Key pointsr 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.r A microsatellite repeat expansion mutation results in RNA toxicity and dysregulation of mRNA processing, which are the primary downstream causes of the disorder.r 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.r 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.r At the cellular level, chronic physical activity attenuated RNA toxicity, liberated Muscleblind-like 1 protein from myonuclear foci and improved mRNA alternative splicing.Abstract 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 A. Manta and others J Physiol 597.5 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.

The age‐related loss of skeletal muscle mass and functionality, known as sarcopenia, is a critical risk factor for morbidity and all‐cause mortality. Resistance exercise training (RET) is the primary countermeasure to fight sarcopenia and ageing. Altered intercellular communication is a hallmark of ageing, which is not well elucidated. Circulating extracellular vesicles (EVs), including exosomes, contribute to intercellular communication by delivering microRNAs (miRNAs), which modulate post‐translational modifications, and have been shown to be released following exercise. There is little evidence regarding how EVs or EV‐miRNAs are altered with age or RET. Therefore, we sought to characterize circulating EVs in young and older individuals, prior to and following a 12‐week resistance exercise programme. Plasma EVs were isolated using size exclusion chromatography and ultracentrifugation. We found that ageing reduced circulating expression markers of CD9, and CD81. Using late‐passage human myotubes as a model for ageing in vitro, we show significantly lower secreted exosome‐like vesicles (ELVs). Further, levels of circulating ELV‐miRNAs associated with muscle health were lower in older individuals at baseline but increased following RET to levels comparable to young. Muscle biopsies show similar age‐related reductions in miRNA expressions, with largely no effect of training. This is reflected in vitro, where aged myotubes show significantly reduced expression of endogenous and secreted muscle‐specific miRNAs (myomiRs). Lastly, proteins associated with ELV and miRNA biogenesis were significantly higher in both older skeletal muscle tissues and aged human myotubes. Together we show that ageing significantly affects ELV and miRNA cargo biogenesis, and release. RET can partially normalize this altered intercellular communication. imageKey points We show that ageing reduces circulating expression of exosome‐like vesicle (ELV) markers, CD9 and CD81. Using late‐passage human skeletal myotubes as a model of ageing, we show that secreted ELV markers are significantly reduced in vitro. We find circulating ELV miRNAs associated with skeletal muscle health are lower in older individuals but can increase following resistance exercise training (RET). In skeletal muscle, we find altered expression of miRNAs in older individuals, with no effect of RET. Late‐passage myotubes also appear to have aberrant production of endogenous myomiRs with lower abundance than youthful counterparts In older skeletal muscle and late‐passage myotubes, proteins involved with ELV‐ and miRNA biogenesis are upregulated

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Radiation exposure is an undeniable health threat encountered in various occupations and procedures. High energy waves in ionizing radiation cause DNA damage and induce reactive oxygen species (ROS) production, which further exacerbate DNA, protein, and lipid damage, increasing risk of mutations. Although endogenous antioxidants such as superoxide dismutase have evolved to upregulate and neutralize ROS, exogenous dietary antioxidants also have the potential to combat ionizing radiation (IR)-induced ROS production. We evaluated a cocktail of ingredients (AOX) purported to have antioxidant and mitochondrial protective properties on the acute effects of IR. We show that IR stimulates DNA damage through phosphorylation of DNA repair proteins in the heart, brain, and liver of mice. AOX showed partial protection in brain and liver, through a lack of significant activation in given repair proteins. In addition, AOX attenuated the IR-induced increase in NF-kβ mRNA and protein expression in brain and liver. Lastly, cytochrome c oxidase complex transcripts were significantly higher in heart and brain following radiation, which was also diminished by prior ingestion of AOX. Together, our findings suggest that a multi-ingredient AOX supplement may attenuate the IR-induced cellular damage response and represents a feasible and cost-effective preventative supplement for at-risk populations of radiation exposure.