Combinatorial chloride and calcium channelopathy in myotonic dystrophy

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 processes in mice. Mice with forced-skipping of exon 29 in Ca V 1.1 calcium channel combined with loss of ClC-1 chloride channel function showed a markedly reduced lifespan, whereas other combinations of splicing mimics did not affect survival. The Ca 2+ /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 Ca 2+ /Cl - bi-channelopathy contributes to muscle impairment in DM1 and is potentially mitigated by common clinically available calcium channel blockers. Summary Repurposing of a calcium channel blocker extends life and mitigates muscle and respiratory dysfunction in a myotonic dystrophy type 1 Ca 2+ /Cl - bi-channelopathy mouse model.