The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia [Aging-Rapamycin data set].
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ABSTRACT:
PROVIDER: PRJNA578743 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10320717_1.fastq.gz | Fastqsanger.gz | |||
| SRR10320717_2.fastq.gz | Fastqsanger.gz | |||
| SRR10320718_1.fastq.gz | Fastqsanger.gz | |||
| SRR10320718_2.fastq.gz | Fastqsanger.gz | |||
| SRR10320719_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: To investigate whether our signatures of mTORC1-driven sarcopenia originate from cells residing at the neuromuscular junction (NMJ), we followed laser-capture microdissection with RNA-seq from adult and sarcopenic tibialis anterior (TA) muscles. Methods: TA muscles were incubated in solution containing fluorescently-labeled bungarotoxin, which binds to post-synaptic AChRs and thereby marks NMJ regions. Approximately 300 synaptic regions (NMJ) and a comparable number of extra-synaptic (xNMJ) regions were collected from 30µM thick sections using laser-capture microdissection (LCM) and processed for RNA-seq. Results: As compared to xNMJ regions, NMJ regions were highly enriched for genes known to be specifically expressed at the NMJ. The analysis demonstrated that genes associated with sarcopenia are significantly enriched at the NMJ in young (10 months) and old (30 months) mice. Furthermore, the age-related reduction in expression of genes associated with extracellular matrix (ECM) remodelling was particularly prominent in NMJ regions but not in xNMJ regions. Conclusions: Diminished expression of ECM genes at the NMJ may impact the stability of the NMJ and its ability to remodel following common age-related remodelling events such as muscle fiber degeneration/regeneration and motor unit loss.
2020-06-19 | GSE139209 | GEO
Project description:Purpose: Despite demonstrating that the overall effect of long-term rapamycin-treatment is overwhelmingly positive in aging skeletal muscle, we observed muscle-specificity in the responsiveness to rapamycin, leading us to hypothesize that the primary drivers of age-related muscle loss and therefore effective intervention strategies may differ between muscles. To address this question and dissect the key signaling nodes associated with mTORC1-driven muscle aging, we created a comprehensive multi-muscle gene expression atlas in adult, sarcopenic and rapamycin-treated mice using RNA-seq. Methods: To examine the impact of long-term rapamycin treatment, male C57BL/6 mice were fed encapsulated rapamycin incorporated into a standardized AIN93M diet at 42 ppm (i.e. mg per kg of food), corresponding to a dose of ~4 mg·kg-1·day-1, from 15- to 30-months of age. This dose of rapamycin has been shown to extend lifespan maximally in male C57BL/6 mice. We performed RNA-seq on gastrocnemius (GAS), tibialis anterior (TA), triceps brachii (TRI) and soleus (SOL) muscles from each of six mice for 10m, 30m and 30mRM groups. The four muscle types were chosen to encompass fore- and hindlimb locations (e.g. TRI and GAS); slow and fast contraction properties (e.g. SOL and GAS); anterior and posterior positioning (e.g. TA and GAS) and the extent of protection by rapamycin (TA and TRI: protected; SOL: partiallly protected; GAS: not protected). Results: Age-related gene expression changes were remarkably consistent across the four different muscles, varying only in magnitude. Despite having the smallest age-related muscle loss of the four muscles, TA had the strongest age-related gene expression response which was associated with an increased reinnervation response. Despite the strong between-muscle commonality of age-related changes, gene expression responses to prolonged rapamycin treatment differed substantially between muscles. Rapamycin partially reversed many age-related changes in mRNA expression in the TA and TRI, but not in SOL or GAS muscle. Principle component analysis (PCA) showed that rapamycin had common 'anti-aging' effects on all muscles, while also exerting muscle-specific pro-aging effects on muscles not protected by rapamycin. Conclusions: Sustained, muscle fiber-specific mTORC1 activity drives sarcopenia-like gene expression programs, and the hyperactive mTORC1 seen in sarcopenic muscle may therefore contribute to sarcopenia.
