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The Skeletal Muscle Molecular Clock Regulates Sarcomere Length Through Titin Splicing [2]

ABSTRACT: The Skeletal Muscle Molecular Clock Regulates Sarcomere Length Through Titin Splicing [2]

PROVIDER: PRJNA784919 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17073984_1.fastq.gz	Fastqsanger.gz
	SRR17073984_2.fastq.gz	Fastqsanger.gz
	SRR17073985_1.fastq.gz	Fastqsanger.gz
	SRR17073985_2.fastq.gz	Fastqsanger.gz
	SRR17073986_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

The Skeletal Muscle Molecular Clock Regulates Sarcomere Length Through Titin Splicing [1]

Project description:Circadian rhythms have been implicated in regulating skeletal muscle structure and function, but no mechanisms have connected the molecular clock to sarcomeric proteins. We identified an isoform shift in the sarcomeric ruler, titin, and showed that the skeletal muscle molecular clock regulates titin isoform and subsequently sarcomere length through RBM20, an RNA binding protein that controls titin splicing.

2022-09-07 | GSE172067 | GEO

The Skeletal Muscle Molecular Clock Regulates Sarcomere Length Through Titin Splicing [2]

2022-09-07 | GSE189863 | GEO

The Skeletal Muscle Molecular Clock Regulates Sarcomere Length Through Titin Splicing

Project description:The Skeletal Muscle Molecular Clock Regulates Sarcomere Length Through Titin Splicing

| PRJNA784914 | ENA

The Skeletal Muscle Molecular Clock Regulates Sarcomere Length Through Titin Splicing [1]

Project description:The Skeletal Muscle Molecular Clock Regulates Sarcomere Length Through Titin Splicing [1]

| PRJNA721950 | ENA

The Skeletal Muscle Molecular Clock Regulates Sarcomere Length Through Titin Splicing

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-09-06 | GSE189865 | GEO

Titin splicing

Project description:Titin is a striated muscle-specific giant elastic protein and largely responsible for the generation of the diastolic force in the cardiac myocyte. Cardiac titin undergoes developmental changes in isoform expression during the course of cardiac development. At present, at least five size classes of titin isoforms (N2B and N2BA-A1, A2, N1, N2) have been identified using SDS agarose gel electrophoresis. The larger titin isoform N2BAs gradually decreased with ages, in contrast, the smaller titin isoform N2B increased in normal cardiomyocyte, and cardiac myocytes containing a higher proportion of the smaller titin isoform N2B have stronger passive tension than that with a lower proportion of the larger titin isoform N2BAs. Recently we found an autosomal dominant mutation which caused totally opposite cardiac titin isoform expression as compared to developmental stages. The larger total titin isoform N2BA increased in mutant rat cardiac myocytes with ages instead of the smaller cardiac titin isoform N2B. For the moment, mechanism of titin isoform switch is still unknown, therefore, the mutant rats will give us nevol sight to elucidate the titin splicing mechanism. Keywords: Titin isoforms, autosomal dominant mutation

2008-06-10 | GSE11137 | GEO

The skeletal muscle circadian clock regulates titin splicing through RBM20.

Project description:Circadian rhythms are maintained by a cell-autonomous, transcriptional-translational feedback loop known as the molecular clock. While previous research suggests a role of the molecular clock in regulating skeletal muscle structure and function, no mechanisms have connected the molecular clock to sarcomere filaments. Utilizing inducible, skeletal muscle specific, Bmal1 knockout (iMSBmal1-/-) mice, we showed that knocking out skeletal muscle clock function alters titin isoform expression using RNAseq, liquid chromatography-mass spectrometry, and sodium dodecyl sulfate-vertical agarose gel electrophoresis. This alteration in titin's spring length resulted in sarcomere length heterogeneity. We demonstrate the direct link between altered titin splicing and sarcomere length in vitro using U7 snRNPs that truncate the region of titin altered in iMSBmal1-/- muscle. We identified a mechanism whereby the skeletal muscle clock regulates titin isoform expression through transcriptional regulation of Rbm20, a potent splicing regulator of titin. Lastly, we used an environmental model of circadian rhythm disruption and identified significant downregulation of Rbm20 expression. Our findings demonstrate the importance of the skeletal muscle circadian clock in maintaining titin isoform through regulation of RBM20 expression. Because circadian rhythm disruption is a feature of many chronic diseases, our results highlight a novel pathway that could be targeted to maintain skeletal muscle structure and function in a range of pathologies.

