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.
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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.
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Project description:Loss of Hectd1 disrupts muscle sarcomere assembly and causes combined desmin-nemaline myopathy
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Project description:Over-expression of wild type PrP in skeletal muscles is sufficient to cause a primary myopathy with no signs of peripheral neuropathy, possibly due to accumulation of a cytotoxic truncated form of PrP and/or PrP aggregation. In this study we used DNA microarrays to identify 1499 transcripts that are temporally deregulated concomitant with inducible PrPC over-expression in the skeletal muscles of transgenic mice. Examination using microarrays revealed a transcriptional profile with both similarities and differences to previously investigated models of myopathies. Down-regulation of genes coding for the myofibrillar proteins MYH2, MYH6, MYH7, MYL2, MYL3 and up-regulation of lysosomal genes CTSS, CTSD, CTSZ, DPEP2, HEXA, HEXB and LAMP1 coincide with the observed myopathy and lysosome accumulation on over-expression of PrPC. Down-regulation of the MEF2C gene, a key regulatory transcriptional factor muscle development and remodeling of adult muscles in response to physiologic and pathologic signals, may contribute to the centrally placed nuclei in the skeletal muscles. Significantly, up-regulation of genes involved in p53 signaling and the induction of p53 protein, suggest a central role for this molecule in the myopathy. Several p53-regulated genes involved in cell cycle arrest (CDNK1A, GADD45a and GADD45b) and apoptosis (BAK1, PMAIP1, BBC3, and BAX) are induced. We suggest that PrPC over-expression in skeletal muscles, possibly in response to accumulation of a cytotoxic truncated form of PrP, causes a primary myopathy involving the induction of p53-dependent pathways.
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Project description:We performed a genome-wide association study in pooled DNA samples from patients with severe statin myopathy and persistent symptoms post-therapy versus pooled DNAs from an age-adjusted statin-tolerant group. Affymetrix 100K SNP arrays were used according to the manufacturers instructions with two pools of 19 and 20 statin myopathy patients and two pools of 20 statin-tolerant controls.
2010-07-09 | E-GEOD-17574 | biostudies-arrayexpress
Project description:<p>Severe myopathic events occur in 0.1-0.5% of patients taking statins. Although genetic association studies have identified some possibly associated gene loci, these have not been reproducible in additional studies with independent patient cohorts. A more reasonable explanation for susceptibility to statin-induced myopathy is the presence of rare pathogenic variants in genes important for skeletal muscle structure and function. In support of this, we have previously reported an increased incidence of pathogenic variants in genes causing metabolic myopathies in patients with statin-induced myopathy (<a href="https://www.ncbi.nlm.nih.gov/pubmed/16671104">Vladutiu et al.</a>,2006). We also reported a patient with statin myopathy who had an <i>RYR1</i> variant known to be causative of malignant hyperthermia susceptibility (MHS) (<a href="https://www.ncbi.nlm.nih.gov/pubmed/21795085">Vladutiu et al.</a>, 2011). There are a number of genes associated with metabolic myopathies triggered by various factors such as extreme exercise, fasting, extremes in temperature, viral infection and exposure to volatile anesthetics. In addition, many of the genes causing congenital myopathies, myofibrillar myopathies and muscular dystrophies have overlapping phenotypes with these genes. We propose that statins act as an additional trigger inducing myopathic symptoms and many patients with severe statin-induced myopathy have causative genetic variants within similar genes associated with MHS and congenital myopathy. We have analyzed the resultant data using a disease model in which rare pathogenic variants, possibly within multiple genes, are causative of statin-induced myopathy. In this study, we have identified potentially causative genetic variants in greater than 50% of the statin-induced myopathy cases and in particular, rare and possibly pathogenic in the RYR1 and CACNA1S genes were present in 25% of the patient samples studied. Vladutiu, G. D., Simmons, Z., Isackson, P.J., Tarnopolsky, M., Peltier, W.L., Barboi, A.C., Sripathi, N., Wortmann, R.L., Phillips, P.S., (<a href="https://www.ncbi.nlm.nih.gov/pubmed/16671104">2006</a>). "Genetic risk factors associated with lipid-lowering drug-induced myopathies." Muscle Nerve 34: 153-162. Vladutiu, G. D., Isackson, P.J., Kaufman, K., Harley, J.B., Cobb, B., Christopher-Stine, L., Wortmann, R.L, (<a href="https://www.ncbi.nlm.nih.gov/pubmed/21795085">2011</a>). "Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies." Mol Genet Metab 104: 167-173. </p>
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