Denervated muscle fibers induce mitochondrial peroxide generation in neighboring innervated fibers: Role in muscle aging

Abstract

Disruption of neuromuscular junctions and denervation of some muscle fibers occurs in ageing skeletal muscle and contribute to loss of muscle mass and function. Aging is associated with mitochondrial dysfunction and loss of redox homeostasis potentially occurs through increased mitochondrial generation of reactive oxygen species (ROS). No specific link between increased mitochondrial ROS generation and denervation has been defined in muscle ageing. To address this, we have examined the effect of experimental denervation of all fibers, or only a proportion of the fibers, in the mouse tibialis anterior (TA) muscle on muscle mitochondrial peroxide generation. Transection of the peroneal nerve of mice caused loss of pre-synaptic axons within 1–3 days with no significant morphological changes in post-synaptic structures up to 10 days post-surgery when decreased TA mass and fiber size were apparent. Mitochondria in the denervated muscle showed increased peroxide generation by 3 days post-transection. Use of electron transport chain (ETC) substrates and inhibitors of specific pathways indicated that the ETC was unlikely to contribute to increased ROS generation, but monoamine oxidase B, NADPH oxidase and phospholipase enzymes were implicated. Transection of one of the 3 branches of the peroneal nerve caused denervation of some TA muscle fibers while others retained innervation, but increased mitochondrial peroxide generation occurred in both denervated and innervated fibers. Thus the presence of recently denervated fibers leads to increased ROS generation by mitochondria in neighboring innervated fibers providing a novel explanation for the increased mitochondrial oxidative stress and damage seen with aging in skeletal muscles.

Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

“…Several reports involving animal and human models of skeletal muscle unloading and denervation have identified profound mitochondrial dysfunction and accompanying increases in ROS production that occur after the injury (65)(66)(67)(68). We also observed increased markers of ROS in injured muscles, including elevated levels of glutathionylated proteins, as well as an increase in the abundance of Prdx3 and Prdx6, which scavenge hydrogen peroxide in the mitochondria and cytoplasm, respectively (69,70).…”

Reduced mitochondrial lipid oxidation leads to fat accumulation in myosteatosis

“…Several reports involving animal and human models of skeletal muscle unloading and denervation have identified profound mitochondrial dysfunction and accompanying increases in ROS production that occur subsequent to the injury (60)(61)(62)(63). We also observed increased markers of ROS in injured muscles, including elevated levels of glutathionylated proteins, as well as an increase in the abundance of Prdx3 and Prdx6 which scavenge hydrogen peroxide in the mitochondria and cytoplasm, respectively (64,65).…”

Impairments in left ventricular mitochondrial bioenergetics precede overt cardiac dysfunction and remodelling in Duchenne muscular dystrophy

“…; Singh & Hood, ; Pollock et al . ). Such PTP formation has also already been implicated in DMD myopathy in response to calcium stress (Godin et al .…”

“…It is thought that impairments in both mitochondrial respiration and H 2 O 2 emission can contribute to the induction of PTP formation and subsequenty activate mitochondria-derived cell death pathways. Indeed, mitochondrial induction of apoptosis and necrosis has been linked to several diseases that also exhibit elevated mitochondrial ROS and impaired oxidative phosphorylation (Adlam et al 2005;Szeto, 2008;Min et al 2011;Powers et al 2011;Singh & Hood, 2011;Pollock et al 2017). Such PTP formation has also already been implicated in DMD myopathy in response to calcium stress Pauly et al 2012).…”