2020-06-19 | GSE139204 | GEO
Project description:Purpose: Sustained muscle fiber-specific mTORC1 activity, through deletion of the mTORC1 upstream inhibitor Tsc1, drives progressive muscle wasting and weakness reminiscent of sarcopenia. We aimed to characterise gene expression changes coinciding with the development of sarcopenia-like features in TSCmKO mice. Methods: Extensorum digitorum longus (EDL) muscles from 3- (weak phenotype) and 9-month-old (severe phenotype) TSCmKO and littermate control mice (Tsc1 floxed, HSA-Cre negative) treated with either vehicle or rapamycin (8 mg.kg.min-1) for 3 days were processed and sequenced. Results: The principal component analysis showed two major gene expression patterns. The first pattern represents an aging-like pattern with gene expression remaining stable between 3 and 9 months in wild type mice, but changing between 3 and 9 months in TSCmKO mice. The second pattern seems to represent early alterations in TSCmKO mice compared to WT, which subside between 3 and 9 months in TSCmKO. Importantly, when comparing changes in the gene expression in TSCmKO mice with natural aging gene expression profiles, there was a significant overrepresentation of commonly increasing and decreasing genes and an underrepresentation of oppositely regulated genes. Likewise, many of the top enriched GO terms for natural aging gene expression profiles were also enriched for genes changing the expression in the premature aging TSCmKO mice. Conclusions: Sustained, muscle fiber-specific mTORC1 activity drives sarcopenia-like gene expression programs, and the hyperactive mTORC1 seen in sarcopenic muscle may therefore contribute to sarcopenia.
2020-06-19 | GSE139213 | GEO
Project description:The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia [NMJ data set].
| PRJNA578746 | ENA
Project description:The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia [TSCmKO data set].
| PRJNA578753 | ENA
Project description:With human median lifespan extending into the 80s in many developed countries, the societal burden of age-related muscle loss (sarcopenia) is increasing. mTORC1 promotes skeletal muscle hypertrophy, but also drives organismal aging. Here, we address the question of whether mTORC1 activation or suppression is beneficial for skeletal muscle aging. We demonstrate that chronic mTORC1 inhibition with rapamycin is overwhelmingly, but not entirely, positive for aging mouse skeletal muscle, while genetic, muscle fiber-specific activation of mTORC1 is sufficient to induce molecular signatures of sarcopenia. Through integration of comprehensive physiological and extensive gene expression profiling in young and old mice, and following genetic activation or pharmacological inhibition of mTORC1, we establish the phenotypically-backed, mTORC1-focused, multi-muscle gene expression atlas, SarcoAtlas (https://sarcoatlas.scicore.unibas.ch/), as a user-friendly gene discovery tool. We uncover inter-muscle divergence in the primary drivers of sarcopenia and identify the neuromuscular junction as a focal point of mTORC1-driven muscle aging.
| S-EPMC7481251 | biostudies-literature
Project description:Molecular mechanisms underlying sarcopenia, the age-related loss of skeletal muscle mass and function, remain unclear. To identify molecular changes that correlated best with sarcopenia and might contribute to its pathogenesis, we determined global gene expression profiles in muscles of rats aged 6, 12, 18, 21, 24, and 27 months. These rats exhibit sarcopenia beginning at 21 months. Correlation of the gene expression versus muscle mass or age changes, and functional annotation analysis identified gene signatures of sarcopenia distinct from gene signatures of aging. Specifically, mitochondrial energy metabolism (e.g., tricarboxylic acid cycle and oxidative phosphorylation) pathway genes were the most downregulated and most significantly correlated with sarcopenia. Also, perturbed were genes/pathways associated with neuromuscular junction patency (providing molecular evidence of sarcopenia-related functional denervation and neuromuscular junction remodeling), protein degradation, and inflammation. Proteomic analysis of samples at 6, 18, and 27 months confirmed the depletion of mitochondrial energy metabolism proteins and neuromuscular junction proteins. Together, these findings suggest that therapeutic approaches that simultaneously stimulate mitochondrogenesis and reduce muscle proteolysis and inflammation have potential for treating sarcopenia.
