FIBCD1 ameliorates weight loss in chemotherapy-induced murine mucositis

Andersen, Maria Christine Ernst; Johansen, Malene W; Nissen, Thomas Nørrelykke; Nexøe, Anders Bathum; Madsen, Gunvor Iben; Sørensen, Grith Lykke; Holmskov, Uffe; Schlosser, Anders; Møeller, Jesper Bonnet; Husby, Steffen; Rathe, Mathias

doi:10.1007/s00520-020-05762-w

Cited by 9 publications

(9 citation statements)

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“…Doxo treated mice lost more weight compared to controls consistent with findings in similar models of CIGT in mice (26,31,32). We observed that Pglyrp2 had an aggravating effect on weight loss.…”

Section: Discussionsupporting

confidence: 89%

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Peptidoglycan Recognition Peptide 2 Aggravates Weight Loss in a Murine Model of Chemotherapy-Induced Gastrointestinal Toxicity

et al. 2021

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Introduction: Chemotherapy-induced gastrointestinal toxicity (CIGT) is a frequent, severe and dose-limiting side effect. Few treatments have proven effective for CIGT. CIGT is characterized by activation of the nuclear factor kappa B pathway which, leads to upregulation of proinflammatory cytokines. The innate immune protein peptidoglycan recognition peptide 2 (PGLYRP2) binds to and hydrolyzes microbial peptidoglycan. Expression of PGLYRP2 is upregulated in the intestine of chemotherapy-treated piglets. In this experimental study, we investigated the role of Pglyrp2 in the development and severity of murine CIGT.Methods:Pglyrp2 wildtype and Pglyrp2 knockout mice received intraperitoneal injections of chemotherapy (Doxorubicin 20 mg/kg) to induce CIGT. Weight was monitored daily, and animals were euthanized after 2 or 7 days. Expression of proinflammatory cytokines in the jejunum was measured by quantitative real-time polymerase-chain reaction and enzyme-linked immunosorbent assay. Villus height, crypt depth, and histologic inflammation were evaluated on haematoxylin and eosin stained tissue specimens.Results: Chemotherapeutic treatment induced weight loss (p < 0.05), shortening of the small intestine (p < 0.05), elongation of villus height (p < 0.05), increased crypt depth (p < 0.05), and led to elevated mRNA levels of II1β (p < 0.05), II6 (p < 0.05), and Tnf (p < 0.001) at day 2. Protein levels of IL1β, IL6, and TNFα did not change after exposure to chemotherapy. Doxorubicin treated wildtype mice had a more pronounced weight loss compared to knockout mice from day 3 to day 7 (D3-D6: p < 0.05 and D7: p < 0.01). No other phenotypic differences were detected.Conclusion:Pglyrp2 aggravates chemotherapy-induced weight loss but does not induce a specific pattern of inflammation and morphological changes in the small intestine.

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Section: Discussionsupporting

confidence: 89%

“…30 Pglyrp2 KO and 33 Pglyrp2 WT mice were included in the study. Mucositis induction was achieved by doxorubicin (Doxo) treatment as described earlier (26). At day−1 baseline weight was measured.…”

Section: Study Design and Settingmentioning

confidence: 99%

Peptidoglycan Recognition Peptide 2 Aggravates Weight Loss in a Murine Model of Chemotherapy-Induced Gastrointestinal Toxicity

et al. 2021

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“…The cytokines Il-1β and Tnf have previously been implicated in the initiation and maintenance of mucositis via NF-kB ( 7 , 26 , 27 ). Previously increased mucosal levels of Tnf and Il-1β have been found in this model ( 17 ), although the results are conflicting ( 28 , 29 ) The increased intestinal expression of Tnf and Il-1β on day 3 in the current model corroborated the presence of NF-kB mediated mucosal inflammation. Previously, increased mucosal levels of Tnf and Il-1β have been found in this model ( 17 ), although the results are conflicting ( 28 , 29 ).…”

