Skeletal Muscle Fibrosis in Pancreatic Cancer Patients with Respect to Survival
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PROVIDER: PRJNA540621 | ENA |
REPOSITORIES: ENA
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Project description:Skeletal muscle wasting is a devastating consequence of cancer that may be responsible for nearly 30% of cancer-related deaths. In addition to muscle atrophy, we have identified significant muscle fiber damage and replacement of muscle with fibrotic tissue in rectus abdominis muscle biopsies from cachectic pancreatic ductal adenocarcinoma (PDAC) patients that associates with poor survival. Transcriptional profiling of muscle harvested from these same patients supported these findings by identifying gene clusters related to wounding, inflammation and cellular response to TGF-B upregulated in cachectic PDAC patients compared with non-cancer controls. In this dataset, we include the expression data obtained from rectus abdominis muscle biopsies fron non-cancer controls patients undergoing abdominal surgery for benign reasons and from PDAC patients undergoing tumor-resection surgery. PDAC patients were further classified as non-cachectic or cachectic. Cachexia was defined as a body weight loss of >5% during the 6 months prior to surgery. The purpose of this study was to identify the broader transcriptional networks changed in cachectic PDAC patients versus non-cancer controls, that may be associated with the histological changes observed in muscle biopsies harvested from these same patients.
2019-12-03 | GSE130563 | GEO
Project description:BackgroundCancer cachexia is a catabolic condition characterized by skeletal muscle wasting, consequent to tumor burden, which negatively impacts tolerance to cancer therapies and contributes to increased mortality. Partly because of the limited knowledge of the underlying mechanisms of cancer cachexia derived from human studies, however, the ability to therapeutically intervene remains elusive. The purpose of the current study was therefore to better define the phenotype of skeletal muscle obtained from patients with pancreatic ductal adenocarcinoma (PDAC), which has one of the highest rates of cachexia.MethodsMorphological analyses were performed on rectus abdominis muscle biopsies obtained from resectable PDAC patients undergoing tumor resection surgery (N = 20) and from weight-stable non-cancer control subjects undergoing benign abdominal surgery (N = 16). PDAC patients with a body weight loss of greater than 5% during the previous 6 months were considered cachectic (N = 15). Statistical tests were two sided.ResultsSkeletal muscle from cachectic PDAC patients had increased collagen content compared with non-cancer control subjects (1.43% vs 9.66%, P = .0004, Dunn test). Across all PDAC patients, collagen content positively correlated with body weight loss (P = .0016, r = 0.672), was increased in patients with lymph node metastasis (P = .007, Mann-Whitney U test), and was associated with survival on univariate (HR = 1.08, 95% confidence interval [CI] = 1.02 to 1.04, P = .008) and multivariable analyses (HR = 1.08, 95% CI = 1.00 to 1.17, P = .038). Cachectic PDAC patients also displayed increased lipid deposition (2.63% vs 5.72%, P = .042), infiltration of CD68+ macrophages (63.6 cells/mm2 vs 233.8 cells/mm2, P = .0238), calcium deposition (0.21% vs 2.51%, P = .030), and evidence of deficient cellular quality control mechanisms (Mann-Whitney U test). Transcriptional profiling of all patients supported these findings by identifying gene clusters related to wounding, inflammation, and cellular response to TGF-β upregulated in cachectic PDAC patients compared with non-cancer control subjects.ConclusionsTo our knowledge, this work is the first to demonstrate increased collagen content in cachectic PDAC patients that is associated with poor survival.
| S-EPMC6322478 | biostudies-literature
Project description:Skeletal muscle fibrosis, characterized by the replacement of functional muscle tissue with fibrotic scarring, leads to muscle function loss and potentially fatal respiratory failure, particularly in muscular dystrophy. The mechanisms driving muscle fibrosis is not yet fully understood. Our study utilized single-cell RNA-seq and single-nuclei ATAC-seq to analyze the transcriptome and chromatin accessibility of regenerating and dystrophic skeletal muscle, identifying a specific subset of fibro-adipogenic precursors (FAPs) enriched in dystrophic muscles, termed fibrotic FAPs. We further demonstrated that chronic inflammation upregulates Fosl1, an early response gene, which activates the expression of Kdm6b in fibrotic FAPs. Kdm6b, a histone demethylase, specifically removes the repressive histone H3K27me3 mark. Notably, targeting Kdm6b genetically and pharmacologically inhibits fibrotic di^erentiation in human and mouse FAPs in vitro and ameliorated muscle fibrosis in mouse models in vivo. Furthermore, constitutive activation of the Fosl1-Kdm6b pathway reduced H3K27me3 modification at critical fibrotic gene loci, leading to their transcriptional activation. Taken together, our findings reveal that chronic inflammation perpetuates the Fosl1-Kdm6b axis in FAPs, causing epigenomic reprogramming and altering the H3K27me3 landscape, which is essential for preventing fibrotic differentiation of FAPs and skeletal muscle fibrosis.
