Compensatory mechanisms in non-muscle organs in myotubular myopathy
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ABSTRACT:
PROVIDER: PRJNA1014460 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR25987543.fastq.gz | Fastqsanger.gz | |||
| SRR25987544.fastq.gz | Fastqsanger.gz | |||
| SRR25987545.fastq.gz | Fastqsanger.gz | |||
| SRR25987546.fastq.gz | Fastqsanger.gz | |||
| SRR25987547.fastq.gz | Fastqsanger.gz |
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Project description:X-Linked myotubular myopathy (XLMTM), is associated with very severe muscle weakness and reduced life expectancy. Liver dysfunction was also reported. The pathomechanism and the impact of non-muscular defects affecting survival are barely known. Here, we investigated organ-specific effects of XLMTM in the faithful Mtm1-/y mouse model. We performed RNA-sequencing to identify a shared mechanism in several skeletal muscles, and to investigate potential phenotypes and/or compensation in heart and liver. The cardiac and hepatic function and structural integrity were also studied in vivo and in vitro. There was no defect in liver function and morphology. A disease signature shared across several skeletal muscles including diaphragm highlighted dysregulations of muscle development, inflammation, cell adhesion and oxidative phosphorylation as main pathomechanisms. Heart displayed only slight functional alterations without obvious structural defects. An opposite dysregulation of specific pathways in cardiac compared to skeletal muscles was revealed at the transcriptome level. More specifically, biochemical and cellular experiments demonstrated that OXPHOS mitochondrial function, cell adhesion and beta integrin trafficking were strongly affected in skeletal muscle and normal in cardiac muscle. Moreover, biomarkers reflecting the molecular activity of MTM1, such as PtdIns3P and dynamin 2 levels, were increased in the skeletal muscles but not in cardiac muscle. Overall, these data identified a compensatory mechanism preserving cardiac function, indicating therapeutic targets to cure the severe skeletal muscle defects in XLMTM.
2024-12-18 | GSE242761 | GEO
Project description:X-linked myotubular myopathy (XLMTM) is a fatal neuromuscular disorder caused by loss of function mutations in MTM1 . At present, there are no directed therapies for XLMTM, and incomplete understanding of disease pathomechanisms. To address these knowledge gaps, we performed a drug screen in mtm1 mutant zebrafish andidentified four positive hits, including valproic acid, which functions as a potent suppressor of the mtm1 zebrafish phenotype via HDAC inhibition. We translated these findings to a mouse XLMTM model, and showed that valproic acid ameliorates the murine phenotype.
2022-08-08 | GSE210642 | GEO
Project description:Tamoxifen therapy in a murine model of myotubular myopathy (TAM4MTM)
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Project description:Natural history of a mouse model of X-linked myotubular myopathy
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Project description:X-linked myotubular myopathy (XLMTM) is a severe monogenetic disorder of the skeletal muscle. It is caused by loss-of-expression/function mutations in the myotubularin (MTM1) gene. Much of what is known about the disease, as well as the treatment strategies, has been uncovered through experimentation in pre-clinical models, particularly the Mtm1 gene knockout mouse line (Mtm1 KO). Despite this understanding, and the identification of potential therapies, much remains to be understood about XLMTM disease pathomechanisms, and about the normal functions of MTM1 in muscle development. To lay the groundwork for addressing these knowledge gaps, we performed a natural history study of Mtm1 KO mice. This included longitudinal comparative analyses of motor phenotype, transcriptome and proteome profiles, muscle structure and targeted molecular pathways.We identified age-associated changes in gene expression, mitochondrial function, myofiber size and key molecular markers, including DNM2. Importantly, some molecular and histopathologic changes preceded overt phenotypic changes, while others, such as triad structural alternations, occurred coincidentally with the presence of severe weakness. In total, this study provides a comprehensive longitudinal evaluation of the murine XLMTM disease process, and thus provides a critical framework for future investigations.
2022-07-08 | GSE207447 | GEO
Project description:X-linked myotubular myopathy (XLMTM) is a fatal congenital disorder caused by mutations in the MTM1 gene. Currently, there are no approved treatments, though AAV8-mediated gene transfer therapy has shown promise in animal models and preliminarily in patients. However, four patients with XLMTM treated with gene therapy have died from progressive liver failure, and hepatobiliary disease has now been recognized more broadly in association with XLMTM. In an attempt to understand whether loss of MTM1 itself is associated with liver pathology, we have characterized a novel liver phenotype in a zebrafish model of this disease. Specifically, we have found that loss-of-function mutations in mtm1 lead to severe liver abnormalities including impaired bile flux, structural abnormalities of the bile canaliculus, and improper endosomal-mediated trafficking of canalicular transporters. Using a reporter tagged Mtm1 zebrafish line, we have established localization of Mtm1 in the liver in association with Rab11 and canalicular transport proteins, and demonstrated that hepatocyte specific re-expression of Mtm1 can rescue the cholestatic phenotype. Lastly, we completed a targeted chemical screen, and found that Dynasore, a dynamin II inhibitor, is able to partially restore bile flow and transporter localization to the canalicular membrane. In summary, we demonstrate for the first time liver abnormalities that are directly caused by MTM1 mutation in a pre-clinical model, thus establishing the critical framework for better understanding and comprehensive treatment of the human disease.
