Redox responses in skeletal muscle following denervation

Abstract

Previous studies have shown a significant increase in the mitochondrial generation of hydrogen peroxide (H2O2) and other peroxides in recently denervated muscle fibers. The mechanisms for generation of these peroxides and how the muscle responds to these peroxides are not fully established. The aim of this work was to determine the effect of denervation on the muscle content of proteins that may contribute to mitochondrial peroxide release and the muscle responses to this generation. Denervation of the tibialis anterior (TA) and extensor digitorum longus (EDL) muscles in mice was achieved by surgical removal of a small section of the peroneal nerve prior to its entry into the muscle. An increase in mitochondrial peroxide generation has been observed from 7 days and sustained up to 21 days following denervation in the TA muscle fibers. This increased peroxide generation was reduced by incubation of skinned fibers with inhibitors of monoamine oxidases, NADPH oxidases or phospholipase A2 enzymes and the muscle content of these enzymes together with peroxiredoxin 6 were increased following denervation. Denervated muscle also showed significant adaptations in the content of several enzymes involved in the protection of cells against oxidative damage. Morphological analyses indicated a progressive significant loss of muscle mass in the TA muscle from 7 days up to 21 days following denervation due to fiber atrophy but without fiber loss. These results support the possibility that, at least initially, the increase in peroxide production may stimulate adaptations in an attempt to protect the muscle fibers, but that these processes are insufficient and the increased peroxide generation over the longer term may activate degenerative and atrophic processes in the denervated muscle fibers.

Neuron‐specific deletion of CuZnSOD leads to an advanced sarcopenic phenotype in older mice

“…The major finding of this study is that reduced expression of the superoxide scavenger CuZnSOD in neuronal tissue, initiated postdevelopment in adult mice, results in an early loss of alpha motor neurons in the ventral spinal cord, followed by a later disruption of neuromuscular junctions and muscle atrophy and weakness in the older mice. (Chipman, Schachner, & Rafuse, 2014;Scalabrin et al, 2019;Vasilaki et al, 2010). Thus, the second hit may involve the muscle reaching a threshold past which it no longer maintains NMJ structure and function allowing downstream effects of muscle mass and function to occur.…”

Loss of HtrA2/Omi protease activity induces mitonuclear imbalance and sarcopenia via differential regulation of mitochondrial biogenesis

“…In the present study, the HtrA2 mnd2(-/-) mice were sacrificed at 30 days postnatal. Considering the fact that mRNA levels, structure and weight of muscle did not significantly altered until 3-7 days after denervation [56][57][58][59][60][61], and that only 11% of specific force decrements are due to denervated fibers in rats [62], it suggests that the sarcopenia features observed in our study were not attributed to motor neurons degeneration. Consistent with our findings, Kang et al showed that HtrA2 mnd2(-/-) mice were rescued from neurodegeneration by transgenic expression of HtrA2/Omi in the brain, and adult transgenic HtrA2 mnd2(-/-) mice still developed accelerated aging phenotypes including muscle atrophy, indicating a role of HtrA2/Omi protease activity in muscle aging.…”

Master Regulators of Muscle Atrophy: Role of Costamere Components

“…Transcripts of both PCG-1α and β, the regulators of mitochondrial proliferation, dramatically decrease after 24 h-denervation [ 237 ], suggesting early impairment of mitochondrial pool renewal. Monoamine oxidase A transcript and protein content was found to be increased between 3–24 h after denervation [ 87 , 244 ]. However, ROS production from mitochondria apparently increased later than 48-h denervation [ 103 , 104 , 244 ], possibly in concomitance with increased mitochondria misplacement at A band [ 245 ].…”

“…Monoamine oxidase A transcript and protein content was found to be increased between 3–24 h after denervation [ 87 , 244 ]. However, ROS production from mitochondria apparently increased later than 48-h denervation [ 103 , 104 , 244 ], possibly in concomitance with increased mitochondria misplacement at A band [ 245 ]. The possibility exists that other ROS sources do contribute to a very early increase in oxidative stress.…”