The effect of exercise on imbalanced mitochondrial dynamics in the skeletal muscle of myotonic dystrophy type 1 mice


Topic:

Pre-Clinical Research

Poster Number: 23

Author(s):

Andrew Mikhail MSc, Alexander Manta MSc, Vladimir Ljubicic PhD

Institutions:

1. McMaster University, 2. McMaster University, 3. McMaster University

Myotonic dystrophy type 1 (DM1) is the most common life-limiting muscular dystrophy in adults. Abnormal mitochondrial function likely contributes to 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. Lastly, MFN2 content was augmented (p < 0.05) immediately following exercise and remained elevated up to 24 hours in HSALR mice, thus, restoring the MFN2-to-DRP1 ratio. Collectively, these data provide further evidence for mitochondrial dysfunction within DM1 biology. Exercise may be a promising intervention to correct the imbalance in mitochondrial dynamics and augment overall mitochondrial function within DM1 muscle.