ACVR2B antagonism preserves skeletal muscle and cardiac function in metastatic colorectal cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE149604 | GEO | 2020/11/17
REPOSITORIES: GEO
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Project description:ACVR2B antagonism preserves skeletal muscle and cardiac function in metastatic colorectal cancer
| PRJNA629345 | ENA
Project description:Skeletal muscle wasting is a devastating consequence of cancer that affects up to 80% of cancer patients and associates with reduced survival. Herein we identified the transcriptional repressor protein, Forkhead box P1 (FoxP1), as a downstream target gene of FoxO1 whose skeletal muscle expression is elevated in multiple models of cancer cachexia and in patients with cancer who exhibit cachexia. Through generation of inducible skeletal muscle-specific FoxP1 over-expressing (FoxP1iSkmTg/Tg) mice, we demonstrate that FoxP1 upregulation is sufficient to induce features of cachexia, including body and skeletal muscle wasting characterized by reduced muscle fiber cross-sectional area of type IIX/B muscle fibers. Muscles from FoxP1iSkmTg/Tg mice also showed significant muscle damage and myopathy characterized by the accumulation of p62 and cellular material-filled vesicles, the presence of centrally nucleated myofibers, and were significantly weaker than controls. In the context of cancer cachexia, blocking FoxP1 upregulation prevented the cancer-induced repression of target genes critical to muscle structural integrity and repair, including Myocyte enhancer factor 2c (Mef2c), improved muscle ultrastructure and significantly attenuated muscle fiber atrophy. We further show that the muscle wasting phenotype induced by FoxP1 required the activity of histone deacetylase (HDAC) proteins, which are well-established to cooperate with FoxP1 to mediate gene repression, and which were necessary for FoxP1-dependent repression of Mef2c. In summary, we identify FoxP1 as a negative transcriptional regulator of skeletal muscle mass and function, whose up-regulation mediates cancer-induced muscle wasting. We used microarrays to investigate the genome-wide transcriptional networks regulated by the FoxO1 and FoxP1 transcription factors in skeletal muscle of tumor-bearing mice.
2021-04-28 | GSE153068 | GEO
Project description:Advanced colorectal cancer (CRC), a leading cause of death worldwide, is often accompanied by the development of liver metastases (LM), as well as skeletal muscle (SkM) wasting, i.e. cachexia. Despite affecting the majority of CRC patients, cachexia remains understudied and uncured. Moreover, only a single model of LM associated with CRC has been developed for the study of cachexia. Here we examined differential gene expression of skeletal muscles deriving from subcutaneous and metastatic C26 tumor hosts. Tumor hosts displaying LM experienced exacerbated muscle wasting compared to tumor hosts without LM.
2020-04-18 | GSE142455 | GEO
Project description:Cancer-induced muscle wasting reduces quality of life, complicates or precludes cancer treatments, and predicts early mortality. Herein, we investigated the requirement of the muscle-specific E3 ubiquitin ligase, MuRF1, for muscle wasting induced by pancreatic cancer. Murine pancreatic cancer (KPC) cells, or saline, were injected into the pancreas of WT and MuRF1-/- mice, and tissues analyzed throughout tumor progression. KPC tumors induced progressive wasting of skeletal muscle and systemic metabolic reprogramming in WT mice, but not MuRF1-/- mice. KPC tumors from MuRF1-/- mice also grew slower, and showed an accumulation of metabolites normally depleted by rapidly growing tumors. Mechanistically, MuRF1 was necessary for the KPC-induced increases in cytoskeletal and muscle contractile protein ubiquitination, and the depression of proteins that support protein synthesis. Together, these data demonstrate that MuRF1 is required for KPC-induced skeletal muscle wasting, whose deletion reprograms the systemic and tumor metabolome and delays tumor growth.
2023-05-15 | PXD039151 | Pride
Project description:Cancer-induced muscle wasting reduces quality of life, complicates or precludes cancer treatments, and predicts early mortality. Herein, we investigated the requirement of the muscle-specific E3 ubiquitin ligase, MuRF1, for muscle wasting induced by pancreatic cancer. Murine pancreatic cancer (KPC) cells, or saline, were injected into the pancreas of WT and MuRF1-/- mice, and tissues analyzed throughout tumor progression. KPC tumors induced progressive wasting of skeletal muscle and systemic metabolic reprogramming in WT mice, but not MuRF1-/- mice. KPC tumors from MuRF1-/- mice also grew slower, and showed an accumulation of metabolites normally depleted by rapidly growing tumors. Mechanistically, MuRF1 was necessary for the KPC-induced increases in cytoskeletal and muscle contractile protein ubiquitination, and the depression of proteins that support protein synthesis. Together, these data demonstrate that MuRF1 is required for KPC-induced skeletal muscle wasting, whose deletion reprograms the systemic and tumor metabolome and delays tumor growth.
2023-05-15 | PXD039158 | Pride
Project description:Cachexia is associated with poor prognosis in patients with chronic heart failure. The underlying mechanisms of cachexia triggered heart failure progression, however, are not well understood. Here, we investigated whether the dysregulation of myokine expression from wasting skeletal muscle and impaired inter-organ crosstalk during advanced heart failure might contribute to progression of the disease. RNA sequencing analysis from wasting skeletal muscles of mice with cardiac cachexia during long-term pressure overload revealed a strongly reduced expression of Ostn. Ostn encodes for the skeletal muscle derived myokine Musclin, which had been previously implicated in the enhancement of natriuretic peptide (NP) signaling. Using newly developed skeletal muscle specific, inducible Ostn knock-out mice, we demonstrated that reduced skeletal muscle Musclin levels exaggerated cardiac dysfunction and myocardial fibrosis compared to littermate control mice after TAC. Restoration of Musclin deficiency during cardiac cachexia via AAV6-mediated skeletal muscle specific Musclin overexpression, in turn, attenuated left ventricular dysfunction and myocardial fibrosis. Mechanistically, we found that Musclin enhanced CNP/NPR2/cGMP signaling in cardiomyocytes, which led to improved contractility by inhibition of the cAMP degrading phosphodiesterase (PDE)3 and augmented cAMP/protein kinase A signaling. In addition, Musclin directly acted on cardiac fibroblasts to inhibit their activation. Together, our study indicates the therapeutic potential of targeting interorgan cross-talk during heart failure, for example by counteracting the impaired secretion of the Musclin from wasting skeletal muscle.
2021-11-02 | GSE129205 | GEO
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:The cancer anorexia cachexia syndrome is a systemic metabolic disorder characterized by the catabolism of stored nutrients in skeletal muscle and adipose tissue that is particularly prevalent in non-small cell lung cancer (NSCLC). Loss of skeletal muscle results in functional impairments and increased mortality. The aim of the current study was to characterize the changes in systemic metabolism in a genetically engineered mouse model of NSCLC. We show that a portion of these animals develop loss of skeletal muscle, loss of adipose tissue, and increased inflammatory markers mirroring the human cachexia syndrome. Using non-cachexic and fasted animals as controls, we report a unique cachexia metabolite phenotype that includes the dependent ketone production by the liver. In this setting, glucocorticoid levels rise and correlate with skeletal muscle degradation and hepatic markers of gluconeogenesis. Restoring prevents the loss of skeletal muscle mass and body weight. These results demonstrate how targeting hepatic metabolism can prevent muscle wasting in lung cancer, and provide evidence for a novel therapeutic strategy.
2017-12-21 | GSE107470 | GEO
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:A limited mechanistic understanding of skeletal muscle wasting after acute spinal cord injury (SCI) precludes targeted molecular interventions. Here, we demonstrate marked systemic wasting also affecting neurologically intact non-paralyzed (supralesional) muscle early after SCI. Systemic muscle mass loss propagates muscle weakness, affects fast type 2 myofibers preferentially, and becomes exacerbated after high (T3) compared to low (T9) thoracic paraplegia indicating lesion-level dependent (“neurogenic”) mechanisms. The wasting of non-paralyzed muscle, its rapid onset and severity beyond what can be explained by disuse implies additional systemic drivers. Muscle transcriptome and biochemical analysis revealed a glucocorticoid-mediated catabolic signature of SCI-induced systemic muscle wasting that was mitigated i) by endogenous glucocorticoid ablation (adrenalectomy), ii) by pharmacological glucocorticoid receptor (GR) blockade, and was iii) completely prevented, relative to T9 SCI, by genetic muscle-specific GR deletion. We provide evidence of neurogenic hypercortisolism underlying a rapid systemic and functionally relevant muscle wasting syndrome after acute SCI.
2024-01-31 | GSE224186 | GEO