Ghrelin prevents tumour‐ and cisplatin‐induced muscle wasting: characterization of multiple mechanisms involved

Chen, Ji An; Splenser, Andres E.; Guillory, Bobby; Luo, Jiaohua; Mendiratta, Meenal; Belinova, Blaga; Halder, Tripti; Zhang, Guohua; Li, Yi-Ping; García, José Manuel Pérez

doi:10.1002/jcsm.12023

Cited by 173 publications

(244 citation statements)

References 56 publications

(96 reference statements)

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“…Also, the vagus nerve has been shown to mediate some of ghrelin's effects via the ghrelin receptor GHSR‐1a (Iwasaki et al ., 2015). Recently, an alternative—yet unidentified—receptor has been proposed as a mechanism for ghrelin to exert effects in vitro in hepatocytes, myocytes, or adipocytes (Chen et al ., 2015). The exact mechanism mediating ghrelin's effects in liver is not well characterized and should be the subject of future studies.…”

Section: Discussionmentioning

confidence: 99%

Ghrelin deletion protects against age‐associated hepatic steatosis by downregulating the C/EBPα‐p300/DGAT1 pathway

et al. 2017

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SummaryNonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. NAFLD usually begins as low‐grade hepatic steatosis which further progresses in an age‐dependent manner to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma in some patients. Ghrelin is a hormone known to promote adiposity in rodents and humans, but its potential role in hepatic steatosis is unknown. We hypothesized that genetic ghrelin deletion will protect against the development of age‐related hepatic steatosis. To examine this hypothesis, we utilized ghrelin knockout (KO) mice. Although no different in young animals (3 months old), we found that at 20 months of age, ghrelin KO mice have significantly reduced hepatic steatosis compared to aged‐matched wild‐type (WT) mice. Examination of molecular pathways by which deletion of ghrelin reduces steatosis showed that the increase in expression of diacylglycerol O‐acyltransferase‐1 (DGAT1), one of the key enzymes of triglyceride (TG) synthesis, seen with age in WT mice, is not present in KO mice. This was due to the lack of activation of CCAAT/enhancer binding protein‐alpha (C/EBPα) protein and subsequent reduction of C/EBPα‐p300 complexes. These complexes were abundant in livers of old WT mice and were bound to and activated the DGAT1 promoter. However, the C/EBPα‐p300 complexes were not detected on the DGAT1 promoter in livers of old KO mice resulting in lower levels of the enzyme. In conclusion, these studies demonstrate the mechanism by which ghrelin deletion prevents age‐associated hepatic steatosis and suggest that targeting this pathway may offer therapeutic benefit for NAFLD.

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Section: Discussionmentioning

confidence: 99%

Ghrelin deletion protects against age‐associated hepatic steatosis by downregulating the C/EBPα‐p300/DGAT1 pathway

et al. 2017

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“…It has been shown that tumor implantation is associated with an increase in the expression of the ubiquitin ligases MAFbx/Atrogin-1 and MuRF1 (20). To investigate whether isofl avones suppress muscle wasting through ubiquitin ligase activation, we examined the expression of MAFbx/Atrogin-1 and MuRF1 mRNA levels in TN, CN, CI and TI mice.…”

Section: Effect Of Dietary Isofl Avones On Expression Of Atrophy-relamentioning

confidence: 99%

Dietary Supplementation with Isoflavones Prevents Muscle Wasting in Tumor-Bearing Mice

Hirasaka

Saito

Yamaguchi

et al. 2016

Journal of Nutritional Science and Vitaminology, J Nutr Sci Vit

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Summary Proinfl ammatory cytokines contribute to the progression of muscle wasting caused by ubiquitin-proteasome-dependent proteolysis. We have previously demonstrated that isofl avones, such as genistein and daidzein, prevent TNF-␣-induced muscle atrophy in C2C12 myotubes. In this study, we examined the effect of dietary fl avonoids on the wasting of muscle. Mice were divided into the following four groups: vehicle-injected (control) mice fed the normal diet (CN); tumor-bearing mice fed the normal diet (TN); control mice fed the isofl avone diet (CI); and tumor-bearing mice fed the isofl avone diet (TI). There were no significant differences in the intake of food or body weight gain among these four groups. The wet weight and myofi ber size of gastrocnemius muscle in TN signifi cantly decreased, compared with those in CN. Interestingly, the wet weight and myofi ber size of gastrocnemius muscle in TI were nearly the same as those in CN and CI, although isofl avone supplementation did not affect the increased tumor mass or concentrations of proinfl ammatory cytokines, such as TNF-␣ and IL-6, in the blood. Moreover, increased expression of muscle-specifi c ubiquitin ligase genes encoding MAFbx/Atrogin-1 and MuRF1 in the skeletal muscle of TN was signifi cantly inhibited by the supplementation of isofl avones. In parallel with the expression of muscle-specifi c ubiquitin ligases, dietary isofl avones signifi cantly suppressed phosphorylation of ERK in tumor-bearing mice. These results suggest that dietary isofl avones improve muscle wasting in tumor-bearing mice via the ERK signaling pathway mediated-suppression of ubiquitin ligases in muscle cells.

