Verapamil mitigates chloride and calcium bi-channelopathy in a myotonic dystrophy mouse model
Lily A. Cisco, Matthew T. Sipple, Katherine M. Edwards, Charles A. Thornton, John D. Lueck
Lily A. Cisco, Matthew T. Sipple, Katherine M. Edwards, Charles A. Thornton, John D. Lueck
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Research Article Muscle biology

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 6

Verapamil treatment significantly improves respiratory function and diaphragm strength in CaV1.1Δe29 ClC-1–/– mice.

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Verapamil treatment significantly improves respiratory function and diap...
WBP for (A, C, and E) 10-week-old WT mice (n = 18; female = 9, male = 9), WT mice treated with 200 mg/kg/d verapamil (n = 10; female = 5, male = 5), CaV1.1Δe29 mice (n = 6; female = 3, male = 3), ClC-1–/– mice (n = 17; female = 8, male = 9), CaV1.1Δe29 ClC-1–/– mice (n = 14; female = 7, male = 7), and CaV1.1Δe29 ClC-1–/– mice treated with verapamil (n = 14, female = 7, male = 7) and (B, D and F) 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 = 10; female = 4, male = 6), ClC-1–/– mice (n = 8; female = 4, male = 4), CaV1.1Δe29 ClC-1–/– mice treated with verapamil (n = 7; female = 4, male = 3). (A and B) PIFR (mL/s) and (C and D) PEFR (mL/s) of respiration. (E and F) Tidal volume (mL) of respiration. (G) Representative tetanic (150 Hz, 500 ms) specific force traces from diaphragm strips isolated from 10-week-old (left) and 20-week-old (right) mice of the indicated genotypes and treatment groups. (H and I) Plot of the average stimulation frequency dependence of specific force generated from diaphragm strips isolated from (H) 10-week-old (n values indicate individual EDL muscles) WT mice (n = 10; female = 5, male = 5), WT mice treated with 200 mg/kg/d verapamil (n = 6; female = 3, male = 3), CaV1.1Δe29 mice (n = 5; female = 3, male = 2), ClC-1–/– mice (n = 5; female = 2, male = 3), CaV1.1Δe29 ClC-1–/– mice (n = 7; female = 4, male = 3), and CaV1.1Δe29 ClC-1–/– mice treated with verapamil (n = 7; female = 3, male = 4)) and (I) 20-week-old (n values indicate individual EDL muscles) WT mice (n = 8; female = 4, male = 4), WT mice treated with 200 mg/kg/d verapamil (n = 8; female = 4, male = 4), CaV1.1Δe29 mice (n = 7; female = 4, male = 3), ClC-1–/– mice (n = 7; female = 3, male = 4), and CaV1.1Δe29 ClC-1–/– mice treated with verapamil (n = 7; female = 4, male = 3). Symbols and open circles represent individual mice; bars and closed circles indicate the mean ± SEM. Note: Untreated CaV1.1Δe29 ClC-1–/– mice did not survive to 20 weeks of age. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA (A–F) and 2-way ANOVA (H and I) with Tukey’s post hoc analysis.