Pivotal role of mitochondria in development and treatment of severe phenotypes of desmin-mutated cardiomyocytes from a patient with myofibrillar myopathy
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ABSTRACT:
PROVIDER: PRJNA1029029 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26410400.fastq.gz | Fastqsanger.gz | |||
| SRR26410401.fastq.gz | Fastqsanger.gz | |||
| SRR26410402.fastq.gz | Fastqsanger.gz | |||
| SRR26410403.fastq.gz | Fastqsanger.gz | |||
| SRR26410404.fastq.gz | Fastqsanger.gz |
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Project description:Desmin-related myofibrillar myopathy, a severe muscle disease, is caused by mutations in the desmin-encoding gene, leading to skeletal myopathies and/or cardiomyopathy. Although previous studies suggested that desmin mutations alter the cellular structure and mitochondria function in myocyte, the pathophysiological mechanism by which mutated desmin impairs cardiac function has been poorly explored in physiologically relevant human disease models. In this attempt, we generated cardiomyocytes from induced pluripotent stem cells (hiPSC) of a patient carrying the heterozygous DESE439K mutation together with an isogenic pair of mutant hiPSC harboring the same mutation. Using 2D and 3D models as well as cardiac biopsies, we demonstrated that in mutant cardiomyocytes this heterozygous desmin mutation leads to disorganization in their cytoarchitecture and to a perturbation of their mitochondrial architecture and function. Finally, we then demonstrated that transfer of exogenous healthy mitochondria rescues the phenotypic impairment of mitochondrial function in desmin-mutated cardiomyocytes leading to the reversion of the diseased phenotype. This work advances our understanding on the critical role of mitochondria in the development of cardiomyopathy related to desmin mutation and opens up new potential therapeutic perspectives for this debilitating and still incurable disease.
2023-12-05 | GSE245583 | GEO
Project description:Desmin, the major intermediate filament (IF) protein in muscle cells, interlinks neighboring myofibrils and connects the whole myofibrillar apparatus to myonuclei, mitochondria, and the sarcolemma. However, desmin is also known to be enriched at postsynaptic membranes of neuromuscular junctions (NMJs). The pivotal role of the desmin IF cytoskeletal network is underscored by the fact that over 100 mutations of the human DES gene cause hereditary and sporadic myopathies and cardiomyopathies. A subgroup of human desminopathies comprises autosomal recessive cases resulting in complete abolition of desmin protein. In these patients, who display a more severe phenotype than the autosomal dominant cases, it has been reported that some individuals also suffer from a myasthenic syndrome in addition to the classical occurrence of myopathy and cardiomyopathy. Since further studies on the NMJ pathology is hampered by the lack of available human striated muscle biopsy specimens, we exploited homozygous desmin knock-out mice which closely mirror the striated muscle pathology of human patients lacking desmin protein. Here, we report on the impact of the lack of desmin on the structure and function of NMJs and on the transcription of genes coding for postsynaptic proteins. Desmin knock-out mice display a fragmentation of NMJs in soleus, but not in extensor digitorum longus muscle. Moreover, soleus muscle fibers show larger NMJs. Further, transcription levels of acetylcholine receptor (AChR) genes are increased in muscles from desmin knock-out mice, especially of the AChR subunit, which is known as a marker of muscle fiber regeneration. Electrophysiological recordings depicted a pathological decrement of nerve-dependent endplate potentials and a faster rise time of the nerve-independent miniature endplate potentials. The latter is indicating an enhanced opening time of the AChR channels. Our study highlights the essential role of desmin for the structural and functional integrity of mammalian neuromuscular junctions.
2020-07-17 | GSE154573 | GEO
Project description:The sarcomere is the muscle contractile unit, whose assembly and disassembly are intimately linked to changes in myofiber size and function. Mutations in sarcomeric proteins are common causes of myopathies, ranging from severe neonatal to adult-onset forms. Here, we identify HECTD1 as an E3 ubiquitin ligase necessary for sarcomere maintenance. We show that silencingHectd1 in myotubesreduces the levels of proteins critical for sarcomere integrity including a-actin, titin, troponins, tropomyosins, and several myosin heavy chain isoforms. We further establish that Hectd1 ubiquitylates and stabilizes the molecular chaperones KLHL40/41, that when dysfunctional destabilize nebulin and other sarcomere thin filament proteins (causing nemaline myopathy). Consequently, skeletal muscle-specific Hectd1 knockout mice (Hectd1 mKO) show progressive muscle weakness, exercise intolerance, and unresolved tissue remodeling. Molecular and histological analysis of Hectd1 mKO muscle revealed subsarcolemmal storage of the scaffold protein desmin, mitochondrial abnormalities, and severe sarcomere disorganization. This work uncovers Hectd1 as an E3 ligase critical for sarcomere assembly, and a novel diagnostic gene for myopathy with features of nemaline and desmin myopathy.
