293 - Skeletal muscle specific overexpression of the mitochondrial H2O2 scavenger, peroxiredoxin 3, rescues mitochondrial dysfunction and sarcopenia phenotypes elicited by redox imbalance

Abstract

Background Reactive oxygen species (ROS) are known to impair contractile function and contribute to muscle atrophy, and one of the primary sources of ROS is mitochondria. The goal of this study is to test whether muscle specific overexpression of mitochondrial hydrogen peroxide scavenger, peroxiredoxin3 (Prdx3), can prevent loss of muscle mass and function associated with sarcopenia. Methods We overexpressed prdx3 by flanking a prdx3 transgene with a stop codon that can be released by skeletal muscle specific expression of cre recombinase driven by the human skeletal actin (HSA) promotor. Muscle specific cre expression allows the transcription of the prdx3 transgene and leads to increased prdx3 expression in skeletal muscle. The prdx3 muscle specific transgenic mice were crossed with an established mouse model of accelerated sarcopenia (Sod1KO) to generate Sod1KO/mPrd3Tg mice. Results In agreement with our previous results, the basal rate of ROS generation was significantly elevated in isolated mitochondria from Sod1KO mice but normalized by prdx3 overexpression in the Sod1KO/mPrd3Tg mice. The reduction in oxygen consumption rate from complex II present in mitochondria from Sod1KO muscle was also restored by prdx3 overexpression. To determine the effects of mitochondrial ROS on skeletal muscle weakness, we tested in vitro contractile properties of extensor digitorum longus (EDL). Maximum isometric specific force was decreased by ~20% in Sod1KO mice, but the reduction in force was rescued inSod1KO/mPrd3Tg mice. Importantly, the loss in gastrocnemius mass that occurs in the Sdo1KO mice was fully restored by prdx3 overexpression. Conclusion Our data demonstrate, for the first time, a direct role of skeletal muscle-specific mitochondrial H2O2 in promoting contractile abnormalities and atrophy of skeletal muscle. This study implicates mitochondrial H2O2 generation as a novel therapeutic target to ameliorate skeletal muscle pathologies.