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

Autor: de Lima Junior EA; Departamento de Biologia Celular e do Desenvolvimento Instituto de Ciências Biomédicas I Avenida Lineu Prestes 1524, Cidade Universitária 05508-900 São Paulo SP Brazil., Yamashita AS; Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas Universidade de São Paulo São Paulo SP Brazil., Pimentel GD; Laboratório de Investigação em Nutrição Clínica e Esportiva(Labince), Faculdade de Nutrição (FANUT) Universidade Federal de Goiás (UFG) Goiânia Goiás Brasil., De Sousa LG; Department of Neurobiology, Physiology and Behavior University of California Davis Davis CA 95616 USA., Santos RV; Departamento de Biociências UNIFESP São Paulo SP Brasil., Gonçalves CL; Laboratório de Fisiopatologia Experimental Universidade do Extremo Sul Catarinense, Av. Universitária, 1105 Criciúma 88806-000 SC Brazil., Streck EL; Laboratório de Fisiopatologia Experimental Universidade do Extremo Sul Catarinense, Av. Universitária, 1105 Criciúma 88806-000 SC Brazil., de Lira FS; Exercise and Immunometabolism Research Group, Department of Physical Education Universidade Estadual Paulista, UNESP Rua Roberto Simonsen, 305 19060-900 Presidente Prudente São Paulo Brazil., Rosa Neto JC; Departamento de Biologia Celular e do Desenvolvimento Instituto de Ciências Biomédicas I Avenida Lineu Prestes 1524, Cidade Universitária 05508-900 São Paulo SP Brazil.
Jazyk: angličtina
Zdroj: Journal of cachexia, sarcopenia and muscle [J Cachexia Sarcopenia Muscle] 2016 Dec; Vol. 7 (5), pp. 615-625. Date of Electronic Publication: 2016 Feb 15.
DOI: 10.1002/jcsm.12104
Abstrakt: Background: 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 15 mg/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.
Databáze: MEDLINE
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