2024-07-26 | GSE272775 | GEO
Project description:Loss of Hectd1 disrupts muscle sarcomere assembly and causes combined desmin-nemaline myopathy
| PRJNA1138709 | ENA
Project description:Background: Mutations of the desmin gene cause familial and sporadic cardiomyopathies and myopathies. Previous studies showed that both the lack of desmin and expression of mutated desmin negatively impact on number, structure and function mitochondria implying a metabolic dysfunction as disease promoting factor. Here, we exploited desmin knock-out mice to analyse the general metabolic performance of cardiac tissue. Methods: We analysed left ventricular cardiac muscle tissue derived from six-month-old homozygous desmin knock-out mice as well as wild-type siblings. Employing a multi-method approach comprising morphological, clinical chemistry, biochemical, genetic, and proteomic techniques, we specifically addressed energy, fatty acid, glucose, and amino acid metabolism. Results: We demonstrated that the lack of desmin in left ventricular cardiac tissue led to a significant decrease in the number of mitochondria in conjunction with ultrastructural defects of mitochondria. Analysis of mitochondria-related metabolic pathways revealed significantly impaired processes of fatty acid transport, activation, and catabolism associated with increased blood levels of short, medium, and long chain acyl-carnitines. In addition to increased amounts of glucose transporter 1 and hexokinase 1, we detected a significantly increased hexokinase enzyme activity. While the amount of mitochondrial creatine kinase was markedly reduced, fetal creatine kinase was increased. The picture of a highly dysbalanced metabolic state was complemented by our quantitative proteomic analysis that revealed significantly reduced levels of multiple proteins centrally involved in electron transport mainly of complexes I and II, oxidative phosphorylation, citrate cycle, beta oxidation including auxiliary pathways, amino acid catabolism, and redox reactions and oxidative stress. Conclusions: Our data denoted a picture of widespread metabolic dysfunction far reaching beyond the level of mitochondria in left ventricular cardiac tissue of desmin knock-out mice. The increase of glucose utilisation along with increased level of fetal creatine kinase likely is a compensatory measure counteracting the severely hampered fatty acid metabolism and oxidative phosphorylation. The degree of metabolic disbalance, already observed in desmin knock-out mice kept under standard ‘sedentary’ housing conditions, renders it likely that acute strenuous physical exercise with its steeply increased energy demand will push the cardiac tissue into severe metabolic crisis.
2022-10-21 | PXD030938 | Pride
Project description:Desmin is a cytoskeletal protein in muscle involved in integrating cellular space and transmitting forces. In this study we sought to determine the effects of desmin deletion on skeletal muscle at the transcriptional level across many pathways of muscle physiology. RNA was isolated from the TA muscle of mice of two genotypes (wildtype (WT) and desmin knockout (KO)) and two ages (7-9 weeks (Adult) and 12-14 months (Aged)). Numbers per group are as follows: WT_Adult (5), WT_Aged (5), KO_Adult (5), KO_Aged (4).
2012-07-10 | E-GEOD-34388 | biostudies-arrayexpress
Project description:Myofibrillar myopathy (MFM) in horses is a late onset disease that affects performance and athleticism. It is characterized by myofibrillar disarray and protein aggregation with no known cause. The objective of this study was to elucidate the molecular drivers of MFM in Warmblood (WB) horses by proteomic profiling (5 MFM WB, 4 non-MFM WB) of gluteal muscle. MFM horses used in this study had a chronic history of poor performance and exercise intolerance as well as accumulation of desmin aggregates in > 4 myofibers per muscle sample. The Equine Neuromuscular Diagnostic Laboratory database at Michigan State University was queried to identify WB horses with snap frozen gluteus medius biopsies available for analysis. Non-MFM control horses were defined as horses with no history of exercise intolerance and no evidence of desmin accumulation or other histopathology in muscle biopsies. Muscle biopsy samples were obtained at rest from horses that had not undertaken strenuous exercise in the preceding 48 hours.
2021-09-09 | PXD019187 | Pride
Project description:C2C12 cell lines were genetically engineered to stably express WT human Desmin or the Desmin mutant R406W or I451M. Non-modified C2C12 cells were used as control. The goal was to determine the effect of different desmin mutation on the gene expression in a myoblast cell line.
2021-10-09 | GSE185589 | GEO
Project description:Desmin is a cytoskeletal protein in muscle involved in integrating cellular space and transmitting forces. In this study we sought to determine the effects of desmin deletion on skeletal muscle at the transcriptional level across many pathways of muscle physiology.
2012-07-11 | GSE34388 | GEO
Project description:a knockin mouse model was generatded that expresses the desmin mutant R405W either heterozygotic or homozygotic. the soleus muscle from 6 wt animals and each 6 aniamls with either heterzygotic or homozygotic mutation of desmin were extracted and embedded for cryotome sectioning. Muscle sections from 10 µm slices were collected in an eppendorf vial for proteomic analysis.
2025-11-10 | PXD042319 | Pride