Formation of colorectal liver metastases induces musculoskeletal and metabolic abnormalities
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE142455 | GEO | 2020/04/18
REPOSITORIES: GEO
Similar Datasets
Project description:Cancer mediated activation of the ActRIIB-ALK4/5 heterodimer by myostatin is strongly associated with muscle wasting. Progressive skeletal muscle wasting, with or without loss of adipose tissue, is observed in up to 50 per cent of all cancer patients. This multifactorial syndrome is known as cachexia, and cannot be fully reversed by conventional nutritional support. Cachexia leads to progressive functional impairment. We investigated in vitro and in vivo the efficacy of ALK4/5 receptor blockers like SB431542 in preventing muscle wasting and in this context determined muscle-related miRNA expression profiles in non-tumor bearing control mice, in SB431542 treated C26 tumor-bearing mice and in cachectic C26 tumor-bearing mice.
2018-09-28 | GSE120593 | GEO
Project description:Cancer cachexia is a devastating metabolic syndrome characterized by systemic inflammation and massive muscle and adipose tissue wasting. Although cancer cachexia is responsible for approximately one third of cancer deaths, no effective therapies are available and the underlying mechanisms have not been fully elucidated.We have found that (+)-JQ1 administration protects tumor-bearing mice from body weight loss, muscle and adipose tissue wasting. Remarkably, in C26-tumor bearing mice (+)-JQ1 administration dramatically prolongs survival, without directly affecting tumor growth. By ChIP-seq analyses, we unveil that the BET proteins directly promote the muscle atrophy program during cachexia. Consistently, BET pharmacological blockade prevents the activation of catabolic genes associated with skeletal muscle atrophy and decreases IL6 systemic levels. Overall, these findings indicate that BET may represent a promising therapeutic target in the management of cancer cachexia.
2017-10-01 | GSE104155 | GEO
Project description:Existing data suggest that NF-kappaB signaling is a key regulator of cancer-induced skeletal muscle wasting. However, identification of the components of this signaling pathway and of the NF-M-NM-:B transcription factors that regulate wasting is far from complete. In muscles of C26 tumor bearing mice, overexpression of d.n. IKKM-NM-2 blocked muscle wasting by 69%, the IM-NM-:BM-NM-1-super repressor blocked wasting by 41%. In contrast, overexpression of d.n. IKKM-NM-1 or d.n. NIK did not block C26-induced wasting. Surprisingly, overexpression of d.n. p65 or d.n. c-Rel did not significantly block muscle wasting. Genome-wide mRNA expression arrays showed upregulation of many genes previously implicated in muscle atrophy. To test if these upregulated genes were direct targets of NF-M-NM-:B transcription factors, we compared genome-wide p65 or p50 binding to DNA in control and cachectic muscle using ChIP-sequencing. Bioinformatic analysis of ChIP-seq data from control and C26 muscles showed increased p65 and p50 binding to a few regulatory and structural genes but only two of these genes were upregulated with atrophy. The p65 and p50 ChIP-seq data are consistent with our finding of no significant change in protein binding to an NF-M-NM-:B oligo in a gel shift assay. Taken together, these data support the idea that although inhibition of IM-NM-:BM-NM-1, and particularly IKKM-NM-2, blocks cancer-induced wasting, the alternative NF-M-NM-:B signaling pathway is not required. In addition, the downstream NF-M-NM-:B transcription factors do not regulate the transcriptional changes. These data are consistent with the growing body of literature showing that there are NF-M-NM-:B-independent substrates of IKKM-NM-2 and IM-NM-:BM-NM-1 that regulate physiological processes. To compare gene expression changes in atrophied muscles from C26 tumor bearing mice, gastrocnemius/plantaris muscles were harvested from 4 C26 tumor-bearing mice, and 3 control non tumor-bearing mice. Total RNA were isolated and pooled (2-3 muslces in the same group per RNA sample ) to make equal amount of total RNA per sample. Three pooled total RNA samples from healthy control muscles and 3 pooled total RNA from muscles of C26 tumor bearing mice were labelled and hybridized on 6 Mouse Affyemtrix Gene 1.0 ST arrays. Two-side t-tests and multiple test corrections were performed to identify differentially expressed genes due to C26 tumor bearing induced cachexia.
