Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Arachidonic acid triggers spermidine synthase secretion from primary tumor to induce skeletal muscle weakness upon irradiation

ABSTRACT: Radiotherapy (RT) reduces the risk of cancer recurrence and death, while accompanied by multiple side effects including muscle weakness, seriously affects the life quality of patients. However, the underlying mechanism is not well defined. Here, we identify cancer cells secrete more spermidine synthase (SRM) protein through small extracellular vesicles (sEVs) to trigger skeletal muscle weakness upon RT. Mechanistically, RT-triggered arachidonic acid (ArA) accumulation elevates the ISGylation of SRM protein, facilitating SRM package into EVs from primary tumor. Circulating SRM proteins enhance spermidine accumulation in skeletal muscle and type I collagen fibers biosynthesis in an eIF5A-dependent manner. Deposition of randomly aligned collogen fibers induced by SRM+ EVs results in skeletal muscle fibrosis and weakness, as well as bone matrix loss. However, losartan treatment blocks the ISGylation of SRM and its subsequent secretion. Collectively, our findings determine that ArA functions in concert for circulating SRM secretion upon RT, which aggravates skeletal muscle fibrosis through rewiring polyamine metabolism, shedding light on the alleviation of RT-mediated muscle weakness when combined with losartan treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285652 | GEO | 2025/04/03

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Cancer cell-secreted spermidine synthase induces skeletal muscle fibrosis upon radiotherapy (Gastrocnemius muscle KD)

Project description:Radiotherapy (RT) reduces the risk of cancer recurrence and death, while accompanied by multiple side effects including muscle fibrosis and weakness, seriously affects the life quality of patients. However, the underlying mechanism is poorly defined. Here, we identify cancer cells secrete more spermidine synthase (SRM) enzyme through small extracellular vesicles (sEVs) to trigger skeletal muscle weakness upon RT. Mechanistically, RT-triggered arachidonic acid (ArA) accumulation elevates the ISGylation of SRM protein, facilitating SRM packaging into EVs from primary tumor. Circulating SRM results in spermidine accumulation in skeletal muscle and type I collagen fiber biosynthesis in an eIF5A-dependent manner. However, losartan treatment blocks the ISGylation of SRM and its subsequent secretion. Collectively, our findings determine that ArA functions in concert for circulating SRM secretion upon RT, which aggravates skeletal muscle fibrosis through rewiring polyamine metabolism, shedding light on the alleviation of RT-mediated muscle weakness when combined with losartan treatment.

2025-04-03 | GSE263508 | GEO

Cancer cell-secreted spermidine synthase induces skeletal muscle fibrosis upon radiotherapy (Gastrocnemius muscle)

2025-04-03 | GSE263507 | GEO

Cancer cell-secreted spermidine synthase induces skeletal muscle fibrosis upon radiotherapy (Xenograft tumor)

2025-04-03 | GSE263506 | GEO

Cancer cell-secreted spermidine synthase induces skeletal muscle fibrosis upon radiotherapy (MDA-MB-231)

2025-04-03 | GSE263505 | GEO

DUX4 promotes mitochondrial impairment in skeletal muscle

Project description:Facioscapulohumeral muscular dystrophy (FSHD) is characterised by a progressive degeneration and weakness of skeletal muscle fibers attributed to inappropriate expression of the transcription factor double homeobox 4 (DUX4). However, the cellular events that precede pathology in DUX4 expressing muscle fibers remain incompletely understood. Using recombinant AAV vectors to activate species-specific DUX transcription factors in murine and human skeletal muscle fibers, we developed models for examining DUX4-induced pathology. RNA-sequencing prior to the onset of muscle pathology reveals that perturbation of metabolic and mitochondrial function is an early event following activation of DUX transcription factors across species. A reduction in mitochondrial membrane potential was confirmed following DUX4 activation in human muscle fibers prior to reductions in force generating capacity. These studies present new models that can be used to delineate the changes in biological processes following acute DUX4 activation in mouse and human skeletal muscle fibers, for greater insight into the pathogenesis of FSHD, and support further investigation of mitochondrial function as a therapeutic target in FSHD.

2021-12-31 | GSE138768 | GEO

Spatial proteomics of skeletal muscle using thin cryosections reveals metabolic adaption at the muscle-tendon transition zone

Project description:Morphological studies of skeletal muscle tissue have provided detailed insights into the architecture of muscle fibers, the surrounding cells, and the extracellular matrix. However, a spatial proteomics analysis of the skeletal muscle, including the muscle-tendon transition zone, is lacking. Here, we prepared thin cryotome muscle sections along the longitudinal axis of the mouse soleus muscle and measured each muscle slice using short LC-MS gradients. We generated more than 3000 high-resolution longitudinal protein profiles of central to distal skeletal muscle regions and created a molecular network of different skeletal muscle regions that reveals the complex architecture of the muscle-tendon transition zone. Among the proteins that show an increasing profile from muscle to tendon, we find proteins related to neuronal activity, fatty acid biosynthesis, and the renin-angiotensin system (RAS). Blocking the RAS in cultured mouse tenocytes using losartan reduces the synthesis of extracellular matrix proteins, including collagen and fibronectin. Overall, our analysis of thin cryotome sections provides a spatial proteome of skeletal muscle and reveals that the RAS acts as an additional regulator of the matrix within muscle-tendon junctions.