2018-08-21 | GSE118825 | GEO
Project description:Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia
| PRJNA486911 | ENA
Project description:Muscle fibroadipogenic progenitor (FAP) cells, which are muscular mesenchymal cells that originate from lateral plate mesoderm have been proposed to act as a critical regulator for adult muscle homeostasis1–7, including the maturation and proper functioning of the neuromuscular junction (NMJ)3, Prx-Bap1 paper. However, the mechanism and intercellular crosstalk by which FAPs regulate the stability and functionality of neuromuscular system remains unknown. Here we show that FAPs not only locally but also systemically regulate the neuromuscular system through the secretion of a serine-type endopeptidase Granzyme E which may imply the previously unidentified endocrine function of FAPs. Local transplantation of wild-type FAPs into the neuromuscular disease model (Prrx1Cre;Bap1f/f, hereafter, cKO) can readily prevent neuromuscular defects, including degeneration of the neuromuscular junction and loss of motor neurons. These effects are found not only in transplanted hindlimb muscles but also in the contralateral hindlimb and even forelimb muscles. Notably, subcutaneous administration of microparticles encapsulating FAP-conditioned media into cKO mice was sufficient to restore normal neuromuscular functions. By analyzing the transcriptomic and secretomic profiles of FAPs, we identified a novel protein, Granzyme E, which is specifically expressed in and secreted by FAPs, and which indispensably regulates the structure and function of NMJ and motor neuron survival. Our study has defined a unique mechanism of Granzyme E-dependent, systemic control of the neuromuscular system by FAPs, which would provide a comprehensive understanding on the neuromuscular systems and their crosstalk with non-neuronal cells. These findings may provide a therapeutic benefit to treat NMJ-related diseases.
2022-08-31 | GSE199660 | GEO
Project description:BackgroundSkeletal muscle is a plastic tissue that can adapt to different stimuli. It is well established that Mammalian Target of Rapamycin Complex 1 (mTORC1) signalling is a key modulator in mediating increases in skeletal muscle mass and function. However, the role of mTORC1 signalling in adult skeletal muscle homeostasis is still not well defined.MethodsInducible, muscle-specific Raptor and mTOR k.o. mice were generated. Muscles at 1 and 7 months after deletion were analysed to assess muscle histology and muscle force.ResultsWe found no change in muscle size or contractile properties 1 month after deletion. Prolonging deletion of Raptor to 7 months, however, leads to a very marked phenotype characterized by weakness, muscle regeneration, mitochondrial dysfunction, and autophagy impairment. Unexpectedly, reduced mTOR signalling in muscle fibres is accompanied by the appearance of markers of fibre denervation, like the increased expression of the neural cell adhesion molecule (NCAM). Both muscle-specific deletion of mTOR or Raptor, or the use of rapamycin, was sufficient to induce 3-8% of NCAM-positive fibres (P < 0.01), muscle fibrillation, and neuromuscular junction (NMJ) fragmentation in 24% of examined fibres (P < 0.001). Mechanistically, reactivation of autophagy with the small peptide Tat-beclin1 is sufficient to prevent mitochondrial dysfunction and the appearance of NCAM-positive fibres in Raptor k.o. muscles.ConclusionsOur study shows that mTOR signalling in skeletal muscle fibres is critical for maintaining proper fibre innervation, preserving the NMJ structure in both the muscle fibre and the motor neuron. In addition, considering the beneficial effects of exercise in most pathologies affecting the NMJ, our findings suggest that part of these beneficial effects of exercise are through the well-established activation of mTORC1 in skeletal muscle during and after exercise.
| S-EPMC7015238 | biostudies-literature