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Abstract
Previous studies have shown that proteasome inhibition can have beneficial effects in dystrophic mouse models. In this study, we have investigated the effects of a new selective proteasome inhibitor, CLi, a strong caspase-like inhibitor of the 20S proteasome, on skeletal and cardiac muscle functions of mdx mice. In the first series of experiments, five-month-old male mdx mice (n = 34) were treated with 2 different doses (20 and 100 μg/kg) of CLi and in the second series of experiments, five-month-old female mdx (n = 19) and wild-type (n = 24) mice were treated with 20 μg/kg CLi and Velcade (1 mg/kg) for 1-month. All animals were treadmill exercised twice a week to worsen the dystrophic features. In the first series of experiments, our results demonstrated that 20 μg/kg CLi did not significantly increase absolute and specific maximal forces in skeletal muscle from male mdx mice. Moreover, the higher susceptibility to contraction induced skeletal muscle injury was worsened by 100 μg/kg CLi since the force drop following lengthening contractions was increased with this high dose. Furthermore, we found no differences in the mRNA levels of the molecular markers implicated in dystrophic features. Concerning cardiac function, CLi had no effect on left ventricular function since ejection and shortening fractions were unchanged in male mdx mice. Similarly, CLi did not modify the expression of genes implicated in cardiac remodeling. In the second series of experiments, our results demonstrated an improvement in absolute and specific maximal forces by CLi, whereas Velcade only increased specific maximal force in female mdx mice. In addition, exercise tolerance was not improved by CLi. Taken together, our results show that CLi treatment can only improve maximal force production in exercised female mdx mice without affecting either exercice tolerance capacity or cardiac function. In conclusion, selective inhibition of caspase-like activity of proteasome with CLi has no compelling beneficial effect in dystrophic mdx mice.
Highlights
Duchenne muscular dystrophy is a fatal genetic disorder affecting both skeletal and cardiac muscles
Proteasomal chymotrypsin-like, trypsin-like and caspase-like activities of the 20S catalytic core were measured using the fluorogenic substrates, after 1 week of treatment. We found that both 20 μg/kg and 100 μg/kg CLi treatments selectively inhibit caspase-like activity of 20S proteasome in skeletal muscle (Fig 1) (p
We found that absolute maximal force and specific maximal force, which is the normalization of absolute maximal force by muscle weight, were not significantly increased in Run+CLi-low mdx as compared to Run mdx (Fig 2A and 2B) (p>0.05), indicating that muscle weakness of mdx mice was not significantly improved by the CLi treatment
Summary
Duchenne muscular dystrophy is a fatal genetic disorder affecting both skeletal and cardiac muscles. Less than 10 lengthening contractions cause an immediate marked force drop in mdx mice but not in wild-type mice [6,7,8,9]. In addition to these skeletal muscle dystrophic features, the heart of mdx mice exhibits signs of cardiomyopathy that are more pronounced in old as compared to young mdx mice [10,11]
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