Inhibition of activin-like kinase 4/5 attenuates cancer cachexia associated muscle wasting

Autor:	S.A. Huisman, J. N. M. Ijzermans, Erik A.C. Wiemer, Gisela Ambagtsheer, M. G. van Vledder, R.W.F. de Bruin, S. van Damme-van Engel, Stef Levolger, J L A van Vugt
Přispěvatelé:	Medical Oncology, Surgery
Jazyk:	angličtina
Rok vydání:	2019
Předmět:	0301 basic medicine Male Cachexia Receptor Transforming Growth Factor-beta Type I Administration Oral lcsh:Medicine Myostatin Mice 0302 clinical medicine Insulin-Like Growth Factor I lcsh:Science Wasting Cancer Multidisciplinary biology Cell Differentiation Activin receptor Ubiquitin ligase medicine.anatomical_structure Benzamides Colonic Neoplasms medicine.symptom Injections Intraperitoneal medicine.medical_specialty Dioxoles Article Cell Line 03 medical and health sciences SDG 3 - Good Health and Well-being In vivo Internal medicine medicine Animals business.industry Body Weight lcsh:R Skeletal muscle medicine.disease 030104 developmental biology Endocrinology Gene Expression Regulation Preclinical research biology.protein Pyrazoles lcsh:Q business Activin Receptors Type I 030217 neurology & neurosurgery Neoplasm Transplantation
Zdroj:	Scientific Reports, Vol 9, Iss 1, Pp 1-11 (2019) Scientific Reports, 9:9826. Nature Publishing Group Scientific Reports
ISSN:	2045-2322
DOI:	10.1038/s41598-019-46178-9
Popis:	Cancer mediated activation of the ActRIIB-ALK4/5 heterodimer by myostatin is strongly associated with muscle wasting. We investigated in vitro and in vivo the efficacy of ALK4/5 receptor blockers SB431542 and GW788388 in preventing muscle wasting, and explored synergy with IGF-I analogue LONG R3 (LR3) IGF-I. In vitro, C2C12 skeletal muscle cells were treated with vehicle, SB431542, GW788388 and LR3 IGF-I. A C26-CD2F1 cachexia model was used to induce cachexia in vivo. Mice were allocated as non-tumour bearing (NTB) or C26 tumour-bearing (C26 TB) vehicle control, treated with SB431542, LR3 IGF-I, SB431542 and LR3 IGF-I, or GW788388 (intraperitoneally or orally). In vitro, differentiation index and mean nuclei count increased using SB431542, GW788388, LR3 IGF-I. In vivo, GW788388 was superior to SB431542 in limiting loss of bodyweight, grip-strength and gastrocnemius weight. and downregulated Atrogin-1 expression comparable to NTB mice. LR3 IGF-I treatment limited loss of muscle mass, but at the expense of accelerated tumour growth. In conclusion, treatment with GW788388 prevented cancer cachexia, and downregulated associated ubiquitin ligase Atrogin-1.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::154fb5e41ad0d9ea4e611119e5de0759 http://link.springer.com/article/10.1038/s41598-019-46178-9 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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