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A Single Dose of Exercise Initiates Corrective Mitochondrial Plasticity in Myotonic Dystrophy Type 1
Author(s) -
Mikhail Andrew,
Manta Alexander,
Ljubicic Vladimir
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.01495
Subject(s) - myotonic dystrophy , mfn2 , fis1 , mitophagy , mitochondrial fission , medicine , skeletal muscle , endocrinology , treadmill , duchenne muscular dystrophy , dnm1l , mitochondrion , biology , mitochondrial dna , mitochondrial fusion , biochemistry , apoptosis , autophagy , gene
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 (HSA LR ) and examine the mitochondrial response following an acute bout of exercise. Both wild‐type (WT) and HSA LR 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‐DRP1 Ser616 ), total DRP1 and Parkin levels were elevated (p < 0.05) in HSA LR mice compared to WT. Furthermore, the mitofusin‐2 (MFN2)‐to‐DRP ratio was significantly lower in HSA LR animals relative to their WT counterparts. Exercise capacity was lower (p < 0.05) in HSA LR mice compared to WT. Immediately following exercise, p‐DRP1 Ser616 levels were significantly increased in WT animals but returned to the resting state at 3 hours post‐exercise. In contrast, HSA LR showed elevated (p < 0.05) p‐DRP1 Ser616 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 HSA LR group. MFN2 content was augmented (p < 0.05) immediately following exercise and remained elevated up to 24 hours in HSA LR 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.