2013-11-15 | E-GEOD-48363 | biostudies-arrayexpress
Project description:Background Loss of skeletal muscle mass in advanced cancer is recognized as an independent predictor of mortality. Mechanisms involved in this wasting process and parameters for early diagnosis are still lacking. As skeletal muscle is considered as a secretory organ, the aim of this present experimental work was to characterize the changes in muscle proteome and secretome associated with cancer-induced cachexia to better understand cellular mechanisms involved in this wasting process and to identify secreted proteins which might reflect the ongoing muscle atrophy process. Methods We investigated first the changes in the muscle proteome associated with cancer-induced cachexia by using differential label-free proteomic analysis on muscle of the C26 mouse model. The differentially abundant proteins were submitted to sequential bioinformatic secretomic analysis in order to identify potentially secreted proteins. Selected reaction monitoring and Western blotting were used to verify the presence of candidate proteins at the circulating level. Their muscle source was demonstrated by assessing their gene expression in skeletal muscle and in cultured myotubes. Finally, we also investigated their regulation in muscle cells. Alterations in several molecular pathways potentially involved in muscle atrophy were highlighted using Gene ontology enrichment analyses. Results Our results revealed a dramatic increased production (2-to 25-fold) by the muscle of several acute phase reactants (APR: Haptoglobin, Serpina3n, Complement C3, Serum amyloid A1) which are also released in the circulation during C26 cancer cachexia. Their production was confirmed in other preclinical models of cancer cachexia as well as in cancer patients. The muscular origin of these APR was demonstrated by their increased expression in skeletal muscle and myotubes. Glucocorticoids and pro-inflammatory cytokines contribute directly to their increased expression in muscle cells in vitro, while the role of IL-6 in the muscular induction of these APR was demonstrated in vivo. Conclusions Cancer is associated with marked changes in muscle secretome during muscle wasting. Our study demonstrates a marked increased production of APR by skeletal muscle in pre-clinical models of cancer cachexia and in cancer patients. Further studies are required to unravel the potential role of these proteins in muscle atrophy and their interest as biomarkers of cancer cachexia.
2020-10-28 | PXD016474 | Pride
Project description:Cachexia is a systemic metabolic syndrome characterized by loss of fat and skeletal muscle mass in chronic wasting diseases such as cancer. The regulation of cellular protein synthesis in response to workload in skeletal muscle is generally blunted in cancer cachexia; however, the precise molecular regulation is largely unknown. In this study, to examine the molecular mechanism of skeletal muscle protein metabolism in cancer cachexia, we analyzed comprehensive gene expression in skeletal muscle using microarrays. CD2F1 mice (male, 7 weeks old) were subcutaneously transplanted (1*10^6 cells per mouse) with a mouse colon cancer-derived cell line (C26) as a model of cancer cachexia. Functional overload of the plantaris muscle by synergist ablation was performed at the 2nd week, and the plantaris muscle was sampled at the 4th week of cancer transplantation. The hypertrophy of skeletal muscle (increased skeletal muscle weight/protein synthesis efficiency and activation of mTOR signaling) associated with compensatory overload was significantly suppressed with the cancer cachexia. Gene expression profiling and pathway analysis by microarray showed that resistance to muscle protein synthesis associated with cancer cachexia was induced by downregulation of insulin-like growth factor-1. These observations show that cancer cachexia induces resistance to muscle protein synthesis, which could be a potential factor inhibiting the adaptation of skeletal muscle growth to physical exercise.
2021-10-15 | GSE185934 | GEO
Project description:Genome-wide analysis of skeletal muscle gene expression in mice with C26 tumor-induced muscle wasting and cachexia
| PRJNA130045 | ENA
Project description:Background
Loss of skeletal muscle mass in cancer cachexia is recognized as an independent predictor of mortality. Mechanisms involved in this wasting process and parameters for early diagnosis are not yet clearly defined. As skeletal muscle is considered as a secretory organ, the aim of this present experimental work was to characterize the changes in the putative muscle secretome associated with cancer-induced cachexia to gain a better understanding of cellular mechanisms involved and to identify secreted proteins which might reflect this wasting process.