Section: Discussionsupporting

confidence: 60%

PET/CT imaging detects intestinal inflammation in a mouse model of doxorubicin-induced mucositis

et al. 2022

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IntroductionA severe side effect of cancer chemotherapy is the development of gastrointestinal mucositis, characterised by mucosal inflammation. We investigated if 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography combined with computed tomography (2-[18F]FDG-PET/CT) could visualise gastrointestinal mucositis in mice treated with the chemotherapeutic agent doxorubicin.MethodsIn this study, gastrointestinal inflammation was longitudinally evaluated by 2-[18F]FDG-PET/CT scans before and 1, 3, 6, and 10 days after treatment with doxorubicin. Doxorubicin-treated mice were compared to saline-treated littermates using the abdominal standard uptake value of 2-[18F]FDG corrected for body weight (SUVBW).ResultsAbdominal SUVBW was significantly increased on day 1 (p < 0.0001), day 3 (p < 0.0001), and day 6 (p < 0.05) in the doxorubicin-treated group compared to controls. Abdominal SUVBW returned to baseline levels on day 10. In the doxorubicin group, the largest weight loss was observed on day 3 (control vs doxorubicin, mean percent of baseline weight: (98.5 ± 3.2% vs 87.9 ± 4.6%, p < 0.0001). Moreover, in the doxorubicin-treated group, villus lengths were decreased by 23-28% on days 1 and 3 in the small intestine (p < 0.05), and jejunal levels of tumour necrosis factor and interleukin-1β were significantly increased on day 3 (p < 0.05).DiscussionTogether, these findings indicate that sequential 2-[18F]FDG-PET/CT scans can objectively quantify and evaluate the development and resolution of intestinal inflammation over time in a mouse model of doxorubicin-induced mucositis.

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“…4 and 6 ) in the diaphragm skeletal muscle. Consistent with a role of Fibcd1 in reducing tissue inflammation, recent studies have found that gut-specific Fibcd1 overexpression reduces intestinal inflammation 76 , 154 and impedes weight loss induced by chemotherapy in mice 154 . Taken together, our study and these recent publications suggest that Fibcd1 reduces tissue inflammation, which is a major driver of cancer-induced muscle wasting 24 .…”

Section: Discussionmentioning

confidence: 61%

The myokine Fibcd1 is an endogenous determinant of myofiber size and mitigates cancer-induced myofiber atrophy

et al. 2022

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Decline in skeletal muscle cell size (myofiber atrophy) is a key feature of cancer-induced wasting (cachexia). In particular, atrophy of the diaphragm, the major muscle responsible for breathing, is an important determinant of cancer-associated mortality. However, therapeutic options are limited. Here, we have used Drosophila transgenic screening to identify muscle-secreted factors (myokines) that act as paracrine regulators of myofiber growth. Subsequent testing in mouse myotubes revealed that mouse Fibcd1 is an evolutionary-conserved myokine that preserves myofiber size via ERK signaling. Local administration of recombinant Fibcd1 (rFibcd1) ameliorates cachexia-induced myofiber atrophy in the diaphragm of mice bearing patient-derived melanoma xenografts and LLC carcinomas. Moreover, rFibcd1 impedes cachexia-associated transcriptional changes in the diaphragm. Fibcd1-induced signaling appears to be muscle selective because rFibcd1 increases ERK activity in myotubes but not in several cancer cell lines tested. We propose that rFibcd1 may help reinstate myofiber size in the diaphragm of patients with cancer cachexia.

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FIBCD1 ameliorates weight loss in chemotherapy-induced murine mucositis

Cited by 9 publications

References 34 publications

Peptidoglycan Recognition Peptide 2 Aggravates Weight Loss in a Murine Model of Chemotherapy-Induced Gastrointestinal Toxicity

Peptidoglycan Recognition Peptide 2 Aggravates Weight Loss in a Murine Model of Chemotherapy-Induced Gastrointestinal Toxicity

PET/CT imaging detects intestinal inflammation in a mouse model of doxorubicin-induced mucositis

The myokine Fibcd1 is an endogenous determinant of myofiber size and mitigates cancer-induced myofiber atrophy

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