Myotonic Dystrophy Transgenic Mice Exhibit Pathologic Abnormalities in Diaphragm Neuromuscular Junctions and Phrenic Nerves

ArticleinJournal of Neuropathology and Experimental Neurology 67(8):763-72 · August 2008with10 Reads
DOI: 10.1097/NEN.0b013e318180ec64 · Source: PubMed
Myotonic dystrophy Type 1 (DM-1) is caused by abnormal expansion of a (CTG) repeat located in the DM protein kinase gene. Respiratory problems have long been recognized to be a major feature of this disorder. Because respiratory failure can be associated with dysfunction of phrenic nerves and diaphragm muscle, we examined the diaphragm and respiratory neural network in transgenic mice carrying the human genomic DM-1 region with expanded repeats of more than 300 CTG, a valid model of the human disease. Morphologic and morphometric analyses revealed distal denervation of diaphragm neuromuscular junctions in DM-1 transgenic mice indicated by a decrease in the size and shape complexity of end-plates and a reduction in the concentration of acetyl choline receptors on the postsynaptic membrane. More importantly, there was a significant reduction in numbers of unmyelinated, but not of myelinated, fibers in DM-1 phrenic nerves; no morphologic alternations of the nerves or loss of neuronal cells were detected in medullary respiratory centers or cervical phrenic motor neurons. Because neuromuscular junctions are involved in action potential transmission and the afferent phrenic unmyelinated fibers control the inspiratory activity, our results suggest that the respiratory impairment associated with DM-1 may be partially due to pathologic alterations in neuromuscular junctions and phrenic nerves.
    • "The effects of lack of ChoKβ in mice are due to differential expression patterns [80, 81] , affect mitochondrial function [82, 83] and alter neuromuscular junctions [84] . Several recent reports demonstrate that inactivating mutations at the CHKB gene are responsible of human muscular dystrophy and myopathy [11,[82][83][84][85][86][87][88][89][90][91][92]. Therefore, since the lack of ChoKβ activity is the cause of muscular dystrophy, any intervention restoring its activity may serve to reinstate normal muscle development in this pathological setting. "
    [Show abstract] [Hide abstract] ABSTRACT: Cancer cells have an altered metabolism that provides advantages to support unregulated growth and higher duplication rates. Among these critical changes, energy generation through aerobic glycolysis as well as increased glutamine catabolism, are essential components associated with altered levels of specific metabolites. Up-regulation of lipid metabolism also occurs frequently in cancer cells. Increased fatty-acid biosynthesis as well as their elongation are among recognized events that define cancer cells. Not surprisingly, the CDP-choline and CDP-ethanolamine pathways responsible for the generation of membrane phospholipids is a major alteration frequently found in human tumours. Choline kinase α (ChoKα) plays a critical role in this latter metabolic route and is the focus of a targeted therapeutic strategy. Small molecule inhibitors of this enzyme are effective and selective anticancer drugs that have recently entered clinical trials. More recently, ChoKα inhibitors have been proposed as a novel therapeutic approach against malaria and rheumatoid arthritis. Here, the evidence that support the use of ChoKα as a novel drug target for precision medicine approaches is discussed.
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    • "In both transgenic mice sub-lines a denervation rate of about 20% of the end-plates (EPs) was calculated and an identical reduction in the size, shape complexity and density of acetylcholine receptors in EPs was measured. In addition, a loss of about 40% of the number of unmyelinated phrenic afferents was observed in both DM600 and DMSXL transgenic mice (Panaite et al., 2008Panaite et al., , 2013). In conclusion, the DM600 and DMSXL mice have a similar respiratory failure indicating that there is no relationship between the severity of the respiratory problems assessed in these mice and the size of CTG triplet. "
    [Show abstract] [Hide abstract] ABSTRACT: Myotonic dystrophy (DM1) is a multisystemic disease caused by an expansion of CTG repeats in the region of DMPK, the gene encoding DM protein kinase. The severity of muscle disability in DM1 correlates with the size of CTG expansion. As respiratory failure is one of the main causes of death in DM1, we investigated the correlation between respiratory impairment and size of the (CTG)n repeat in DM1 animal models. Using pressure plethysmography the respiratory function was assessed in control and transgenic mice carrying either 600 (DM600) or >1300 CTG repeats (DMSXL). The statistical analysis of respiratory parameters revealed that both DM1 transgenic mice sub-lines show respiratory impairment compared to control mice. In addition, there is no significant difference in breathing functions between the DM600 and DMSXL mice. In conclusion: these results indicate that respiratory impairment is present in both transgenic mice sub-lines, but the severity of respiratory failure is not related to the size of the (CTG)n expansion.
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    • "We previously generated transgenic mice expressing DMPK transcripts in multiple tissues under the control of the human DMPK gene promoter, within the environment of the human myotonic dystrophy type 1 locus. In contrast with control DM20 lines (mice overexpressing short 20 CTG tracts), homozygous mice from two independent DM300 expansion lines (carrying 500–600 CTG), expressing sufficient toxic DMPK transcripts, showed wide RNA foci accumulation in a variety of tissues and developed a multisystemic phenotype (Seznec et al., 2001; Guiraud-Dogan et al., 2007; Panaite et al., 2008). Dramatic intergenerational instability in DM300 mice generated DMSXL animals carrying 41000 CTG, who develop a more severe phenotype (Gomes-Pereira et al., 2007; Huguet et al., 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: Myotonic dystrophy type 1 is a complex multisystemic inherited disorder, which displays multiple debilitating neurological manifestations. Despite recent progress in the understanding of the molecular pathogenesis of myotonic dystrophy type 1 in skeletal muscle and heart, the pathways affected in the central nervous system are largely unknown. To address this question, we studied the only transgenic mouse line expressing CTG trinucleotide repeats in the central nervous system. These mice recreate molecular features of RNA toxicity, such as RNA foci accumulation and missplicing. They exhibit relevant behavioural and cognitive phenotypes, deficits in short-term synaptic plasticity, as well as changes in neurochemical levels. In the search for disease intermediates affected by disease mutation, a global proteomics approach revealed RAB3A upregulation and synapsin I hyperphosphorylation in the central nervous system of transgenic mice, transfected cells and post-mortem brains of patients with myotonic dystrophy type 1. These protein defects were associated with electrophysiological and behavioural deficits in mice and altered spontaneous neurosecretion in cell culture. Taking advantage of a relevant transgenic mouse of a complex human disease, we found a novel connection between physiological phenotypes and synaptic protein dysregulation, indicative of synaptic dysfunction in myotonic dystrophy type 1 brain pathology.
    Full-text · Article · Mar 2013
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