| S-EPMC9473687 | biostudies-literature

Aberrant developmental titin splicing and dysregulated sarcomere length in Thymosin β4 knockout mice.

Project description:Sarcomere assembly is a highly orchestrated and dynamic process which adapts, during perinatal development, to accommodate growth of the heart. Sarcomeric components, including titin, undergo an isoform transition to adjust ventricular filling. Many sarcomeric genes have been implicated in congenital cardiomyopathies, such that understanding developmental sarcomere transitions will inform the aetiology and treatment. We sought to determine whether Thymosin β4 (Tβ4), a peptide that regulates the availability of actin monomers for polymerization in non-muscle cells, plays a role in sarcomere assembly during cardiac morphogenesis and influences adult cardiac function. In Tβ4 null mice, immunofluorescence-based sarcomere analyses revealed shortened thin filament, sarcomere and titin spring length in cardiomyocytes, associated with precocious up-regulation of the short titin isoforms during the postnatal splicing transition. By magnetic resonance imaging, this manifested as diminished stroke volume and limited contractile reserve in adult mice. Extrapolating to an in vitro cardiomyocyte model, the altered postnatal splicing was corrected with addition of synthetic Tβ4, whereby normal sarcomere length was restored. Our data suggest that Tβ4 is required for setting correct sarcomere length and for appropriate splicing of titin, not only in the heart but also in skeletal muscle. Distinguishing between thin filament extension and titin splicing as the primary defect is challenging, as these events are intimately linked. The regulation of titin splicing is a previously unrecognised role of Tβ4 and gives preliminary insight into a mechanism by which titin isoforms may be manipulated to correct cardiac dysfunction.

| S-EPMC5319848 | biostudies-literature

Systematic transcriptomics reveals a biphasic mode of sarcomere morphogenesis in flight muscles regulated by Spalt

Project description:Muscles organise a pseudo-crystalline array of actin, myosin and titin filaments to build force-producing sarcomeres. To study how sarcomeres are built, we performed mRNA-sequencing of developing Drosophila flight muscles and identified 40 distinct expression profile clusters. Strikingly, two clusters are strongly enriched for sarcomeric components. Temporal gene expression together with detailed morphological analysis enabled us to define two distinct phases of sarcomere development, both of which require the transcriptional regulator Spalt major. During the first sarcomere formation phase, 2.0 µm long immature sarcomeres assemble myofibrils that spontaneously contract. In the second sarcomere maturation phase, sarcomeres grow to their final 3.2 µm length and 1.5 µm diameter and acquire stretch-sensitivity. Interestingly, the final number of myofibrils per flight muscle fiber is determined at the onset of the first phase and remains constant. Together, this defines a biphasic mode of sarcomere and myofibril morphogenesis – a new concept which may also apply to vertebrate muscle or heart development.

2017-12-01 | GSE107247 | GEO

Titin truncating variant associated with atrial fibrillation leads to cell type-specific effects in atrial and ventricular patient hiPSC-CM models

Project description:Protein truncating mutations in the titin gene are associated with increased risk of atrial fibrillation (AF). However, little is known regarding the underlying pathophysiology. We identified a heterozygous titin truncating variant in a patient with unexplained early-onset AF using whole exome sequencing. We used atrial and ventricular patient induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), CRISPR/Cas9 genetic correction, and engineered heart tissue (EHT) constructs to evaluate the impact of the titin truncating variant on electrophysiology, sarcomere structure, contractility, and gene expression.

2025-11-25 | GSE234141 | GEO

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