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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

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

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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 3

CaV1.1Δe29 ClC-1–/– and ClC-1–/– muscle exhibits severe transient weakness that is significantly improved by the addition of verapamil.

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CaV1.1Δe29 ClC-1–/– and ClC-1–/– muscle exhibits severe transient weakne...
(A and C) Normalized representative force traces of the first 15 tetani (100 Hz, 500 ms) separated by 4 seconds, recorded ex vivo from EDL muscles isolated from 6-week-old ClC-1–/– (blue) and CaV1.1Δe29 ClC-1–/– (red) mice in the (A) absence and (C) presence of 20 μM verapamil added to the bath. (B and D) Average peak tetanic EDL forces normalized to the initial stimulus, elicited by 44 subsequent 100 Hz, 500 ms tetanic stimulations separated by 4 seconds. EDL muscles were from 6-week-old WT (black, n = 4), ClC-1–/– (blue, n = 4), CaV1.1Δe29 (orange, n = 4), and CaV1.1Δe29 ClC-1–/– red, n = 4) mice in the (B) absence and (D) presence of 20 μM verapamil added to the bath for ClC-1–/– (blue, n = 4) and CaV1.1Δe29 ClC-1–/– (red, n = 4) EDLs. Dashed lines in D represent the average data presented in B as a reference for pretreatment. (B and D) WT (n = 4; female = 2, male = 2), CaV1.1Δe29 (n = 4; female = 2, male = 2), ClC-1–/– (n = 4; female = 2, male = 2), CaV1.1Δe29 ClC-1–/– (n = 4; female = 2, male = 2). Symbols and closed circles indicate the mean ± SEM. (B and D) Statistical significance was determined by 2-way ANOVA with Tukey’s post hoc analysis.

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