The primary objective of this study was to determine whether alterations in mitochondria affect recovery of skeletal muscle strength and mitochondrial enzyme activities following myotoxic injury. 3-methyladenine (3-MA) was administered daily to blunt autophagy (15mg/kg) and the creatine analog guanidionpropionic acid (β-GPA) (1% in chow) was administered daily to enhance oxidative capacity. Male C57BL/6 mice were randomly assigned to non-treatment (Con; n=6), 3-MA (n=6), or β-GPA (n=8) groups for 10 wk of treatment. Mice were sacrificed two weeks after myotoxic injury to assess mitochondrial remodeling during regeneration and its association with the recovery of muscle strength. Injured muscles had a greater expression of several autophagy-related proteins (e.g., pUlk1 ~2-4 fold, p<0.049) compared to uninjured muscles indicating a relationship between muscle regeneration/remodeling and autophagy. By 2 weeks post-injury, 3-MA-treated mice had significantly less recovery of strength (18% less, p=0.03) and lower mitochondrial enzyme activity (e.g., citrate synthase (CS): 22% less, p =0.049) compared to Con, suggesting that the autophagy process plays an important role during muscle regeneration. In contrast, muscle regeneration was nearly complete in β-GPA-treated mice, i.e., strength recovered to 93% of baseline vs.78% for Con mice. Remarkably, 14 d was sufficient for a near complete recovery of mitochondrial function in β-GPA-treated mice (e.g., no difference between injured and uninjured in CS activity, p=0.49), indicating a robust mitochondrial remodeling process during muscle regeneration. In conclusion, autophagy is likely activated following muscle injury and appears to play an important role in functional muscle regeneration.
- unc-51 like autophagy activating kinase 1
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