2025-02-28 | GSE275143 | GEO
Project description:Skeletal muscle fibrosis, characterized by the replacement of functional muscle tissue with fibrotic scarring, leads to muscle function loss and potentially fatal respiratory failure, particularly in muscular dystrophy. The mechanisms driving muscle fibrosis is not yet fully understood. Our study utilized single-cell RNA-seq and single-nuclei ATAC-seq to analyze the transcriptome and chromatin accessibility of regenerating and dystrophic skeletal muscle, identifying a specific subset of fibro-adipogenic precursors (FAPs) enriched in dystrophic muscles, termed fibrotic FAPs. We further demonstrated that chronic inflammation upregulates Fosl1, an early response gene, which activates the expression of Kdm6b in fibrotic FAPs. Kdm6b, a histone demethylase, specifically removes the repressive histone H3K27me3 mark. Notably, targeting Kdm6b genetically and pharmacologically inhibits fibrotic di^erentiation in human and mouse FAPs in vitro and ameliorated muscle fibrosis in mouse models in vivo. Furthermore, constitutive activation of the Fosl1-Kdm6b pathway reduced H3K27me3 modification at critical fibrotic gene loci, leading to their transcriptional activation. Taken together, our findings reveal that chronic inflammation perpetuates the Fosl1-Kdm6b axis in FAPs, causing epigenomic reprogramming and altering the H3K27me3 landscape, which is essential for preventing fibrotic di^erentiation of FAPs and skeletal muscle fibrosis.
2025-02-28 | GSE275142 | GEO
Project description:Skeletal muscle fibrosis, characterized by the replacement of functional muscle tissue with fibrotic scarring, leads to muscle function loss and potentially fatal respiratory failure, particularly in muscular dystrophy. The mechanisms driving muscle fibrosis is not yet fully understood. Our study utilized single-cell RNA-seq and single-nuclei ATAC-seq to analyze the transcriptome and chromatin accessibility of regenerating and dystrophic skeletal muscle, identifying a specific subset of fibro-adipogenic precursors (FAPs) enriched in dystrophic muscles, termed fibrotic FAPs. We further demonstrated that chronic inflammation upregulates Fosl1, an early response gene, which activates the expression of Kdm6b in fibrotic FAPs. Kdm6b, a histone demethylase, specifically removes the repressive histone H3K27me3 mark. Notably, targeting Kdm6b genetically and pharmacologically inhibits fibrotic di^erentiation in human and mouse FAPs in vitro and ameliorated muscle fibrosis in mouse models in vivo. Furthermore, constitutive activation of the Fosl1-Kdm6b pathway reduced H3K27me3 modification at critical fibrotic gene loci, leading to their transcriptional activation. Taken together, our findings reveal that chronic inflammation perpetuates the Fosl1-Kdm6b axis in FAPs, causing epigenomic reprogramming and altering the H3K27me3 landscape, which is essential for preventing fibrotic differentiation of FAPs and skeletal muscle fibrosis.
2025-02-28 | GSE275141 | GEO
Project description:D-galactose (D-gal) is a widely used chemical to induce cellular senescence. Cells undergoing senescence induced by D-gal exhibit mitochondrial structural damage and a decline in energy metabolism, which are highly related to cellular aging Studies have confirmed that D-gal can induce senescence, fibrosis, and redox imbalance in skeletal muscle fibroblasts. Our results confirm that D-galactose effectively induces cellular senescence and skeletal muscle fibrosis in both cellular and animal models. The increase in senescence markers and fibrosis-related proteins, along with the observed decline in muscle strength and mass, are consistent with previous studies that highlight the role of D-galactose in modeling aging-associated pathologies. The observed lethargy and reduction in muscle fiber cross-sectional area further validate the model's relevance to sarcopenia research.
