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Calpain activation impairs neuromuscular transmission in a mouse model of the slow-channel myasthenic syndrome
Jason S. Groshong, … , Richard J. Miller, Christopher M. Gomez
Jason S. Groshong, … , Richard J. Miller, Christopher M. Gomez
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):2903-2912. https://doi.org/10.1172/JCI30383.
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Research Article Neuroscience Article has an altmetric score of 3

Calpain activation impairs neuromuscular transmission in a mouse model of the slow-channel myasthenic syndrome

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Abstract

The slow-channel myasthenic syndrome (SCS) is a hereditary disorder of the acetylcholine receptor (AChR) of the neuromuscular junction (NMJ) that leads to prolonged AChR channel opening, Ca2+ overload, and degeneration of the NMJ. We used an SCS transgenic mouse model to investigate the role of the calcium-activated protease calpain in the pathogenesis of synaptic dysfunction in SCS. Cleavage of a fluorogenic calpain substrate was increased at the NMJ of dissociated muscle fibers. Inhibition of calpain using a calpastatin (CS) transgene improved strength and neuromuscular transmission. CS caused a 2-fold increase in the frequency of miniature endplate currents (MEPCs) and an increase in NMJ size, but MEPC amplitudes remained reduced. Persistent degeneration of the NMJ was associated with localized activation of the non-calpain protease caspase-3. This study suggests that calpain may act presynaptically to impair NMJ function in SCS but further reveals a role for other cysteine proteases whose inhibition may be of additional therapeutic benefit in SCS and other excitotoxic disorders.

Authors

Jason S. Groshong, Melissa J. Spencer, Bula J. Bhattacharyya, Elena Kudryashova, Bhupinder P.S. Vohra, Roberto Zayas, Robert L. Wollmann, Richard J. Miller, Christopher M. Gomez

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Figure 6

CS overexpression corrects MEPC frequency in SCS transgenic mice.

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CS overexpression corrects MEPC frequency in SCS transgenic mice.
(A–D) ...
(A–D) Representative MEPC recorded in excised diaphragm muscle from 7 εL269F (A), 8 CS/εL269F (B), 5 CS (C), and 5 WT (D) mice studied. MEPC decay phases (E), amplitudes (F), and frequency (G) for all genotypes. (E) Decay phases of both εL269F and CS/εL269F mice were prolonged approximately 4-fold more than those for WT or CS littermates (P < 0.05). Decay phases of εL269F mice were slightly greater than those of CS/εL269F mice, but the difference was not significant (P = 0.1). Results for CS and WT littermates were similar: εL269F: 9.83 ± 0.98 ms, n = 27, vs. CS/εL269F: 8.29 ± 0.75 ms, n = 34, vs. CS: 2.82 ± 0.14, n = 24, vs. WT: 2.51 ± 0.15 ms, n = 24). (F) MEPC amplitudes of εL269F and CS/εL269F mice were smaller than those of WT and CS mice, and CS/εL269F MEPC amplitudes were slightly smaller than those of εL269F mice, although the difference was not statistically significant (P = 0.04). Results for CS and WT littermates were similar (εL269F: 1.61 ± 0.12 nA, n = 26, vs. CS/εL269F: 1.39 ± 0.026, n = 71, vs. CS: 2.06 ± 0.13 nA, n = 30, vs. WT: 2.21 ± 0.10 nA, n = 31). (G). The frequency in εL269F was diminished by more than 2-fold when compared with WT littermates. Frequency in CS/εL269F was increased by approximately 2-fold when compared with εL269F (P < 0.05) and indistinguishable from that in WT mice (P = 0.41). Frequency of CS was approximately 2-fold greater than recorded in WT (P < 0.05) littermates (εL269F: 0.29 ± 0.02 s–1, n = 23, vs. CS/εL269F: 0.51 ± 0.06 s–1, n = 22, vs. CS: 1.17 ± 0.17 s–1, n = 14, vs. WT: 0.57 ± 0.02 s–1, n = 57 NMJs).

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