Doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscle

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dc.citation.issue5
dc.citation.volume7
dc.contributor.authorde Lima Junior, Edson Alves
dc.contributor.authorYamashita, Alex Shimura
dc.contributor.authorPimentel, Gustavo Duarte
dc.contributor.authorDe Sousa, Luis G. O.
dc.contributor.authorSantos, Ronaldo Vagner Thomatieli dos [UNIFESP]
dc.contributor.authorGoncalves, Cinara Ludvig
dc.contributor.authorStreck, Emilio Luiz
dc.contributor.authorde Lira, Fabio Santos
dc.contributor.authorRosa Neto, Jose Cesar
dc.coverageHoboken
dc.date.accessioned2020-07-31T12:47:13Z
dc.date.available2020-07-31T12:47:13Z
dc.date.issued2016
dc.description.abstractBackground Cancer is considered the second leading cause of death in the world, and for the treatment of this disease, pharmacological intervention strategies are frequently based on chemotherapy. Doxorubicin (DOX) is one of the most widely used chemotherapeutic agents in clinical practice for treating a number of solid tumours. The treatment with DOX mimics some effects of cancer cachexia, such as anorexia, asthenia, decreases in fat and skeletal muscle mass and fatigue. We observed that treatment with DOX increased the systemic insulin resistance and caused a massive increase in glucose levels in serum. Skeletal muscle is a major tissue responsible for glucose uptake, and the positive role of AMPk protein (AMP-activated protein kinase) in GLUT-4 (Glucose Transporter type 4) translocation, is well established. With this, our aim was to assess the insulin sensitivity after treatment with DOX and involvement of AMPk signalling in skeletal muscle in this process. Methods We used Wistar rats which received a single dose of doxorubicin (DOX group) or saline (CT group) intraperitoneally at a dose of 15mg/kg b.w. The expression of proteins involved in insulin sensitivity, glucose uptake, inflammation, and activity of electron transport chain was assessed in extensor digitorum longus muscle, as well as the histological evaluation. In vitro assays were performed in L6 myocytes to assess glucose uptake after treatment with DOX. Agonist of AMPk [5-aminoimidazole-4-carboxamide (AICAR)] and the antioxidant n-acetyl cysteine were used in L6 cells to evaluate its effect on glucose uptake and cell viability. Results The animals showed a significant insulin resistance, hyperglycaemia, and hyperinsulinemia. A decrease in the expression of AMKP and GLUT-4 was observed in the extensor digitorum longus muscle. Also in L6 cells, DOX leads to a decrease in glucose uptake, which is reversed with AICAR. Conclusions DOX leads to conditions similar to cachexia, with severe glucose intolerance both in vivo and in vitro. The decrease of AMPk activity of the protein is modulated negatively with DOX, and treatment with agonist of AMPk (AICAR) has proved to be a possible therapeutic target, which is able to recover glucose sensitivity in skeletal muscle.en
dc.description.affiliationInst Ciencias Biomed I, Dept Biol Celular & Desenvolvimento, Ave Lineu Prestes 1524,Cidade Univ, BR-05508900 Sao Paulo, SP, Brazil
dc.description.affiliationUniv Sao Paulo, Inst Ciencias Biomed, Dept Fisiol & Biofis, Sao Paulo, SP, Brazil
dc.description.affiliationUniv Fed Goias, Fac Nutr FANUT, Lab Invest Nutr Clin & Esport Labince, Goiania, Go, Brazil
dc.description.affiliationUniv Calif Davis, Dept Neurobiol Physiol & Behav, Davis, CA 95616 USA
dc.description.affiliationUniv Fed Sao Paulo, Dept Biociencias, Sao Paulo, SP, Brazil
dc.description.affiliationUniv Extremo Sul Catarinense, Lab Fisiopatol Expt, Av Univ 1105, BR-88806000 Criciuma, SC, Brazil
dc.description.affiliationUniv Estadual Paulista, UNESP, Dept Phys Educ, Exercise & Immunometab Res Grp, Rua Roberto Simonsen, BR-30519060 Presidente Prudente, SP, Brazil
dc.description.affiliationUnifespDepartamento de Biociências, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brasil
dc.description.sourceWeb of Science
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipIDFAPESP: 2013/09367-4
dc.format.extent615-625
dc.identifierhttp://dx.doi.org/10.1002/jcsm.12104
dc.identifier.citationJournal Of Cachexia Sarcopenia And Muscle. Hoboken, v. 7, n. 5, p. 615-625, 2016.
dc.identifier.doi10.1002/jcsm.12104
dc.identifier.issn2190-5991
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/56671
dc.identifier.wosWOS:000388495400014
dc.language.isoeng
dc.publisherWiley-Blackwell
dc.relation.ispartofJournal Of Cachexia Sarcopenia And Muscle
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectDoxorubicinen
dc.subjectSkeletal muscleen
dc.subjectAMPken
dc.subjectGlucose intoleranceen
dc.subjectHyperglycaemiaen
dc.subjectChemotherapyen
dc.subjectAnthracyclineen
dc.titleDoxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscleen
dc.typeinfo:eu-repo/semantics/article
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