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“…We have thus far evaluated a single rapid model of experimental cachexia which necessarily limits the broader interpretation of our findings. The short treatment window (<14 days) afforded by the C-26 model in our hands also severely curtailed our ability to demonstrate overt anabolic effects following GTx-024 treatment relative to other anabolic agents in less severe models [93]. Evaluation of combination treatment in other experimental models of cachexia are ongoing.…”

Section: Cc-by-nc-nd 40 International License It Is Made Available Umentioning

confidence: 98%

“…Likewise, the doses of GTx-024 used were higher than what would be expected to provide anabolic benefit [93]. Dose optimization is critical to both improve efficacy and minimize toxicity as the tolerance for additional side effects associated with anti-cachexia therapy in already heavily treated cancer patients is low.…”

Section: Cc-by-nc-nd 40 International License It Is Made Available Umentioning

confidence: 99%

“…http://dx.doi.org/10.1101/214155 doi: bioRxiv preprint first posted online Nov. 6, 2017; Cross-talk between multiple signaling pathways governing anabolism and catabolism in skeletal muscle have been described, suggesting that targeting a single pathway can lead to concurrent therapeutic pro-anabolic and anti-catabolic effects on skeletal muscle [94]. As such both anti-catabolic and anabolic therapies have been shown as single agents to attenuate skeletal muscle losses associated with tumor burden in models of cancer wasting [37,93,95].…”

Section: Combined Anabolic and Anti-catabolic Therapy In Cancer Cachexiamentioning

confidence: 99%

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Overcoming Resistance to Anabolic Selective Androgen Receptor Modulator (SARM) Therapy in Experimental Cancer Cachexia with Histone Deacetylase Inhibitor AR-42

Tseng

Liva

Dauki

et al. 2017

Preprint

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BackgroundCancer cachexia impacts the majority of advanced cancer patients but no approved anticachexia therapeutic exits. Recent late stage clinical failures of anabolic anti-cachexia therapy revealed heterogeneous responses to anabolic therapies and a limited ability to translate improved body composition into functional benefit. It is currently unclear what governs anabolic responsiveness in cachectic patient populations. Methods We evaluated anabolic androgen therapy combined with the novel anti-cachectic histone deacetylase inhibitor (HDACi) AR-42 in a series of studies using the C-26 mouse model of experimental cachexia. The ability of treatment to suppress tumor-mediated catabolic signaling and promote anabolic effects were characterized. Results Anabolic anti-cachexia monotherapy with the selective androgen receptor modulator (SARM) GTx-024 or enobosarm had no impact on cachectic outcomes in the C-26 model. A minimally effective dose of AR-42 provided mixed anti-cachectic benefits when administered alone but when combined with GTx-024 significantly improved bodyweight (p <0.0001), hind limb muscle mass (p <0.05), and voluntary grip strength (p <0.0001) versus tumor bearing controls. Similar efficacy resulted from the combination of AR-42 with multiple androgens. Anti-cachectic efficacy was associated with the ability to reverse pSTAT3 and atrogene induction in gastrocnemius muscle of tumor-bearing animals in the absence of treatment-mediated changes in serum IL-6 or LIF. Conclusions Anabolic GTx-024 monotherapy is incapable of overcoming catabolic signaling in the C-26 model of experimental cachexia. Anti-cachectic androgen therapy is greatly improved by successful blockade of STAT3 mediated atrophy with AR-42. Combined androgen and HDAC inhibitor administration represents promising approach to improve anabolic response in cachectic patient populations.

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Ghrelin prevents tumour‐ and cisplatin‐induced muscle wasting: characterization of multiple mechanisms involved

Cited by 173 publications

References 56 publications

Ghrelin deletion protects against age‐associated hepatic steatosis by downregulating the C/EBPα‐p300/DGAT1 pathway

Ghrelin deletion protects against age‐associated hepatic steatosis by downregulating the C/EBPα‐p300/DGAT1 pathway

Dietary Supplementation with Isoflavones Prevents Muscle Wasting in Tumor-Bearing Mice

Overcoming Resistance to Anabolic Selective Androgen Receptor Modulator (SARM) Therapy in Experimental Cancer Cachexia with Histone Deacetylase Inhibitor AR-42

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