Muscle mitochondrial catalase expression prevents neuromuscular junction disruption, atrophy, and weakness in a mouse model of accelerated sarcopenia

Abstract

Background Oxidative stress and damage are associated with a number of ageing phenotypes, including age‐related loss of muscle mass and reduced contractile function (sarcopenia). Our group and others have reported loss of neuromuscular junction (NMJ) integrity and increased denervation as initiating factors in sarcopenia, leading to mitochondrial dysfunction, generation of reactive oxygen species and peroxides, and loss of muscle mass and weakness. Previous studies from our laboratory show that denervation‐induced skeletal muscle mitochondrial peroxide generation is highly correlated to muscle atrophy. Here, we directly test the impact of scavenging muscle mitochondrial hydrogen peroxide on the structure and function of the NMJ and muscle mass and function in a mouse model of denervation‐induced muscle atrophy CuZnSOD (Sod1−/− mice, Sod1KO). Methods Whole‐body Sod1KO mice were crossed to mice with increased expression of human catalase (MCAT) targeted specifically to mitochondria in skeletal muscle (mMCAT mice) to determine the impact of reduced hydrogen peroxide levels on key targets of sarcopenia, including mitochondrial function, NMJ structure and function, and indices of muscle mass and function. Results Female adult (~12‐month‐old) Sod1KO mice show a number of sarcopenia‐related phenotypes in skeletal muscle including reduced mitochondrial oxygen consumption and elevated reactive oxygen species generation, fragmentation, and loss of innervated NMJs (P < 0.05), a 30% reduction in muscle mass (P < 0.05), a 36% loss of force generation (P < 0.05), and a loss of exercise capacity (305 vs. 709 m in wild‐type mice, P < 0.05). Muscle from Sod1KO mice also shows a 35% reduction in sarco(endo)plasmic reticulum ATPase activity (P < 0.05), changes in the amount of calcium‐regulating proteins, and altered fibre‐type composition. In contrast, increased catalase expression in the mMCAT × Sod1KO mice completely prevents the mitochondrial and NMJ‐related phenotypes and maintains muscle mass and force generation. The reduction in exercise capacity is also partially inhibited (~35%, P < 0.05), and the loss of fibre cross‐sectional area is inhibited by ~50% (P < 0.05). Conclusions Together, these striking findings suggest that scavenging of mitochondrial peroxide generation by mMCAT expression efficiently prevents mitochondrial dysfunction and NMJ disruption associated with denervation‐induced atrophy and weakness, supporting mitochondrial H2O2 as an important effector of NMJ alterations that lead to phenotypes associated with sarcopenia.

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

“…Our group also investigated the role of mitochondria‐targeted catalase in skeletal muscle (mMCAT) in redox‐dependent sarcopenia. Contrary to our results in mPRDX3Tg, the mMCAT mice were fully protected from NMJ disruption as well as muscle atrophy and weakness in Sod1KO mice (Xu et al, 2021). The reasons for the discrepancy remain unclear, but one possibility would be the cofactor involvement for PRDX3, which is not required for catalase.…”

“…To further assess cytoplasmic calcium kinetics in muscle, we determined the activity of the Sarco‐Endoplasmic Reticulum Calcium ATPase (SERCA) pump, which plays a critical role in calcium reuptake during muscle relaxation. Consistent with our previous reports (Xu et al, 2021), the SERCA activity was significantly impaired in Sod1KO mice, but was partially improved in the Sod1KO/mPRDX3Tg mice (Figure 3f,g). It is possible that calcium storage proteins are increased inside of SR, as recently demonstrated by a model of mitochondrial‐targeted catalase overexpression (Xu et al, 2021) or that PRDX3 overexpression can modulate the oxidation of specific residues in the SEARCA ATPase that are known to be inactivated by oxidation (Dremina et al, 2007).…”

“…Consistent with our previous reports (Xu et al, 2021), the SERCA activity was significantly impaired in Sod1KO mice, but was partially improved in the Sod1KO/mPRDX3Tg mice (Figure 3f,g). It is possible that calcium storage proteins are increased inside of SR, as recently demonstrated by a model of mitochondrial‐targeted catalase overexpression (Xu et al, 2021) or that PRDX3 overexpression can modulate the oxidation of specific residues in the SEARCA ATPase that are known to be inactivated by oxidation (Dremina et al, 2007). Increased mPRDX3 expression improves muscle quality, which are associated with enhanced calcium kinetics and handling in the cytoplasm.…”

“…This would be consistent with the results reported in a similar model expressing muscle‐specific mitochondrial‐targeted catalase in the Sod1KO mice. The mMCAT expression in the Sod1KO mice resulted in a significant increase in exercise tolerance (Xu et al, 2021). Improvements in mitochondrial functions by PRDX3 may or may not be related to an increase in mitochondrial contents.…”

Role of Myostatin in Muscle Degeneration by Random Positioning Machine Exposure: An in vitro Study for the Treatment of Sarcopenia

“…In addition, during the aging process there is a progressive loss of motor neurons, leading to a decline in the neuromuscular system (Larsson et al, 2019). These alterations are associated with others that promote the sarcopenia progression, such as altered microcirculation, mitochondrial damage, and loss of regenerative potential (Ryan et al, 2006;Degens, 2010;Xu et al, 2021). The muscle decline strongly affects bone tropism, mobility, and skeletal system characteristics (Scimeca et al, 2015).…”