Verapamil mitigates chloride and calcium bi-channelopathy in a myotonic dystrophy mouse model
Lily A. Cisco, … , Charles A. Thornton, John D. Lueck
Lily A. Cisco, … , Charles A. Thornton, John D. Lueck
Published January 2, 2024
Citation Information: J Clin Invest. 2024;134(1):e173576. https://doi.org/10.1172/JCI173576.
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Research Article Muscle biology Therapeutics

Verapamil mitigates chloride and calcium bi-channelopathy in a myotonic dystrophy mouse model

Abstract

Myotonic dystrophy type 1 (DM1) involves misregulated alternative splicing for specific genes. We used exon or nucleotide deletion to mimic altered splicing of genes central to muscle excitation-contraction coupling in mice. Mice with forced skipping of exon 29 in the CaV1.1 calcium channel combined with loss of ClC-1 chloride channel function displayed markedly reduced lifespan, whereas other combinations of splicing mimics did not affect survival. The Ca2+/Cl– bi-channelopathy mice exhibited myotonia, weakness, and impairment of mobility and respiration. Chronic administration of the calcium channel blocker verapamil rescued survival and improved force generation, myotonia, and respiratory function. These results suggest that Ca2+/Cl– bi-channelopathy contributes to muscle impairment in DM1 and is potentially mitigated by common clinically available calcium channel blockers.

Authors

Lily A. Cisco, Matthew T. Sipple, Katherine M. Edwards, Charles A. Thornton, John D. Lueck

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Figure 2

Heterozygous and homozygous CaV1.1Δe29 mice exhibit similar CaV1.1 voltage dependence and peak current densities in FDB muscle.

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Heterozygous and homozygous CaV1.1Δe29 mice exhibit similar CaV1.1 volta...
(A) Representative current density traces from whole-cell patch clamp recordings of FDB fibers isolated from 4-week-old WT (black), CaV1.1Δe29/+ (red, dashed), and CaV1.1Δe29/Δe29 (red, solid) mice at 0 mV (top), +20 mV (middle), and +40 mV (bottom). (B) Plot of average current-voltage relationship of CaV1.1 activity measured in WT (black), CaV1.1Δe29/+ (red and black circles, red dashed), and CaV1.1Δe29/Δe29 (red circle, solid red line) FDB fibers isolated from 4-week-old mice. (C) RT-PCR products of CaV1.1 RNA isolated from tibialis anterior from 10-week-old mice. PCR amplifications are from exons 27–31 of Cacna1s cDNA. Ld, ladder. Statistical significance was determined by 1-way ANOVA with Tukey’s post hoc analysis (B).