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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.
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.
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