Mechanisms of altered skeletal muscle action potentials in the R6/2 mouse model of Huntington's disease.
Mechanisms of altered skeletal muscle action potentials in the R6/2 mouse model of Huntington's disease.
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亨廷顿病 R6/2 小鼠模型中骨骼肌动作电位改变的机制。
DOI：
10.1152/ajpcell.00153.2020
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Voss,AndrewA
中科院分区：
文献类型：
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作者：
Miranda,DanielR;Reed,Eric;Jama,Abdulrahman;Bottomley,Michael;Ren,Hongmei;Rich,MarkM;Voss,AndrewA
亨廷顿氏病（HD）患者患有进行性和衰弱性运动功能障碍，目前仅可进行姑息治疗。先前，我们发现R6/2 HD转基因小鼠骨骼肌Cl−通道（ClC-1）和内向整流K+通道（Kir）电流减少。为了进一步研究ClC-1和Kir电流在HD骨骼肌病理学中的作用，我们使用双电极电流钳测量了降低的ClC-1和Kir电流对R6/2小鼠动作电位（AP）重复放电的影响。我们发现，R6/2 AP与野生型（WT）相比，具有显著较低的峰值振幅，去极化最大复极化，和延长的衰减时间。在这些差异中，只有最大复极化是由ClC-1和Kir电流的减少引起的，表明存在额外的离子通道缺陷。我们发现，与WT相比，R6/2骨骼肌中的KV1.5和KV3.4 mRNA水平均显著降低，这解释了R6/2 AP的衰减时间延长。总体而言，我们发现WT和R6/2肌肉中的AP在活动期间显著且进行性地改变以维持峰值振幅，尽管Na+通道失活累积。即使有这种弹性，R6/2 AP的持续降低的峰值幅度预计会导致早期疲劳，并可能有助于解释HD患者经历的运动不持久性。这项工作为将R6/2 HD小鼠的电变化与力产生缺陷联系起来以及检查WT肌肉中控制AP的调节事件奠定了基础。
Huntington’s disease (HD) patients suffer from progressive and debilitating motor dysfunction for which only palliative treatment is currently available. Previously, we discovered reduced skeletal muscle Cl−channel (ClC-1) and inwardly rectifying K+channel (Kir) currents in R6/2 HD transgenic mice. To further investigate the role of ClC-1 and Kir currents in HD skeletal muscle pathology, we measured the effect of reduced ClC-1 and Kir currents on action potential (AP) repetitive firing in R6/2 mice using a two-electrode current clamp. We found that R6/2 APs had a significantly lower peak amplitude, depolarized maximum repolarization, and prolonged decay time compared with wild type (WT). Of these differences, only the maximum repolarization was accounted for by the reduction in ClC-1 and Kir currents, indicating the presence of additional ion channel defects. We found that both KV1.5 and KV3.4 mRNA levels were significantly reduced in R6/2 skeletal muscle compared with WT, which explains the prolonged decay time of R6/2 APs. Overall, we found that APs in WT and R6/2 muscle significantly and progressively change during activity to maintain peak amplitude despite buildup of Na+channel inactivation. Even with this resilience, the persistently reduced peak amplitude of R6/2 APs is expected to result in earlier fatigue and may help explain the motor impersistence experienced by HD patients. This work lays the foundation to link electrical changes to force generation defects in R6/2 HD mice and to examine the regulatory events controlling APs in WT muscle.