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

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...

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Bibliographic Details
Published in:The Journal of clinical investigation 2024-01, Vol.134 (1), p.1-14
Main Authors: Cisco, Lily A, Sipple, Matthew T, Edwards, Katherine M, Thornton, Charles A, Lueck, John D
Format: Article
Language:English
Subjects:
Alternative Splicing
Analysis
Animals
Biomedical research
Calcium - metabolism
Calcium channels
Calcium channels (voltage-gated)
Calcium chloride
Channelopathies - genetics
Channelopathies - metabolism
Channelopathy
Chloride
Chloride Channels - genetics
Chloride Channels - metabolism
Chlorides - metabolism
Dosage and administration
Drug therapy
Excitation-contraction coupling
Gene deletion
Kinases
Life span
Mice
Muscle contraction
Muscle function
Muscle, Skeletal - metabolism
Myotonia
Myotonia - metabolism
Myotonic dystrophy
Myotonic Dystrophy - drug therapy
Myotonic Dystrophy - genetics
Myotonic Dystrophy - metabolism
Patient outcomes
Respiratory function
Survival
Verapamil
Verapamil - metabolism
Verapamil - pharmacology
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Description
Summary: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.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI173576