Effect of Muscle Fiber Denervation on Mitochondrial Hydrogen Peroxide Generation in Adjacent Innervated Muscle Fibres: Role in Sarcopenia?

Abstract

Nerve transection causes dramatic increases in mitochondrial generation of hydrogen peroxide (H2O2) in the denervated skeletal muscle of rodents. We hypothesized that denervation of a limited number of fibers, such as that observed in muscles during aging, could influence H2O2 generation by both denervated and innervated fibers throughout the muscle. Thy1‐YFP mice (expressing YFP in neurons) underwent full transection of the peroneal nerve or transection of only one of the 3 branches entering the anterior tibialis (AT) muscle. Following up to 10days recovery, generation of H2O2 by mitochondria in permeablised fibers with intact mitochondra from different portions of the AT was assessed using Amplex Red. Results demonstrated increased H2O2 generation by 3days after full transection compared with sham control, which remained elevated at 10days. In situ imaging showed loss of innervation of endplates with no evidence of post‐synaptic changes. Immuno‐fluorescent staining for markers of denervation showed neuronal cell adhesion molecule positive muscle fibers by 7days post‐surgery. Transection of the single branch of the peroneal nerve caused denervation of a portion of the AT and mitochondrial H2O2 generation in the denervated portion was elevated by 3days post‐transection in a similar manner to the fully denervated muscle. Denervation of some just fibers was associated with increased mitochondrial H2O2 generation in all areas of the muscle. Thus data support the hypothesis that the effect of partial denervation on muscle H2O2 generation is mirrored in fully innervated fibers of the same muscle, an effect which may be mirrored in sarcopenia. Supported by the UK Biotechnology and Biological Sciences Research Council.