2025-01-09 | GSE285869 | GEO
Project description:Skeletal muscle fibrosis, characterized by the replacement of functional muscle tissue with fibrotic scarring, leads to muscle function loss and potentially fatal respiratory failure, particularly in muscular dystrophy. The mechanisms driving muscle fibrosis is not yet fully understood. Our study utilized single-cell RNA-seq and single-nuclei ATAC-seq to analyze the transcriptome and chromatin accessibility of regenerating and dystrophic skeletal muscle, identifying a specific subset of fibro-adipogenic precursors (FAPs) enriched in dystrophic muscles, termed fibrotic FAPs. We further demonstrated that chronic inflammation upregulates Fosl1, an early response gene, which activates the expression of Kdm6b in fibrotic FAPs. Kdm6b, a histone demethylase, specifically removes the repressive histone H3K27me3 mark. Notably, targeting Kdm6b genetically and pharmacologically inhibits fibrotic di^erentiation in human and mouse FAPs in vitro and ameliorated muscle fibrosis in mouse models in vivo. Furthermore, constitutive activation of the Fosl1-Kdm6b pathway reduced H3K27me3 modification at critical fibrotic gene loci, leading to their transcriptional activation. Taken together, our findings reveal that chronic inflammation perpetuates the Fosl1-Kdm6b axis in FAPs, causing epigenomic reprogramming and altering the H3K27me3 landscape, which is essential for preventing fibrotic di^erentiation of FAPs and skeletal muscle fibrosis.
2025-02-28 | GSE275140 | GEO
Project description:Reversible ε-amino acetylation of lysine residues regulates transcription as well as metabolic flux; however, roles for specific lysine acetyltransferases in skeletal muscle physiology and function is unknown. In this study, we investigated the role of the related acetyltransferases p300 and CBP in skeletal muscle transcriptional homeostasis and physiology in adult mice. These data reveal that p300 and CBP are required for the control and maintenance of contractile function and transcriptional homeostasis in skeletal muscle, and ultimately, organism survival.
2019-12-12 | GSE141857 | GEO
Project description:Reversible epsilon-amino acetylation of lysine residues regulates transcription as well as metabolic flux; however, roles for specific lysine acetyltransferases in skeletal muscle physiology and function remain enigmatic. In this study, we investigated the role of the homologous acetyltransferases p300 and CBP in skeletal muscle transcriptional homeostasis and physiology in adult mice. Mice with skeletal muscle-specific and inducible knockout of p300 and/or CBP were generated by crossing mice with a tamoxifen-inducible Cre recombinase expressed under the human alpha-skeletal actin (HSA) promoter with mice harboring LoxP sites flanking exon 9 of both the Ep300 and Crebbp genes. Knockout was induced at 13-15 weeks of age via oral gavage of tamoxifen. We demonstrate that loss of both p300 and CBP in adult mouse skeletal muscle severely impairs contractile function and results in lethality within one week – a phenotype that is reversed by the presence of a single allele of either p300 or CBP. The loss of muscle function in p300/CBP double knockout mice is paralleled by substantial transcriptional alterations in gene networks central to skeletal muscle contraction and structural integrity. Changes in protein expression patterns, determined by 10-plex TMT labeling, were linked to impaired muscle function also manifest within days (WT mice were compared to day 3 and day 5 knock out mice). Together, these data reveal the requirement of p300 and CBP for the control and maintenance of contractile function and transcriptional homeostasis in skeletal muscle, and ultimately, organism survival. By extension, modulating p300/CBP function holds promise for the treatment of disorders characterized by impaired contractile function in humans.
2020-04-03 | PXD015694 | Pride
Project description:Tissue extracellular matrix provides structural support and creates unique niches for resident cells . However, the identities of cells responsible for creating specific ECM niches have not been determined. In striated muscle, the identity of these cells becomes important in disease when ECM changes result in fibrosis and subsequent increased tissue stiffness and dysfunction. Here we describe a novel approach to isolate and identify cells that maintain ECM niches in both healthy and fibrotic muscle. Using a collagen I reporter mouse, we show that there are three distinct cell populations that express collagen I in both healthy and fibrotic skeletal muscle. Interestingly, the number of collagen I expressing cells in all three cell populations increase proportionally in fibrotic muscle indicating that all cell types participate in the fibrosis process. Furthermore, it is shown that the ECM gene expression profile is not qualitatively altered in fibrotic muscle. This suggests that muscle fibrosis in this model results from an increased number of collagen I expressing cells and not the initiation of a specific fibrotic gene expression program. Finally, in fibrotic muscle, we show that these collagen I expressing cell populations differentially express distinct ECM proteins – fibroblasts express the fibrillar components of ECM, fibro/adipogenic progenitors cells differentially express basal laminar proteins and skeletal muscle progenitor cells differentially express genes important for the satellite cell niche.
2016-12-04 | GSE89633 | GEO