2023-08-10 | GSE235571 | GEO
Project description:Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy
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Project description:X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition
| PRJNA866536 | ENA
Project description:Purpose: The goal of this study was to investigate the transcriptional profile of genes expressed in the quadriceps muscle of myotubularin deficient (Mtm1-/-) mice, and determine whether improvements in the pathophysiology of tamoxifen treated Mtm1-/- mice are a consequence of ER-dependent transcriptional modulation. Methods: Muscle mRNA profiles from quadriceps of 36-day-old wild-type (WT), myotubularin deficient (Mtm1-/-) mice, and tamoxifen treated WT and Mtm1-/- mice were generated by deep sequencing, in triplicate or quadruplicate, using Illumina HiSeq 2500. Read sets from each of the 14 samples across the four conditions were aligned to the reference genome (GRCm38/MM10 version of the Mus musculus genome) and transcriptome using STAR (Dobin et al. Bioinformatics 2013 PMID: 23104886) two-step alignment to generate a Binary Alignment Map file (BAM file). Coordinate sorted BAM files were used to quantify transcript abundance (count data) using HTSeq (Anders et al. Bioinformatics 2014, PMID: 25260700). Raw read counts generated were used as input for differential gene expression analysis, carried out using both DESeq (Anders and Huber 2010) and edgeR (Robinson, McCarthy, and Smyth 2010) R/Bioconductor packages. This was carried out in a pair-wise manner between any two conditions that were considered. FDR adjusted p-values from both edgeR and DESeq was used to determine genes that are significantly differentially expressed between the conditions tested. Finally, we used the GoSeq R/Bioconductor package (Young MD, et al Genome Biology, 11, pp. R14) to identify pathways that were significantly enriched for differentially expressed genes between any two conditions. Results: Using an established data analysis workflow, 65 million reads were aligned per sample (>90% exonic). We observed 849 differentially expressed transcripts in untreated mtm1-/-mice (p< 0.01) in comparison to wild-type (WT) controls. Furthermore, we identified 29 differentially expressed genes (p<0.01) between mtm1-/- mice and their TAM-treated mtm1-/- mice. In particular, we observed that the transcriptional profiles of mtm1 -/- mice and tamoxifen-treated mtm1-/- mice cluster together and are distinct from wild-type contros. Moreover, no significant changes were observed in the expression of estrogen-response genes that are known gene targets of tamoxifen; no significant transcriptional changes were observed in well-known MTM-related genes.This strongly indicates that, contrary to its well-established function as a transcriptional modulator, tamoxifen improves the pathophysiology of myotubular myopathy in a post-transcriptional manner. Concusions: Our study represents the first comprehensive analysis of the whole transcriptome of the Mtm1-/- and tamoxifen treated Mtm1-/- mouse, generated by RNA-seq technology. The data reported here provides a framework a comparative investigation of the expression profiles in Mtm1-/- mice and tamoxifen treated Mtm1-/- mice. Importantly, our results demonstrate that in our MTM murine model, tamoxifen does not appear to alter the transcriptional profile of many estrogen-receptor (ER) related genes, and moreover does not appear to alter the transcriptional profile of genes that are abnormally expressed in Mtm1-/- mice alone. This suggests that tamoxifen is acting to improve the pathophysiology of the MTM mouse model in a transcriptionally-indepedent manner.
2018-09-23 | GSE120336 | GEO
Project description:Centronuclear myopathy (CNM) is an inherited neuromuscular disorder characterised by clinical features of a congenital myopathy and centrally placed nuclei on muscle biopsy.The incidence of X-linked myotubular myopathy is estimated at 2/100000 male births but epidemiological data for other forms are not currently available.The clinical picture is highly variable. The X-linked form usually gives rise to a severe phenotype in males presenting at birth with marked weakness and hypotonia, external ophthalmoplegia and respiratory failure. Signs of antenatal onset comprise reduced foetal movements, polyhydramnios and thinning of the ribs on chest radiographs; birth asphyxia may be the present. Affected infants are often macrosomic, with length above the 90th centile and large head circumference. Testes are frequently undescended. Both autosomal-recessive (AR) and autosomal-dominant (AD) forms differ from the X-linked form regarding age at onset, severity, clinical characteristics and prognosis. In general, AD forms have a later onset and milder course than the X-linked form, and the AR form is intermediate in both respects.Mutations in the myotubularin (MTM1) gene on chromosome Xq28 have been identified in the majority of patients with the X-linked recessive form, whilst AD and AR forms have been associated with mutations in the dynamin 2 (DNM2) gene on chromosome 19p13.2 and the amphiphysin 2 (BIN1) gene on chromosome 2q14, respectively. Single cases with features of CNM have been associated with mutations in the skeletal muscle ryanodine receptor (RYR1) and the hJUMPY (MTMR14) genes.Diagnosis is based on typical histopathological findings on muscle biopsy in combination with suggestive clinical features; muscle magnetic resonance imaging may complement clinical assessment and inform genetic testing in cases with equivocal features. Genetic counselling should be offered to all patients and families in whom a diagnosis of CNM has been made.The main differential diagnoses include congenital myotonic dystrophy and other conditions with severe neonatal hypotonia.Management of CNM is mainly supportive, based on a multidisciplinary approach. Whereas the X-linked form due to MTM1 mutations is often fatal in infancy, dominant forms due to DNM2 mutations and some cases of the recessive BIN1-related form appear to be associated with an overall more favourable prognosis.
| S-EPMC2572588 | biostudies-literature