Conditioned media from Cancer cell lines regulate mRNAs in differentiated human muscle stem cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE206662 | GEO | 2023/05/03
REPOSITORIES: GEO
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Project description:Individuals with hepatic steatosis often display several metabolic abnormalities including insulin resistance and muscle atrophy. Previously, we found that hepatic steatosis results in an altered hepatokine secretion profile, thereby inducing skeletal muscle insulin resistance via inter-organ crosstalk. In this study, we aimed to investigate whether the altered secretion profile in the state of hepatic steatosis also induces skeletal muscle atrophy via effects on muscle protein turnover. To investigate this, eight-week-old male C57BL/6J mice were fed a chow (4.5% fat) or a high-fat diet (HFD; 45% fat) for 12 weeks to induce hepatic steatosis, after which the livers were excised and cut into ~200 µm slices. Slices were cultured to collect secretion products (conditioned medium; CM). Differentiated L6-GLUT4myc myotubes were incubated with chow or HFD CM to measure glucose uptake. Differentiated C2C12 myotubes were incubated with chow or HFD CM to measure protein synthesis and breakdown, and gene expression via RNA sequencing. Furthermore, proteomics analysis was performed in chow and HFD CM. It was found that HFD CM caused insulin resistance in L6-GLUT4myc myotubes compared with chow CM, as indicated by a blunted insulin-stimulated increase in glucose uptake. Furthermore, protein breakdown was increased in C2C12 cells incubated with HFD CM, while there was no effect on protein synthesis. RNA profiling of C2C12 cells indicated that 197 genes were differentially expressed after incubation with HFD CM, compared with chow CM, and pathway analysis showed that pathways related to anatomical structure and function were enriched. Proteomic analysis of the CM showed that 32 proteins were differentially expressed in HFD CM compared with chow CM. Pathway enrichment analysis indicated that these proteins had important functions with respect to insulin-like Growth Factor transport and uptake, and affect post-translational processes, including protein folding, protein secretion and protein phosphorylation. In conclusion, the results of this study support the hypothesis that secretion products from the liver contribute to the development of muscle atrophy in individuals with hepatic steatosis.
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Project description:Treatment strategies of critical nerve injuries involving nerve gaps more than 3 cm are still not optimal. The need for an alternative to the standard autologous nerve grafts has led to the exploration of adipose derived stem cells (ASC) seeded in bioartificial nerve conduits for enhancement of peripheral nerve regeneration. ASC can be differentiated into Schwann cell like cells, which is believed to improve their neurotrophic potency. Nevertheless, the differentiation process requires several weeks and there is no evidence that the cells maintain their differentiated phenotype in vivo. Thus, the present study evaluated the synergistic effect of undifferentiated ASC with exogenously added growth factors in vitro with the aim to improve the neurotrophic potency of undifferentiated ASC through short ex-vivo stimulation with growth factors. The study furthermore provides a comparative in vitro assay of the six well-known neurotrophic factors NGF, GDNF, BDNF, CNTF, NT3 and NT4. ASC were cultured and thus stimulated in the presence of the respective exogenous growth factor for three days and resulting conditioned medium was evaluated in an in vitro axonal outgrowth assay. In addition, also unstimulated ASC’s conditioned medium was tested in combination with the respective exogenous growth factor for the same assay, which was perfomed on dorsal root ganglion (DRG) explants from 10 days old embryonic chicken. DRG explants from most promising conditions were further analyzed for upregulated STAT-3 and GAP-43 by qRT-PCR. Furthermore, also proteomics and phosphoproteomics were performed for ASC and DRG explants using mass spectrometry. The quantity of selected proteins contained in the ASC’s conditioned medium was investigated by ELISA. Combination of ASC’s conditioned medium with growth factors generally resulted in significantly enhanced axonal outgrowth when compared with their control of DRG explants cultured with the respective growth factor only. Specifically, conditioned medium derived from NT3-stimulated as well as ASC’s conditioned medium supplemented with NT3 or BDNF elicited significant axonal outgrowth from DRG explants in contrast to all other experimental conditions. Significant upregulation of STAT-3 and GAP-43 was evidenced for DRG explants grown in NT3-stimulated ASC’s conditioned medium and to a certain extent also for DRG cultured in ASC’s conditioned medium supplemented with NT3.
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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.
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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.
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