The Role of Mitochondrial Peroxide Release in the Mechanisms Underlying Age‐Related Sarcopenia

Age related loss of muscle mass and function (sarcopenia) is a major contributor to reduced quality of life in the elderly. Previous studies from our laboratory have shown that denervation induced alterations in muscle mitochondrial reactive oxygen species (ROS) generation is an integral player in this process. To specifically determine the role of mitochondrial function, generation of ROS and lipid peroxides in denervation atrophy, we utilized two transgenic mouse models with increased expression of the hydrogen peroxide scavengers catalase or peroxiredoxin 3, specifically in skeletal muscle. First, we asked whether these mitochondrial antioxidants can reduce denervation induced changes in muscle mitochondrial ROS production and reduce muscle atrophy in a surgical denervation model. Gastrocnemius mass is significantly reduced (~20%) at 7 days post‐sciatic nerve transection in wildtype, skmPrdx3 and skmMCAT mice, i.e., there was no protective effect of hydrogen peroxide scavengers on denervation atrophy. ROS production measured using the fluorescent probe Amplex Red was elevated in permeabilized muscle fibers and isolated mitochondria from denervated hindlimb 7 days post transection and neither Prdx3 or MCAT expression inhibits the signal. This data supports that the Amplex Red signal does not represent hydrogen peroxide alone, but includes the response from other lipid peroxide species and suggests that hydrogen peroxide scavenging is not sufficient to reduce denervation induced atrophy. Next, we asked whether Prdx3 muscle specific expression can modulate the sarcopenia phenotype in an established mouse model of accelerated sarcopenia, mice lacking CuZnSOD (Sod1KO/skmPrdx3Tg mice). ROS generation is significantly elevated in isolated muscle mitochondria from Sod1KO mice, and normalized by Prdx3 overexpression in the Sod1KO/skmPrdx3Tg mice. The oxygen consumption rate is reduced in skeletal muscle mitochondria isolated from Sod1KO muscle and restored by Prdx3 overexpression. We also found that in vitro contractile force generation was decreased by ~20% in Sod1KO mice, and the force reduction wwas rescued in Sod1KO/skmPrdx3Tg mice. Importantly, the muscle atrophy that occurs in the Sod1KO mice is fully restored by Prdx3 overexpression. This finding demonstrates a direct role of skeletal muscle‐specific mitochondrial H2O2 in promoting contractile abnormalities and muscle atrophy. Together these results implicate mitochondrial H2O2 generation as a novel therapeutic target to ameliorate skeletal muscle pathologies and support further studies to elucidate the role of lipid peroxide mediators released by mitochondria in denervation induced atrophy. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .