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 1

CaV1.1Δe29 and ClC-1–/– alleles exhibit synthetic lethality and result in significantly reduced body weight and severe muscle weakness in mice.

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CaV1.1Δe29 and ClC-1–/– alleles exhibit synthetic lethality and result i...
(A) Kaplan-Meier survival analysis of WT (n = 10; female = 5, male = 5), CaV1.1Δe29/+ (n = 13; female = 7, male = 6), CaV1.1Δe29 (n = 15; female = 7, male = 8), RyR1Δe70/Δe70 (n = 21; female = 10, male = 11), SERCA1Δe22/Δe22 (n = 19; female = 10, male = 9), CaV1.1Δe29 RyR1Δe70/Δe70 (n = 11; female = 5, male = 6), CaV1.1Δe29 SERCA1Δe22/Δe22 (n = 10; female = 6, male = 4), RyR1Δe70/Δe70 SERCA1Δe22/Δe22 (n = 15; female = 4, male = 11), CaV1.1Δe29 RyR1Δe70/Δe70 SERCA1Δe22/Δe22 (n = 19; female = 6, male = 13), ClC-1–/– (n = 27; female = 12, male = 15), RyR1Δe70/Δe70 ClC-1–/– (n = 14; female = 7, male = 7), SERCA1Δe22/Δe22 ClC-1–/– (n = 27; female = 14, male = 13), CaV1.1Δe29/+ ClC-1–/– (n = 8; female = 3, male = 5), and CaV1.1Δe29/Δe29 ClC-1–/– (n = 11; female = 6, male = 5) mice. (B) Weekly body weight change and (C) percentage of body weight change from weaning at 10 weeks of age for WT (n = 20; female = 10, male = 10), CaV1.1Δe29 (n = 21; female = 12, male = 9), RyR1Δe70/Δe70 (n = 15; female = 5, male = 10), SERCA1Δe22/Δe22 (n = 14; female = 7, male = 7), CaV1.1Δe29 RyR1Δe70/Δe70 (n = 11; female = 5, male = 6), CaV1.1Δe29 SERCA1Δe22/Δe22 (n = 10; female = 6, male = 4), RyR1Δe70/Δe70 SERCA1Δe22/Δe22 (n = 15; female = 4, male = 11), CaV1.1Δe29 RyR1Δe70/Δe70 SERCA1Δe22/Δe22 (n = 19; female = 6, male = 13), ClC-1–/– (n = 23; female = 13, male = 10), CaV1.1Δe29 ClC-1–/– (n = 17; female = 8, male = 9), RyR1Δe70/Δe70 ClC-1–/– (n = 11; female = 5, male = 6), and SERCA1Δe22/Δe22 ClC-1–/– (n = 12; female = 8, male = 4) mice. (D) Representative traces and (E) average peak specific force elicited by 150 Hz (500 ms) tetanic stimulation of isolated EDLs from mice at 10 weeks. (F) Average frequency dependence of specific force generation elicited from isolated EDLs at 10 weeks. (E and F) WT (n = 17; female = 8, male = 9), CaV1.1Δe29 (n = 10; female = 5, male = 5), ClC-1–/– (n = 9; female = 4, male = 5), CaV1.1Δe29 ClC-1–/– (n = 19; female = 8, male = 11) mice were used. (G) Weekly TRR analysis of CaV1.1Δe29 ClC-1–/– (red), ClC-1–/– (blue), CaV1.1Δe29 (orange), WT (black) mice. (H) Correlation of the TRR to death for CaV1.1Δe29 ClC-1–/– mice. Dots represent individual mice, and duplications indicate TRR trials. In B–H, results in red represent heterozygous and homozygous CaV1.1Δe29 mice that are ClC-1–/–, and results in orange indicate heterozygous and homozygous CaV1.1Δe29 alleles. Symbols and open circles indicate individual mice; bars and closed circles indicate the mean ± SEM. *P < 0.05, **P < 0.01, and ****P < 0.0001, by log-rank analysis (A); 2-way ANOVA (B, F, and G) and 1-way ANOVA (C and E) with Tukey’s post hoc analysis; and linear regression analysis (H).