Inducible deletion of Raptor and mTOR from adult skeletal muscle impairs muscle contractility and relaxation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA889746 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21872052.fastq.gz | Fastqsanger.gz | |||
| SRR21872053.fastq.gz | Fastqsanger.gz | |||
| SRR21872054.fastq.gz | Fastqsanger.gz | |||
| SRR21872055.fastq.gz | Fastqsanger.gz | |||
| SRR21872056.fastq.gz | Fastqsanger.gz |
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Project description:Skeletal muscle weakness has been associated with different pathological conditions, including sarcopenia and muscular dystrophy, and is accompanied by altered mTOR signaling. Here we wanted to better elucidate the functional role of mTOR on muscle contractility. Most loss of function studies for mTOR signaling have used the drug rapamycin to inhibit some of the signaling downstream of mTOR. However, as rapamycin does not completely inhibit all mTOR signaling, we generated a double k.o. for mTOR and for the scaffold protein of mTORC1, Raptor, in skeletal muscle. We found that dk.o. mice results in a more severe phenotype compared to Raptor or mTOR deletion alone. Indeed, they display muscle weakness, increased fiber denervation, and a slower muscle relaxation following tetanic stimulation. This is accompanied by a shift towards slow-twitch fibers and changes in the expression levels of calcium-related genes, like Serca1 and Casq1. Indeed, dk.o. mice show a decrease in calcium decay kinetics after tetanus in vivo, suggestive of a reduced calcium reuptake. In addition, RNA sequencing analysis revealed that many downregulated genes are linked to sarcomere organization, like Tcap and Fhod3. These results suggest a key role for mTOR signaling in maintaining a proper fiber relaxation in skeletal muscle.
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Project description:Recent studies have shown that mTOR signalling have a promotive effect on cancer. In our clinical work, we found that mTOR signalling is commonly activated in laryngeal cancer tissues and influence the metabolism of cancer cells. To investigate how mTORC1 exerts these functions and its downstream regulatory genes, we knocked down Raptor in the laryngeal cancer cell line LIU-LSC-1 and sequenced the transcriptome of wild-type and Raptor knockdown cells.
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Project description:The aim of the experiment was to determine the effect of cyclic stretch-relaxation ("stretch") on gene expression patterns in normal diploid human bladder smooth muscle cells. Cells plated on silicone elastomer bottomed 6-well culture dishes were grown to ~80% confluence, serum-depleted for 48h and subjected to cyclic stretch-relaxation at 20% elongation for 4h. Cells seeded in stretch plates but not subjected to stretch served as controls. Total RNA was extracted from both groups of cells, reverse-transcribed, biotin-labeled, fragmented and hybridized to HG-U133A. Four biological replicates were generated for each treatment group (non-stretched or stretched).
2007-08-04 | E-GEOD-1595 | biostudies-arrayexpress
Project description:Weakened sarcomeric contractility distinguishes Facio Scapulo Humeral Dystrophy muscle fibers
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Project description:Uterine contractile dysfunction leads to pregnancy complications such as preterm birth and labor dystocia. Progesterone is necessary to suppress uterine contractions to prevent premature labor. As humans maintain high levels of progesterone throughout parturition, a functional progesterone withdrawal hypothesis suggests that relative levels of myometrial progesterone receptor isoforms PGR-A and PGR-B switch at parturition, where PGR-B promotes a relaxed state and PGR-A result in increased uterine contractility. Our objective is to determine the effects of altered levels of PGR-B and PGR-A in the mouse myometrium on pregnancy and parturition using transgenic mouse models in which the relative levels of these isoforms are altered specifically in the myometrium. Overexpression of PGR-B is associated with a markedly increased gestational length compared to control mice. In both ex vivo and in vivo experiments, myometrium of PGR-B overexpressing mice have prolonged labor, a significant decrease in uterine contractility, and a high incidence of labor dystocia. Conversely, overexpression of PGR-A is associated with an increase in uterine contractility without a change in gestational length. Uterine RNAseq at mid-pregnancy identified isoform-specific downstream targets and genes that were commonly regulated by both PGR isoforms. Gene signature analyses further revealed that PGR-B promotes muscle relaxation and that PGR-A is pro-inflammation. High levels of PGR-B manifest a genetic profile of a blunted phospholipase C pathway that mediates oxytocin and angiotensin II induced muscle contraction. These findings provided in vivo support that PGR isoform levels determine distinct transcriptomic landscapes and pathways in myometrial function and labor.
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Project description:Little is known about the role of mTOR signaling in plasma cell differentiation and function. Furthermore, for reasons not understood, mTOR inhibition reverses antibody-associated disease in a murine model of systemic lupus erythematosus. Here, we have demonstrated that induced B-lineage specific deletion of the gene encoding RAPTOR, an essential signaling adaptor for the rapamycin-sensitive mTOR complex 1 (mTORC1) abrogated the generation of antibody-secreting plasma cells in mice. Acute treatment with rapamycin recapitulated the effects of RAPTOR deficiency, while both strategies led to the ablation of newly formed plasma cells in the spleen and bone marrow while also obliterating pre-existing germinal centers. Surprisingly, although perturbing mTOR activity caused a profound decline in serum antibodies that were specific for exogenous antigen or DNA, frequencies of long-lived bone marrow plasma cells were unaffected. Instead, mTORC1 inhibition led to decreased expression of immunoglobulin binding protein (BiP) and other factors needed for robust protein synthesis. Consequently, blockade of antibody synthesis was rapidly reversed after termination of rapamycin treatment. We conclude that mTOR signaling plays critical but diverse roles in early and late phases of antibody responses and plasma cell differentiation.
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