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

Article Article scientifique Article CaMKIIβ deregulation contributes to neuromuscular junction destabilization in Myotonic Dystrophy type I eng 2024-05-21 2024-05-21 author Falcetta Denis author Quirim Sandrine 940996 author Cocchiararo Ilaria 915865 Département de physiologie cellulaire et métabolisme (PHYME) author Chabry Florent 883080 Département de physiologie cellulaire et métabolisme (PHYME) author Theodore Marine 403255 author Stiefvater Adeline author Lin Shuo author Tintignac Lionel author Ivanek Robert author Kinter Jochen author Rüegg Markus A. author Sinnreich Michael author Castets Perrine 0000-0002-6181-4791 930953 Département de physiologie cellulaire et métabolisme (PHYME) 11 10.1186/s13395-024-00345-3 38769542 2044-5040 PMC11106974 https://skeletalmusclejournal.biomedcentral.com/articles/10.1186/s13395-024-00345-3 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 HSA LR and Mbnl1 ΔE3/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 Mbnl1 ΔE3/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. CaMKII Fibre type Myotonic dystrophy Neuromuscular junctions Synaptic genes Dewey 612 134 Département de physiologie cellulaire et métabolisme 21C false 1288 Muscle et jonction neuromusculaire 1007 https://doi.org/10.26037/yareta:qx7k7d2vcva2fo7jr5t3bn2bly https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE226676 Skeletal muscle 14 1 e34e3b66-9e82-4de9-9502-dfe4587123dc Article (Published version) Public Article_scientifique_from_crossref.pdf 4959869 application/pdf CC BY-4.0 6c550f864e073888f9f55768b11f406cb396b78100b2447180dd69271114d9de 41e7f7b0-7f2a-4ce3-88e0-9fba26355324 Supplemental data Public 13395_2024_345_MOESM1_ESM.pdf 3723982 application/pdf 7b3a776f9c222ce5347281cb7a743feb2c6c3257ff038a12d2a9a776ac2b8c6f openAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

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CaMKIIβ deregulation contributes to neuromuscular junction destabilization in Myotonic Dystrophy type I	Skeletal muscle			2024	196	224

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