PDF(Pubmed)
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：
强直性肌营养不良1型（DM1）涉及特定基因的可变剪接失调。我们使用外显子或核苷酸缺失来模拟小鼠肌肉兴奋-收缩偶联中心基因的剪接改变。在CaV1.1钙通道中外显子29的强迫跳跃与ClC-1氯通道功能丧失的小鼠显示出显著的寿命减少,而其他剪接模拟组合并不影响生存.Ca2+/Cl-双通道病小鼠表现出肌强直，弱点,以及运动和呼吸的损害。钙通道阻滞剂维拉帕米的长期给药挽救了生存率并改善了力的产生，肌强直,和呼吸功能。这些结果表明，Ca2/Cl-双通道作用会导致DM1中的肌肉损伤，并可能被临床上常见的钙通道阻滞剂减轻。
