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Understanding the pathomechanisms leading to muscle alterations in Myotonic Dystrophy type 1: Consequences of CaMKII deregulation on the maintenance of neuromuscular junctions

Falcetta, Denis. Understanding the pathomechanisms leading to muscle alterations in Myotonic Dystrophy type 1: Consequences of CaMKII deregulation on the maintenance of neuromuscular junctions. 2020, Doctoral Thesis, University of Basel, Faculty of Science.

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Abstract

Myotonic Dystrophy Type 1 (DM1) is a multisystemic autosomal dominant disorder and represents the most common form of muscular dystrophy in adults. DM1 is caused by a (CTG)n repeat expansion in the 3` UTR of the DMPK gene. Once transcribed, the aberrant (CUG)n transcripts form stable double-stranded structures, which sequester multiple RNA-binding proteins, resulting in the defective splicing of numerous genes. Since the discovery that RNA-gain-of-function constitutes a major pathological event in DM1, therapeutic strategies have mainly focused on targeting mis-splicing events to counteract the spliceopathy. Although refinement of experimental and therapeutic approaches have allowed a better understanding of DM1 pathophysiology, there is still no cure available. Over the last years, studies unveiled the contribution of different deregulated cellular processes to DM1 muscle pathology. In particular, previous results in the group showed that the key metabolic pathways AMPK and mTORC1 are perturbed in DM1 muscle. They further suggested a major deregulation of Ca2+/calmodulin-dependent protein kinase (CaMK) proteins in DM1 muscle. To get further insights into the pathomechanisms underlying DM1, I investigated whether and how deregulation of CaMKIIs contribute to DM1 muscle affliction. CaMKIIs have been shown to be essential for muscle plasticity, including remodeling of muscle synapses. To this end, CaMKIIs regulate activation and translocation of key factors governing activity-dependent gene expression. In addition, CaMKIIs actively promote the recycling of AChRs to the surface of muscle membrane after their internalization, making them pivotal players in the maintenance of post-synaptic sites. Although studies have reported changes in pre- and post-synaptic compartments of neuromuscular junctions (NMJs) in muscle from DM1 patients and mouse models, a potential contribution of NMJ alterations to DM1 muscle pathogenesis remains under debate. Here I showed that the muscle-specific isoform of CaMKIIβ (CaMKIIβM) is lost in muscle of HSALR and Mbnl1Δ3/Δ3 mice, two well-characterized DM1 mouse models. Fluorescent-based staining approaches of NMJs revealed that HSALR and Mbnl1Δ3/Δ3 muscle exhibit an increased fragmentation of the motor endplates in both, basal conditions and when challenged with nerve injury. Analysis of activity-dependent pathways pointed to a deregulation of HDAC4 and synaptic gene expression, which may involve CaMKII deficiency in HSALR and Mbnl1Δ3/Δ3 muscles. Moreover, I showed that AChR turnover is increased in muscles from HSALR and Mbnl1Δ3/Δ3 mice under basal conditions. This was accompanied by a reduction in AChR recycling at post-synaptic sites of DM1 muscle, which may also arise from CaMKII deficiency. Lastly, Mbnl1Δ3/Δ3 mice showed defective up-regulation of synaptic genes upon nerve injury, while AChR turnover was strongly increased. This abnormal response to denervation may involve yet unknown CaMKII-independent mechanisms. Overall, these findings suggest that defective maintenance of NMJs in DM1 muscle may involve CaMKII-dependent and -independent processes, and may be key events contributing to DM1 muscle pathophysiology.
Advisors:Rüegg, Markus A. and Castets, Perrine and Sinnreich, Michael and Allamand, Valérie
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A. and Castets, Perrine and Sinnreich, Michael
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13951
Thesis status:Complete
Number of Pages:X, 95
Language:English
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss139517
edoc DOI:
Last Modified:02 Mar 2021 05:30
Deposited On:01 Mar 2021 13:32

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