Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia
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ABSTRACT:
PROVIDER: PRJNA318027 | ENA |
REPOSITORIES: ENA
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Project description:This SuperSeries is composed of the SubSeries listed below.
2016-05-01 | GSE80142 | GEO
Project description:Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-induced gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. shRNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of cancer cachexia-induced muscle atrophy and highlight potential therapeutic targets for this disorder.
2024-07-12 | GSE272085 | GEO
Project description:Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-induced gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. shRNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of cancer cachexia-induced muscle atrophy and highlight potential therapeutic targets for this disorder.
2024-07-12 | GSE272084 | GEO
Project description:Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-induced gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. shRNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of cancer cachexia-induced muscle atrophy and highlight potential therapeutic targets for this disorder.
2024-07-12 | GSE272083 | GEO
Project description:The essential amino acid methionine plays a pivotal role in one-carbon metabolism, facilitating the production of S-adenosylmethionine (SAMe), a critical supplier for DNA methylation. Here we find the disruption of methionine metabolism by rapid SAMe depletion in skeletal muscle in cancer cachexia, leading to endoplasmic reticulum (ER) stress and the overexpression of regulated in development and DNA damage responses (REDD1). Targeting the DNA methylation process via DNA methyltransferases (DNMTs) and REDD1 knockout can alleviate cancer cachexia-induced skeletal muscle atrophy. Methionine supplementation maintains the DNA methylation of DNA damage-inducible transcript 4 (Ddit4) by DNMT3A, thereby inhibiting activating transcription factor 4 (ATF4)-mediated Ddit4 transcription. Our study suggests that methionine or SAMe supplementation can effectively reverse muscle atrophy in cancer cachexia, providing valuable mechanistic insights and a promising therapeutic strategy for clinical application.
2024-10-11 | GSE275001 | GEO
Project description:Cachexia is an exacerbating event in many types of cancer that is strongly associated with a poor prognosis. We have identified cytokine, signaling and transcription factors that are required for cachexia in the mouse C26 colon carcinoma model of cancer. C2C12 myotubes treated with conditioned medium from C26 cancer cells induced atrophy and activated a STAT-dependent reporter gene but not reporter genes dependent on SMAD, FOXO, C/EBP, NF-ĸB, or AP-1. Of the gp130 family members IL-11, IL-6, oncostatin M (OSM), and leukemia inhibitory factor (LIF), only OSM and LIF were sufficient to activate the STAT reporter in myotubes. A LIF blocking antibody abolished C26 CM-induced STAT reporter activation STAT3 phosphorylation and myotube atrophy, but blocking antibodies to IL-6 or OSM did not. JAK2 inhibitors also blocked the C26 CM-induced STAT reporter activation, STAT3 phosphorylation, and atrophy in myotubes. LIF at levels found in the C26 CM was sufficient for STAT reporter activation and atrophy in myotubes. In vivo, an increase in serum LIF preceded the increase in IL-6 in mice with C26 tumors. Overexpression of a dominant negative Stat3Cβ-EGFP gene in myotubes and in mouse muscle blocked the atrophy caused by C26 CM or C26 tumors, respectively. Taken together these data support an important role of LIF- JAK2-STAT3 in C26 cachexia and point to a therapeutic approach for at least some types of cancer cachexia. from three replicate wells of cells at each treatment, pools of total RNA were used to create cDNA which were evaluated on Affymetrix mouse gene 1.0 ST v.1 arrays.
2015-06-25 | E-GEOD-68827 | biostudies-arrayexpress
Project description:Cachexia is a devastating muscle wasting syndrome that occurs in patients suffering from chronic diseases, most commonly observed in 80% of advanced cancer patients. One of the primary causes of cachexia-associated morbidity and mortality is involuntary muscle wasting. And while many cachexia patients show hypermetabolism, its causative role in muscles had remained unclear. To understand the molecular basis of this muscle wasting, accurate models of cachexia are necessary. Using transcriptomics and cytokine profiling of human muscle stem cell-based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors which rapidly led to higher levels of fatty acid metabolism and the activation of a p38 stress response signature, before the cachectic muscle wasting is manifested. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, leading to oxidative stress, p38 activation, and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also significantly improved muscle mass and total weight in cancer cachexia models in vivo. Therefore, fatty acid-induced oxidative stress could be targeted to prevent cancer cachexia.
