Verapamil Mitigates Chloride and Calcium Bi-channelopathy in a Myotonic Dystrophy Mouse Model

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2024 Jan 2

PMID 38165038

Authors

Lily A Cisco

Matthew T Sipple

Katherine M Edwards

Charles A Thornton

John D Lueck

Affiliations

Soon will be listed here.

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.

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