuse, whereas AMPK-PRMT1 interactions were reduced following 168 h of denervation. Our data suggest that PRMT biology is integral to the mechanisms that precede and initiate skeletal muscle atrophy during conditions of neurogenic disuse. This study furthers our understanding of the role of PRMTs in governing skeletal muscle plasticity. [ABSTRACT FROM AUTHOR]

R4602 --> Myotonic Dystrophy type I (DM1) is the most prevalent adult form of muscular dystrophy and is characterized by myotonia, skeletal muscle weakness and wasting. The disease pathogenesis is characterized by a CTG microsatellite repeat expansion, leading to the dysregulation of pre‐messenger RNA splicing of numerous muscle genes. There is currently no cure for this disorder, but recent evidence indicate that exercise is a safe and modestly effective therapy. AMP‐activated protein kinase (AMPK) is critical to the acute responses and chronic adaptations to physical activity at the cellular and molecular level in the healthy condition, as well as in various disease states. However, the AMPK‐signaling response to exercise in DM1 remains largely unknown. Therefore, the purpose of this study is to examine whether a single bout of exercise 1) activates AMPK and its downstream signalling network in DM1 skeletal muscle, and 2) modulates the DM1 molecular signature. Wild‐type (WT) and HSA‐LR (DM1) mice ran on a motor‐driven treadmill until the inability to continue exercise was objectively determined, and the molecular response to physical activity at various timepoints post‐exercise was examined using Western blotting, immunofluorescence microscopy, and qPCR techniques. WT mice ran for 937.6 ± 193.8 meters, which was significantly greater than DM1 mice at 573.3 ± 181.4meters. In the skeletal muscle of WT mice, AMPK activation status was significantly augmented immediately after exercise. This coincided with an increase (p < 0.05) in peroxisome proliferator‐activated receptor γ coactivator‐1α (PGC‐1α) transcript levels, as well as significant elevations in unc‐51‐like kinase 1 (ULK1) and calcium/calmodulin‐dependent protein kinase type 2β (CAMKIIβ) activation. In DM1 mice, acute exercise also significantly stimulated AMPK, however, PGC‐1α, ULK1 and CAMKIIβ were unaffected. In resting muscle, several markers related to autophagy downstream of AMPK, for example ULK1 activation status, p62 protein level, and the lipidated form of microtubule‐associated protein 1‐light chain 3, were significantly elevated in DM1 mice compared to their WT counterparts. These normalized after exercise. Acute physical activity did not impact either the prevalence of toxic myonuclear foci formed by the CTG microsatellite repeat or the proportion of mis‐spliced muscle‐specific chloride channel in DM1 mice. Collectively, these results indicate that while exercise‐induced AMPK phosphorylation was preserved in the skeletal muscle of DM1 mice, markers of upstream and downstream AMPK signalling were attenuated in response to acute physical activity. Nonetheless, our data also suggest that exercise‐evoked AMPK activation normalizes perturbations in the autophagy pathway observed in DM1 muscle. Thus, skeletal muscle AMPK stimulation after a single bout of exercise is very likely necessary but insufficient to elicit beneficial structural and functional adaptations in DM1. [ABSTRACT FROM AUTHOR]

R1495 --> Myotonic dystrophy type 1 (DM1) is the most common life‐limiting muscular dystrophy in adults. Abnormal mitochondrial function and dynamics have been observed in DM1 patient derived cells, which likely exacerbates the muscle pathology in DM1. Exercise is safe, low‐cost, and accessible medicine that reaps robust benefits to mitochondrial biology. However, in DM1 muscle, in vivo assessments of mitochondrial dynamics and mitophagy, as well as the effects of exercise therein, remain unexamined. Therefore, this study aims to further elucidate mitochondrial properties in a mouse model of DM1 (HSALR) and examine the mitochondrial response following an acute bout of exercise. Both wild‐type (WT) and HSALR mice performed a progressive, vigorous bout of exercise on a treadmill until the inability to continue running was objectively determined. Muscle samples were collected at rest and at various timepoints following exercise. At rest, phosphorylated dynamin‐related protein 1 (p‐DRP1Ser616), total DRP1 and Parkin levels were elevated (p < 0.05) in HSALR mice compared to WT. Furthermore, the mitofusin‐2 (MFN2)‐to‐DRP ratio was significantly lower in HSALR animals relative to their WT counterparts. Exercise capacity was lower (p < 0.05) in HSALR mice compared to WT. Immediately following exercise, p‐DRP1Ser616 levels were significantly increased in WT animals but returned to the resting state at 3 hours post‐exercise. In contrast, HSALR showed elevated (p < 0.05) p‐DRP1Ser616 until 3 hours post‐exercise before returning to basal levels at 12 hours. Mitochondrial fission 1 (Fis1) protein content significantly increased 3 hours post‐exercise in WT animals and 12 hours post‐exercise in the HSALR group. MFN2 content was augmented (p < 0.05) immediately following exercise and remained elevated up to 24 hours in HSALR mice only, thus, restoring the MFN2‐to‐DRP1 ratio. Lastly, fission and mitophagy related mRNA transcripts were blunted immediately and 3 hours (p < 0.05) following exercise while the transcription of fusion related genes was augmented (p < 0.05). In contrast, the expression of mitophagy related genes was significantly increased 12 and 24 hours following the exercise bout. Collectively, these data provide further evidence for mitochondrial dysfunction within DM1 biology. An imbalance in fusion and fission processes could greatly diminish mitochondrial function, which could in turn accelerate skeletal muscle atrophy. Exercise may be a promising intervention to correct the imbalance in mitochondrial dynamics and augment overall mitochondrial function within DM1 muscle. [ABSTRACT FROM AUTHOR]