2016-05-01 | GSE80080 | GEO
Project description:Cachexia is a devastating muscle wasting syndrome that occurs in patients suffering from chronic diseases, most commonly observed in 80% of advanced cancer patients. One of the primary causes of cachexia-associated morbidity and mortality is involuntary muscle wasting. And while many cachexia patients show hypermetabolism, its causative role in muscles had remained unclear. To understand the molecular basis of this muscle wasting, accurate models of cachexia are necessary. Using transcriptomics and cytokine profiling of human muscle stem cell-based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors which rapidly led to higher levels of fatty acid metabolism and the activation of a p38 stress response signature, before the cachectic muscle wasting is manifested. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, leading to oxidative stress, p38 activation, and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also significantly improved muscle mass and total weight in cancer cachexia models in vivo. Therefore, fatty acid-induced oxidative stress could be targeted to prevent cancer cachexia.
2016-05-01 | GSE80081 | GEO
Project description:Here, we investigate the systematic impact of tumor cachexia on muscle function. From a nutritional supplementation perspective, we examine the influence of fatty acid metabolism on the cachectic state, revealing that dietary supplementation with high-fat diet does not alleviate the muscle and fat dysfunction induced by tumors but instead accelerates muscle degradation. Utilizing RNA-seq transcriptome data from muscle tissue, we identify metabolic abnormalities in muscle during cachexia, with the PDK4 gene being activated initially and showing significant enrichment of PPARδ targets. We find that inhibiting PDK4 can mitigate the cachectic state and observe a relationship between the activation of muscle PDK4 and PPARδ during cachexia. This is supported by epigenomic data revealing that PDK4 is a transcriptional target gene of PPARδ in muscle. Activation and mechanical modulation of PPARδ in vivo significantly impact muscle atrophy caused by cachexia. Our research suggests that targeting PPARδ could serve as a therapeutic drug target for tumor cachexia.
2025-07-03 | GSE246122 | GEO
Project description:Background Placental metabolic abnormalities are linked to pregnancy complications such as preeclampsia, gestational diabetes mellitus, and fetal growth restriction. However, little is known about how the metabolic processes regulate placental development and trophoblast differentiation. The adipokine chemerin has elevated serum levels in pregnant women and regulates placental lipid metabolism, potentially playing a role in both placental development and trophoblast differentiation. Results In this study, we observed the increased chemerin expression on the serum and placenta from the pregnant mice. Chemerin is highly expressed in the extraembryonic primary parietal trophoblast giant cells and the ectoplacental cone (EPC) trophoblast cells. Excessive chemerin treatment in mice results in the increased placental lipid accumulation, promotes the expansion of glycogen trophoblast cell (GlyT) and syncytiotrophoblast, and restricts the growth of spongiotrophoblast (SpT) and sinusoidal trophoblast giant cell (S-TGC). Chemerin deficiency led to increased expression of placental fatty acid oxidation enzymes and disrupted the proliferation of SpT and S-TGC in the labyrinth. Furthermore, we utilized the fatty acid oxidation inhibitor etomoxir, demonstrated that blocking fatty acid oxidation hinders the proliferation of SpT and S-TGC in the labyrinth. Conclusions Our study demonstrated that chemerin-related lipid metabolism is crucial for EPC trophoblast differentiation during placental development, providing evidence that chemerin determines the growth of SpT and S-TGC through fatty acid oxidation. These findings also imply a possible pathological mechanism for pregnancy complications associated with chemerin.
2025-06-05 | GSE298315 | GEO