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Abstract：
BACKGROUND: Myotonic Dystrophy type I (DM1) is the most common muscular dystrophy in adults. Previous reports have highlighted that neuromuscular junctions (NMJs) deteriorate in skeletal muscle from DM1 patients and mouse models thereof. However, the underlying pathomechanisms and their contribution to muscle dysfunction remain unknown.
METHODS: We compared changes in NMJs and activity-dependent signalling pathways in HSALR and Mbnl1ΔE3/ΔE3 mice, two established mouse models of DM1.
RESULTS: Muscle from DM1 mouse models showed major deregulation of calcium/calmodulin-dependent protein kinases II (CaMKIIs), which are key activity sensors regulating synaptic gene expression and acetylcholine receptor (AChR) recycling at the NMJ. Both mouse models exhibited increased fragmentation of the endplate, which preceded muscle degeneration. Endplate fragmentation was not accompanied by changes in AChR turnover at the NMJ. However, the expression of synaptic genes was up-regulated in mutant innervated muscle, together with an abnormal accumulation of histone deacetylase 4 (HDAC4), a known target of CaMKII. Interestingly, denervation-induced increase in synaptic gene expression and AChR turnover was hampered in DM1 muscle. Importantly, CaMKIIβ/βM overexpression normalized endplate fragmentation and synaptic gene expression in innervated Mbnl1ΔE3/ΔE3 muscle, but it did not restore denervation-induced synaptic gene up-regulation.
CONCLUSIONS: Our results indicate that CaMKIIβ-dependent and -independent mechanisms perturb synaptic gene regulation and muscle response to denervation in DM1 mouse models. Changes in these signalling pathways may contribute to NMJ destabilization and muscle dysfunction in DM1 patients.
METHODS: We compared changes in NMJs and activity-dependent signalling pathways in HSALR and Mbnl1ΔE3/ΔE3 mice, two established mouse models of DM1.
RESULTS: Muscle from DM1 mouse models showed major deregulation of calcium/calmodulin-dependent protein kinases II (CaMKIIs), which are key activity sensors regulating synaptic gene expression and acetylcholine receptor (AChR) recycling at the NMJ. Both mouse models exhibited increased fragmentation of the endplate, which preceded muscle degeneration. Endplate fragmentation was not accompanied by changes in AChR turnover at the NMJ. However, the expression of synaptic genes was up-regulated in mutant innervated muscle, together with an abnormal accumulation of histone deacetylase 4 (HDAC4), a known target of CaMKII. Interestingly, denervation-induced increase in synaptic gene expression and AChR turnover was hampered in DM1 muscle. Importantly, CaMKIIβ/βM overexpression normalized endplate fragmentation and synaptic gene expression in innervated Mbnl1ΔE3/ΔE3 muscle, but it did not restore denervation-induced synaptic gene up-regulation.
CONCLUSIONS: Our results indicate that CaMKIIβ-dependent and -independent mechanisms perturb synaptic gene regulation and muscle response to denervation in DM1 mouse models. Changes in these signalling pathways may contribute to NMJ destabilization and muscle dysfunction in DM1 patients.
摘要：
背景：强直性肌营养不良I型（DM1）是成人中最常见的肌营养不良。先前的报道已经强调来自DM1患者及其小鼠模型的骨骼肌中的神经肌肉接头(NMJs)恶化。然而,潜在的病理机制及其对肌肉功能障碍的影响尚不清楚.
方法：我们比较了HSALR和Mbnl1ΔE3/ΔE3小鼠中NMJ和活性依赖性信号通路的变化，建立两种DM1小鼠模型。
结果：来自DM1小鼠模型的肌肉显示钙/钙调蛋白依赖性蛋白激酶II（CaMKIs）的主要失调，它们是调节NMJ突触基因表达和乙酰胆碱受体（AChR）再循环的关键活性传感器。两种小鼠模型均显示终板碎片增加，在肌肉退化之前。NMJ的终板碎片没有伴随着AChR周转的变化。然而,突变型神经支配肌肉中突触基因的表达上调,连同组蛋白脱乙酰酶4（HDAC4）的异常积累，CaMKII的已知目标.有趣的是,去神经支配诱导的DM1肌肉突触基因表达和AChR更新的增加受到阻碍。重要的是,神经支配的Mbnl1ΔE3/ΔE3肌肉中CaMKIIβ/βM过表达标准化终板片段化和突触基因表达，但它并没有恢复去神经支配诱导的突触基因上调。
结论：我们的结果表明，在DM1小鼠模型中，CaMKIIβ依赖性和非依赖性机制扰乱了突触基因调节和肌肉对神经支配的反应。这些信号通路的变化可能导致DM1患者的NMJ失稳和肌肉功能障碍。
方法：我们比较了HSALR和Mbnl1ΔE3/ΔE3小鼠中NMJ和活性依赖性信号通路的变化，建立两种DM1小鼠模型。
结果：来自DM1小鼠模型的肌肉显示钙/钙调蛋白依赖性蛋白激酶II（CaMKIs）的主要失调，它们是调节NMJ突触基因表达和乙酰胆碱受体（AChR）再循环的关键活性传感器。两种小鼠模型均显示终板碎片增加，在肌肉退化之前。NMJ的终板碎片没有伴随着AChR周转的变化。然而,突变型神经支配肌肉中突触基因的表达上调,连同组蛋白脱乙酰酶4（HDAC4）的异常积累，CaMKII的已知目标.有趣的是,去神经支配诱导的DM1肌肉突触基因表达和AChR更新的增加受到阻碍。重要的是,神经支配的Mbnl1ΔE3/ΔE3肌肉中CaMKIIβ/βM过表达标准化终板片段化和突触基因表达，但它并没有恢复去神经支配诱导的突触基因上调。
结论：我们的结果表明，在DM1小鼠模型中，CaMKIIβ依赖性和非依赖性机制扰乱了突触基因调节和肌肉对神经支配的反应。这些信号通路的变化可能导致DM1患者的NMJ失稳和肌肉功能障碍。
