Impaired neuromuscular transmission and skeletal muscle fiber necrosis in mice lacking Na/Ca exchanger 3
Sophie Sokolow, … , Andre Herchuelz, Stéphane Schurmans
Sophie Sokolow, … , Andre Herchuelz, Stéphane Schurmans
Published January 15, 2004
Citation Information: J Clin Invest. 2004;113(2):265-273. https://doi.org/10.1172/JCI18688.
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Article Neuroscience

Impaired neuromuscular transmission and skeletal muscle fiber necrosis in mice lacking Na/Ca exchanger 3

Abstract

We produced and analyzed mice deficient for Na/Ca exchanger 3 (NCX3), a protein that mediates cellular Ca2+ efflux (forward mode) or Ca2+ influx (reverse mode) and thus controls intracellular Ca2+ concentration. NCX3-deficient mice (Ncx3–/–) present a skeletal muscle fiber necrosis and a defective neuromuscular transmission, reflecting the absence of NCX3 in the sarcolemma of the muscle fibers and at the neuromuscular junction. The defective neuromuscular transmission is characterized by the presence of electromyographic abnormalities, including low compound muscle action potential amplitude, a decremental response at low-frequency nerve stimulation, an incremental response, and a prominent postexercise facilitation at high-frequency nerve stimulation, as well as neuromuscular blocks. The analysis of quantal transmitter release in Ncx3–/– neuromuscular junctions revealed an important facilitation superimposed on the depression of synaptic responses and an elevated delayed release during high-frequency nerve stimulation. It is suggested that Ca2+ entering nerve terminals is cleared relatively slowly in the absence of NCX3, thereby enhancing residual Ca2+ and evoked and delayed quantal transmitter release during repetitive nerve stimulation. Our findings indicate that NCX3 plays an important role in vivo in the control of Ca2+ concentrations in the skeletal muscle fibers and at the neuromuscular junction.

Authors

Sophie Sokolow, Mario Manto, Philippe Gailly, Jordi Molgó, Clarisse Vandebrouck, Jean-Marie Vanderwinden, Andre Herchuelz, Stéphane Schurmans

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Electromyographic findings in Ncx3–/– mice. (a) Recruitment curves of mu...
Electromyographic findings in Ncx3–/– mice. (a) Recruitment curves of muscle responses evoked in the gastrocnemius muscle by stimulation of the sciatic nerve at increasing intensities. Mean CMAPs obtained in Ncx3+/+ (n = 5; filled circles) and Ncx3–/– (n = 5; open circles) mice are illustrated. (b and c) Effects of repetitive stimulation of the sciatic nerve at 10 (b) and 30 Hz (c) in Ncx3+/+ and Ncx3–/– mice. The graphs shown are representative of all the mice tested in the same group, except for Ncx3–/– mice at HRRS, where the graph is representative of one out of the 4/8 mice with an incremental CMAP. (d and e) Time course of the fifth response amplitude/first response amplitude ratios during LRRS (d) and HRRS (e) before and after exercise (20 minutes of repetitive stimuli) in Ncx3+/+ (n = 5; black bars) and Ncx3–/– (n = 5; gray bars) mice. (f) Ratios of the values illustrated in (d) and (e) (filled circles, Ncx3+/+ mice; open circles, Ncx3–/– mice). (g and h) MCDs expressed in microseconds and blocking rates expressed in percent in Ncx3+/+ mice (n = 22 fibers; MCDs, filled circles; blocking rate, open circles) and Ncx3–/– mice (n = 23 fibers; filled triangles, MCDs; open triangles, blocking rate). Statistics (in a, d–h): mean ± SEM; *P ≤ 0.05; **P ≤ 0.01.