Scavenging mitochondrial hydrogen peroxide by peroxiredoxin 3 overexpression attenuates contractile dysfunction and muscle atrophy in a murine model of accelerated sarcopenia

Abstract

Age‐related muscle atrophy and weakness, or sarcopenia, are significant contributors to compromised health and quality of life in the elderly. While the mechanisms driving this pathology are not fully defined, reactive oxygen species, neuromuscular junction (NMJ) disruption, and loss of innervation are important risk factors. The goal of this study is to determine the impact of mitochondrial hydrogen peroxide on neurogenic atrophy and contractile dysfunction. Mice with muscle‐specific overexpression of the mitochondrial H2O2 scavenger peroxiredoxin3 (mPRDX3) were crossed to Sod1KO mice, an established mouse model of sarcopenia, to determine whether reduced mitochondrial H2O2 can prevent or delay the redox‐dependent sarcopenia. Basal rates of H2O2 generation were elevated in isolated muscle mitochondria from Sod1KO, but normalized by mPRDX3 overexpression. The mPRDX3 overexpression prevented the declines in maximum mitochondrial oxygen consumption rate and calcium retention capacity in Sod1KO. Muscle atrophy in Sod1KO was mitigated by ~20% by mPRDX3 overexpression, which was associated with an increase in myofiber cross‐sectional area. With direct muscle stimulation, maximum isometric specific force was reduced by ~20% in Sod1KO mice, and mPRDX3 overexpression preserved specific force at wild‐type levels. The force deficit with nerve stimulation was exacerbated in Sod1KO compared to direct muscle stimulation, suggesting NMJ disruption in Sod1KO. Notably, this defect was not resolved by overexpression of mPRDX3. Our findings demonstrate that muscle‐specific PRDX3 overexpression reduces mitochondrial H2O2 generation, improves mitochondrial function, and mitigates loss of muscle quantity and quality, despite persisting NMJ impairment in a murine model of redox‐dependent sarcopenia.

Peroxiredoxin, Senescence, and Cancer

“…The expression level of MondoA decreases with age that drives cellular senescence by impaired mitochondrial homeostasis through the expression of PRX3 [ 86 ]. In agreement with this finding, muscle-specific overexpression of PRX3 can attenuate contractile dysfunction and muscle atrophy in a SOD1 KO mouse model of accelerated sarcopenia by improving mitochondrial function [ 71 ].…”

Lipid hydroperoxides and oxylipins are mediators of denervation induced muscle atrophy

“…Elevated muscle levels of these mitochondrial H 2 O 2 scavengers did not protect muscle mass in a 7-day sciatic nerve transection model, which may be because oxidized lipid and oxylipin levels were not impacted by these interventions. In contrast, elevated levels of Prdx3 and mitochondrial targeted catalase were protective in mitigating muscle loss in the CuZnSOD knockout mouse model (Sod1KO) of accelerated sarcopenia and frailty [ 51 , 52 ]. In the case of overexpression of muscle mitochondrial targeted catalase, the neuromuscular junction (NMJ) disruption seen in the Sod1KO mice was completely prevented preserving muscle mass and contractile function in the Sod1KO mice [ 51 ].…”

“…In the case of overexpression of muscle mitochondrial targeted catalase, the neuromuscular junction (NMJ) disruption seen in the Sod1KO mice was completely prevented preserving muscle mass and contractile function in the Sod1KO mice [ 51 ]. However, overexpression of PRDX3 did not protect the NMJ; however, there still was a protection in muscle mass and force [ 52 ]. There is evidence that supports that PRDX3 may directly reduce lipid peroxidation in liver tissue (reduced F 2 isoprostanes and 4-HNE adducts) [ 53 ].…”

Impact of aging and oxidative stress on specific components of excitation contraction coupling in regulating force generation

“…Therefore, we asked whether cellular Ca 2+ homeostasis was disturbed in muscle from these two models and whether there was an impact on mitochondrial Ca 2+ metabolism or respiration. To test this, we challenged the mitochondrial CRC in isolated mitochondria from muscles in all three groups as previously described ( 4 , 27 ). We observed a significant decrease in CRC in mitochondria from both Sod1 KO and aging muscles compared to WT muscles, indicating a significant impairment in mitochondrial Ca 2+ buffering capacity, which is similar to what Picard et al ( 52 ) reported in aging muscles from rats.…”