CaMKIIβ deregulation contributes to neuromuscular junction destabilization in Myotonic Dystrophy type I.

IF 5.3 2区 医学 Q2 CELL BIOLOGY Skeletal Muscle Pub Date : 2024-05-21 DOI:10.1186/s13395-024-00345-3
Denis Falcetta, Sandrine Quirim, Ilaria Cocchiararo, Florent Chabry, Marine Théodore, Adeline Stiefvater, Shuo Lin, Lionel Tintignac, Robert Ivanek, Jochen Kinter, Markus A Rüegg, Michael Sinnreich, Perrine Castets
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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.

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CaMKIIβ失调导致肌营养不良症 I 型神经肌肉接头失稳
背景:I 型肌营养不良症(DM1)是成人中最常见的肌肉营养不良症。以前的报告强调,DM1 患者和小鼠模型骨骼肌中的神经肌肉接头(NMJ)会退化。然而,其潜在的病理机制及其对肌肉功能障碍的影响仍然未知:方法:我们比较了 HSALR 小鼠和 Mbnl1ΔE3/ΔE3 小鼠这两种已建立的 DM1 小鼠模型中 NMJ 和活动依赖性信号通路的变化:结果:DM1小鼠模型的肌肉显示出钙/钙调蛋白依赖性蛋白激酶II(CaMKIIs)的严重失调,而钙/钙调蛋白依赖性蛋白激酶II是调节突触基因表达和乙酰胆碱受体(AChR)在NMJ循环的关键活动传感器。这两种小鼠模型的终板碎裂程度都有所增加,并先于肌肉变性。终板碎裂并不伴随 NMJ 上乙酰胆碱受体周转的变化。然而,突变神经支配肌肉中突触基因的表达上调,同时组蛋白去乙酰化酶 4(HDAC4)异常积累,而 HDAC4 是 CaMKII 的已知靶标。有趣的是,在 DM1 肌肉中,神经支配诱导的突触基因表达增加和 AChR 转换受到阻碍。重要的是,在神经支配的Mbnl1ΔE3/ΔE3肌肉中,CaMKIIβ/βM过表达可使终板破碎和突触基因表达正常化,但不能恢复神经支配诱导的突触基因上调:我们的研究结果表明,在 DM1 小鼠模型中,CaMKIIβ 依赖性和非依赖性机制会扰乱突触基因调控和肌肉对神经支配的反应。这些信号通路的变化可能会导致 DM1 患者的 NMJ 不稳定和肌肉功能障碍。
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来源期刊
Skeletal Muscle
Skeletal Muscle CELL BIOLOGY-
CiteScore
9.10
自引率
0.00%
发文量
25
审稿时长
12 weeks
期刊介绍: The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.
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