2024-05-22 | PXD046596 | Pride

The FSHD effector protein Dux promotes myopathy via Myostatin-Smad signaling

Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant condition that is characterised by a progressive degeneration and weakness of skeletal muscle fibers. The underlying cause of FSHD has been attributed to inappropriate expression of the transcription factor double homeobox (Dux); however, the mechanisms leading to myopathy in response to Dux expression remain incompletely understood. To study the acute effects of Dux activation in mammalian skeletal muscle fibers, we generated a recombinant adeno-associated viral vector allowing tunable Dux expression. Consistent with previous findings, we confirmed that the ectopic expression of Dux in mouse skeletal muscle results in a degenerative myopathy. Building on these findings, we observed that the acute expression of Dux in muscle fibers causes profound transcriptome changes prior to the onset of pathology. Furthermore, muscles expressing Dux display elevated levels of the TGF-beta superfamily member, Myostatin and increased Smad2/3 activity. Notably, inhibition of Myostatin is sufficient to prevent Dux-induced myopathy. Collectively, these findings support further investigation of interventions targeting the Myostatin-Smad2/3 pathway as prospective approaches to treating myopathy associated with Dux mis-expression.

2021-12-31 | GSE108828 | GEO

Skeletal muscle-specific methyltransferase METTL21C trimethylates p97 and regulates autophagy-associated protein breakdown

Project description:Protein aggregates and cytoplasmic vacuolization are major hallmarks of multisystem proteinopathies (MSP) that lead to muscle weakness. Here, we identify METTL21C as a novel skeletal muscle-specific lysine methyltransferase. Insertion of a -galactosidase cassette into the Mettl21c mouse locus revealed METTL21C is specifically expressed in MYH7 positive skeletal muscle fibers. Ablation of the Mettl21c gene reduced endurance capacity and led to accumulation of cellular residuals due to incomplete autophagy in the skeletal muscle of Mettl21c-/- mutants during aging. Moreover, denervation-induced muscle atrophy highlighted further impairments of autophagy-related proteins, including LC3, p62, and cathepsins in Mettl21c-/- muscles. In addition, we demonstrate METTL21C interacts with the ATPase p97 (VCP), which is mutated in various human MSP conditions. We also reveal METTL21C trimethylates p97 on Lys315 residue, and found loss of this modification reduced p97 hexamer formation and ATPase activity in vivo. We conclude the methyltransferase METTL21C is an important modulator of protein degradation in skeletal muscle under both normal and enhanced protein breakdown conditions due to its ability to trimethylate and regulate p97.

2018-05-04 | PXD008145 | Pride

Aberrant calcium influx causes fiber type shift and mitochondrial loss in skeletal muscle

Project description:Skeletal muscle excitation-contraction (EC) coupling is independent of calcium influx. In fact alternative splicing of the voltage-gated calcium channel CaV1.1 actively suppresses calcium currents in mature muscle. Why this might be necessary is not known. However, splicing defects causing aberrant expression of the calcium-conducting embryonic CaV1.1e splice variant correlate with muscle weakness in myotonic dystrophy. Here we deleted CaV1.1 exon 29 in mice. The continued expression of CaV1.1e resulted in increased calcium influx during EC coupling and spontaneous calcium sparks. While overall motor performance was normal, muscle force was reduced, endurance enhanced, and the fiber type composition shifted toward slower fibers. In contrast, oxidative enzyme activity and the mitochondrial content declined. Together with the dysregulation of key regulators of the slow program these findings indicate that limiting calcium influx during skeletal muscle EC coupling is important for the calcium signalâs secondary function in the activity-dependent regulation of fiber type composition. Differential gene expression between soleus and EDL muscle fibres from wildtype and Cav1.1 delta E29 mice.

2016-04-01 | E-GEOD-67803 | biostudies-arrayexpress

Gadd45a Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4

Project description:Skeletal muscle atrophy is a serious and highly prevalent condition that remains poorly understood at the molecular level. Previous work found that skeletal muscle atrophy involves an increase in skeletal muscle Gadd45a expression, which is necessary and sufficient for skeletal muscle fiber atrophy. However, the direct mechanism by which Gadd45a promotes skeletal muscle atrophy was unknown. To address this question, we biochemically isolated skeletal muscle fiber proteins that associate with Gadd45a as it induces skeletal muscle atrophy in living mice. We found that Gadd45a interacts with multiple proteins in skeletal muscle fibers, including, most prominently, the MAP kinase kinase kinase MEKK4. Furthermore, by forming a complex with MEKK4 in skeletal muscle fibers, Gadd45a increases MEKK4 protein kinase activity, which is sufficient to induce skeletal muscle fiber atrophy and required for Gadd45a-mediated skeletal muscle fiber atrophy. Together, these results identify a direct biochemical mechanism by which Gadd45a induces skeletal muscle atrophy and provide new insight into way that skeletal muscle atrophy occurs at the molecular level.

2016-05-17 | MSV000079730 | MassIVE

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data