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维拉帕米减轻肌强直性营养不良小鼠模型中的氯离子和钙离子双通道病。

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

机构信息

Department of Pharmacology and Physiology.

Department of Neurology.

出版信息

J Clin Invest. 2024 Jan 2;134(1):e173576. doi: 10.1172/JCI173576.

DOI:10.1172/JCI173576
PMID:38165038
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10760957/
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.

摘要

肌强直性营养不良 1 型（DM1）涉及特定基因的异常剪接调控。我们使用外显子或核苷酸缺失来模拟肌肉兴奋-收缩偶联中关键基因的异常剪接。在 CaV1.1 钙通道中强制跳过外显子 29 并结合 ClC-1 氯离子通道功能缺失的小鼠，其寿命明显缩短，而其他剪接模拟物的组合则不影响存活。Ca2+/Cl- 双通道病小鼠表现出肌强直、无力以及运动和呼吸功能受损。慢性给予钙通道阻滞剂维拉帕米可挽救存活并改善肌力、肌强直和呼吸功能。这些结果表明，Ca2+/Cl- 双通道病导致 DM1 中的肌肉损伤，并且可能被常用的临床可用钙通道阻滞剂减轻。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51ac/10760957/9688eee5d82b/jci-134-173576-g142.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51ac/10760957/92ab02493743/jci-134-173576-g137.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51ac/10760957/af0a5d68259f/jci-134-173576-g138.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51ac/10760957/528ed844c71b/jci-134-173576-g139.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51ac/10760957/819231583236/jci-134-173576-g140.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51ac/10760957/65b1a0aa96fb/jci-134-173576-g141.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51ac/10760957/9688eee5d82b/jci-134-173576-g142.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51ac/10760957/92ab02493743/jci-134-173576-g137.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51ac/10760957/af0a5d68259f/jci-134-173576-g138.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51ac/10760957/528ed844c71b/jci-134-173576-g139.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51ac/10760957/819231583236/jci-134-173576-g140.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51ac/10760957/65b1a0aa96fb/jci-134-173576-g141.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/51ac/10760957/9688eee5d82b/jci-134-173576-g142.jpg

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