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 5

Verapamil treatment improves survival, body weight, and motility of CaV1.1Δe29 ClC-1–/– mice.

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Verapamil treatment improves survival, body weight, and motility of CaV1...
(A) Kaplan-Meier survival analysis of WT mice (n = 10; female = 5, male = 5), WT mice treated with 200 mg/kg/d verapamil (verap) (n = 10; female = 5, male = 5), CaV1.1Δe29 ClC-1–/– mice (n = 19; female = 9, male = 10), and CaV1.1Δe29 ClC-1–/– mice treated with verapamil (n = 9; female = 5, male = 4). Verapamil was dosed in mouse nutrition/hydration food cups. Note: log-rank analysis of CaV1.1Δe29 ClC-1–/– versus WT mice, WT mice treated with 200 mg/kg/d verapamil, and CaV1.1Δe29 ClC-1–/– mice treated with 200 mg/kg/d verapamil; P < 0.0001, P < 0.0001, and P < 0.0001, respectively. (B) Percentage of body weight change from weaning at 10 weeks in WT mice (n = 20; female = 10, male = 10), WT mice treated with 200 mg/kg/d verapamil (n = 10; female = 5, male = 5), CaV1.1Δe29 ClC-1–/– mice (n = 35; female = 14, male = 21), and CaV1.1Δe29 ClC-1–/– mice treated with verapamil (n = 9; female = 5, male = 4). (C) Weekly time of righting reflex analysis of CaV1.1Δe29 ClC-1–/– mice (red), ClC-1–/– mice (light blue), CaV1.1Δe29 mice (orange), WT mice (black), CaV1.1Δe29 ClC-1–/– mice treated with verapamil (green), and WT mice treated with verapamil (gray). (D) Average time of righting reflex in vehicle- and verapamil-treated mice at 10 and 20 weeks of age. Note: Untreated CaV1.1Δe29 ClC-1–/– mice did not survive to 20 weeks of age, therefore the last recording before death was documented. Box indicates Q1, the median, and Q3; whiskers show the minimum and maximum. (C and D) Ten- and 20-week-old WT mice (n = 10; female = 5, male = 5), WT mice treated with 200 mg/kg/d verapamil (n = 10; female = 5, male = 5), CaV1.1Δe29 mice (n = 8; female = 4, male = 4), ClC-1–/– mice (n = 19; female = 9, male = 10), CaV1.1Δe29 ClC-1–/– mice (n = 15; female = 7, male = 8), CaV1.1Δe29 ClC-1–/– mice treated with verapamil (10-week-old mice, n = 16; female = 7, male = 9), CaV1.1Δe29 ClC-1–/– mice treated with verapamil (20-week-old mice, n = 7; female = 4, male = 3). (E) Paired before (light circles) and after (dark circles) 2 weeks of verapamil treatment of ClC-1–/– mice at 100 mg/kg/d (left; n = 5; female = 3, male = 2) and 200 mg/kg/d (right; n = 6; female = 3, male = 3) dosing in nutrition/hydration food cups. Symbols and closed circles indicate individual mice; open circles indicate the mean ± SEM. *P < 0.05, **P < 0.01, and ****P < 0.0001, by log-rank analysis (A); 1-way ANOVA (B and D) and 2-way ANOVA (C) with Tukey’s post hoc analysis; and paired t test (E).