Methods
We investigated first the changes in the muscle proteome associated with cancer-induced cachexia by using differential label-free proteomic analysis on muscle of the C26 mouse model. The differentially abundant proteins were then submitted to sequential bioinformatic secretomic analysis in order to identify potentially secreted proteins. Multiple reaction monitoring and Western blotting were used to verify the presence of candidate proteins at the circulating level. Finally, we investigated the regulation of the production of these secreted proteins by muscle in vitro and in vivo.
Results
Our results revealed a dramatic increased muscular production (2-to 25-fold) of several acute phase reactants (APR: haptoglobin, serpina3n, complement C3, serum amyloid A1) which are released in the circulation during C26 cancer cachexia. This observation was confirmed in two other preclinical models of cancer cachexia as well as in cancer patients. The muscular origin of these APR was demonstrated by their increased expression in skeletal muscle and myotubes. Our results showed also that IL-6 plays a major role in the muscular induction of these APR in vivo, while glucocorticoids and pro-inflammatory cytokines stimulate directly their increased expression in muscle cells in vitro.
Conclusions
Muscle wasting caused by cancer is associated with marked changes in muscle secretome. Our study demonstrates a marked increased production of APR by skeletal muscle in pre-clinical models of cancer cachexia and in cancer patients. Further studies are required to unravel the potential role of these proteins in muscle atrophy and their interest as biomarkers of cancer cachexia.
2021-01-24 | PXD019433 | panorama
Project description:Cachexia is a systemic wasting syndrome that develops in many cancers and increases mortality. Despite its importance, it is largely unknown how cachexia progressively and differentially induces tissue wasting. Although cachexia occurs also in pediatric patients, little is known on the underlying mechanisms. Here, we have used pediatric melanoma xenografts to determine the progression and tissue-specific impact of juvenile cachexia on skeletal muscles, heart, white and brown adipose, liver, and brain. We find that the heart and muscles undergo wasting at early stages and are the tissues most strongly impacted transcriptionally. Beyond wasting, we identify general and organ-specific transcriptional changes that likely indicate derangement of organ/tissue function by cachexia. Moreover, also the transcriptome of tissues that do not undergo wasting, such as the brain, is profoundly remodeled by cachexia. Altogether, this study provides insight into the progression of melanoma-induced pediatric cachexia and its differential impact on distinct organ systems.
2022-12-15 | GSE184018 | GEO
Project description:Cachexia is a systemic wasting syndrome that develops in many cancers and increases mortality. Despite its importance, it is largely unknown how cachexia progressively and differentially induces tissue wasting. Although cachexia occurs also in pediatric patients, little is known on the underlying mechanisms. Here, we have used pediatric melanoma xenografts to determine the progression and tissue-specific impact of juvenile cachexia on skeletal muscles, heart, white and brown adipose, liver, and brain. We find that the heart and muscles undergo wasting at early stages and are the tissues most strongly impacted transcriptionally. Beyond wasting, we identify general and organ-specific transcriptional changes that likely indicate derangement of organ/tissue function by cachexia. Moreover, also the transcriptome of tissues that do not undergo wasting, such as the brain, is profoundly remodeled by cachexia. Altogether, this study provides insight into the progression of melanoma-induced pediatric cachexia and its differential impact on distinct organ systems.
2022-12-15 | GSE183611 | GEO
Project description:Cachexia is a systemic wasting syndrome that develops in many cancers and increases mortality. Despite its importance, it is largely unknown how cachexia progressively and differentially induces tissue wasting. Although cachexia occurs also in pediatric patients, little is known on the underlying mechanisms. Here, we have used pediatric melanoma xenografts to determine the progression and tissue-specific impact of juvenile cachexia on skeletal muscles, heart, white and brown adipose, liver, and brain. We find that the heart and muscles undergo wasting at early stages and are the tissues most strongly impacted transcriptionally. Beyond wasting, we identify general and organ-specific transcriptional changes that likely indicate derangement of organ/tissue function by cachexia. Moreover, also the transcriptome of tissues that do not undergo wasting, such as the brain, is profoundly remodeled by cachexia. Altogether, this study provides insight into the progression of melanoma-induced pediatric cachexia and its differential impact on distinct organ systems.
2022-12-15 | GSE214981 | GEO