Abstract
Elevated reactive oxygen species (ROS) production and ROS-dependent protein damage is a common observation in the pathogenesis of many muscle wasting disorders, including sarcopenia. However, the contribution of elevated ROS levels to –a breakdown in neuromuscular communication and muscle atrophy remains unknown. In this study, we examined a copper zinc superoxide dismutase [CuZnSOD (Sod1)] knockout mouse (Sod1 −/−), a mouse model of elevated oxidative stress that exhibits accelerated loss of muscle mass, which recapitulates many phenotypes of sarcopenia as early as 5 months of age. We found that young adult Sod1 −/− mice display a considerable reduction in hind limb skeletal muscle mass and strength when compared to age-matched wild-type mice. These changes are accompanied by gross alterations in neuromuscular junction (NMJ) morphology, including reduced occupancy of the motor endplates by axons, terminal sprouting and axon thinning and irregular swelling. Surprisingly however, the average density of acetylcholine receptors in endplates is preserved. Using in vivo electromyography and ex vivo electrophysiological studies of hind limb muscles in Sod1 −/− mice, we found that motor axons innervating the extensor digitorum longus (EDL) and gastrocnemius muscles release fewer synaptic vesicles upon nerve stimulation. Recordings from individually identified EDL NMJs show that reductions in neurotransmitter release are apparent in the Sod1 −/− mice even when endplates are close to fully innervated. However, electrophysiological properties, such as input resistance, resting membrane potential and spontaneous neurotransmitter release kinetics (but not frequency) are similar between EDL muscles of Sod1 −/− and wild-type mice. Administration of the potassium channel blocker 3,4-diaminopyridine, which broadens the presynaptic action potential, improves both neurotransmitter release and muscle strength. Together, these results suggest that ROS-associated motor nerve terminal dysfunction is a contributor to the observed muscle changes in Sod1 −/− mice.
Highlights
There is a delicate balance between reactive oxygen species (ROS) production and detoxification resulting in a limited amount of free ROS
Our previous studies have shown that mice deficient in CuZnSOD (Sod12/2), a model of oxidative stress and sarcopenia, have significantly increased levels of oxidative damage biomarkers, such as F2-isoprostanes, protein carbonyls and 8-oxo-dG in various tissues including skeletal muscle [6,15]
Neuronal and muscle dysfunction, muscle weakness and muscle mass loss [24,25]. It remains unknown whether oxidative stress on its own can modulate neurotransmission and elicit deficits that contribute to muscle dysfunction
Summary
There is a delicate balance between reactive oxygen species (ROS) production and detoxification resulting in a limited amount of free ROS. The resultant oxidative stress is believed to be responsible for many tissue changes including the loss of skeletal muscle mass and strength, impairment of neurotransmitter release, and neuronal degeneration. Reducing cellular antioxidant capacity by disruption of the Cu/Zn superoxide dismutase gene in mice (Sod12/2) results in very high levels of oxidative stress and oxidative damage in all tissues and an acceleration of age-related loss of skeletal muscle mass [6,7]. Skeletal muscle atrophy in these mice is accompanied by neuromuscular junction (NMJ) morphologic changes, increased denervation and an elevated production of superoxide and hydrogen peroxide by muscle mitochondria [6,8]. Elevated levels of ROS can contribute to muscle loss and weakness through a variety of pathways, e.g., oxidative damage and elevated degradation of contractile proteins or oxidative modification of proteins involved in calcium homeostasis and excitation contraction coupling. Elevated ROS have been shown to activate calpain and ubiquitin proteolytic systems and could lead to loss of muscle mass [9,10]
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