The Lack of CuZnSOD leads to impaired neurotransmitter release, neuromuscular junction destabilization and reduced muscle strength in mice

Yun Shi, Maxim V. Ivannikov, Michael E. Walsh, Yuhong Liu, Yiqiang Zhang, Carlos A. Jaramillo, Gregory T. Macleod, Holly Van Remmen

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere100834
JournalPLoS One
Volume9
Issue number6
DOIs
StatePublished - Jun 27 2014

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muscle strength
Neuromuscular Junction
Muscle Strength
neurotransmitters
Neurotransmitter Agents
Muscle
muscles
reactive oxygen species
mice
Reactive Oxygen Species
axons
sarcopenia
Sarcopenia
Muscles
limbs (animal)
animal models
Axons
Skeletal Muscle
Extremities
muscular atrophy

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Shi, Y., Ivannikov, M. V., Walsh, M. E., Liu, Y., Zhang, Y., Jaramillo, C. A., ... Van Remmen, H. (2014). The Lack of CuZnSOD leads to impaired neurotransmitter release, neuromuscular junction destabilization and reduced muscle strength in mice. PLoS One, 9(6), [e100834]. https://doi.org/10.1371/journal.pone.0100834

The Lack of CuZnSOD leads to impaired neurotransmitter release, neuromuscular junction destabilization and reduced muscle strength in mice. / Shi, Yun; Ivannikov, Maxim V.; Walsh, Michael E.; Liu, Yuhong; Zhang, Yiqiang; Jaramillo, Carlos A.; Macleod, Gregory T.; Van Remmen, Holly.

In: PLoS One, Vol. 9, No. 6, e100834, 27.06.2014.

Research output: Contribution to journalArticle

Shi, Y, Ivannikov, MV, Walsh, ME, Liu, Y, Zhang, Y, Jaramillo, CA, Macleod, GT & Van Remmen, H 2014, 'The Lack of CuZnSOD leads to impaired neurotransmitter release, neuromuscular junction destabilization and reduced muscle strength in mice', PLoS One, vol. 9, no. 6, e100834. https://doi.org/10.1371/journal.pone.0100834
Shi, Yun ; Ivannikov, Maxim V. ; Walsh, Michael E. ; Liu, Yuhong ; Zhang, Yiqiang ; Jaramillo, Carlos A. ; Macleod, Gregory T. ; Van Remmen, Holly. / The Lack of CuZnSOD leads to impaired neurotransmitter release, neuromuscular junction destabilization and reduced muscle strength in mice. In: PLoS One. 2014 ; Vol. 9, No. 6.
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