Metabolic effects of doxorubicin on the muscle and adipose tissue: do exercise and metformin reduce the damage?

• Grant number: 13/09367-4
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2013
• End date: October 31, 2015
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: José Cesar Rosa Neto
• Grantee: José Cesar Rosa Neto
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Doxorubicin is an antibiotic of antracyclines family, that is the most to use in clinical practice, in treatment of solid tumours. However, this drug cause great cardiotoxicity. Moreover is common the patients development several fatigue and asthenia, during the treatment. Recents works showed that others organs are still injured by doxorubicin treatment, as adipose tissue, skeletal muscle, liver an others. Our results showed that doxorubicin causes hyperglycemia, and insulin resistance in skeletal muscle, with decreased in the protein and phosphorylation protein levels of AMP protein kinase in skeletal muscle. This enzyme has central role in regulation of oxidative metabolism, and glucose uptake without insulin. The healthy quality, life expectant and efficiency of chemotherapy are prejudiced by side effects of doxorubicin treatment. A lack of studies that investigate the metabolic disorders the doxorubicin treatment in skeletal muscle and adipose tissue. The main of this project is investigate the role of doxorubicin in glucose uptake, and insulin sensitivity in skeletal muscle and adipose tissue and investigate the effect of physical training and metformin, that are two stimuli to glucose uptake, by increased the activity the AMPK, and validity these treatments as such adjuvant therapy in doxorubicin treatment. The mices receive, intraperitoneal, six doses of doxorubicin, each 72 hours (2.5mg/kg body weight). The animals will are divided in: control group (without administration of drugs and training), doxorubicin group, doxorubicin plus physical training, and doxorubicin plus metformin (doses of 300mg/kg body weight, daily, administrated by gavage), starting with doxorubicin treatment. We evaluate the insulin sensitivity and glucose uptake in skeletal muscle (soleus), and retroperitoneal adipose tissue, and we will analyze the molecular response of the insulin and AMPK. (AU)

Scientific publications

(12)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

LIRA, FABIO S.; ANTUNES, BARBARA DE M. M.; SEELAENDER, MARILIA; ROSA NETO, JOSE C.. The therapeutic potential of exercise to treat cachexia. Current Opinion in Supportive and Palliative Care, v. 9, n. 4, p. 317-324, DEC 2015. (12/50079-0, 13/09367-4)

SANCHES SILVEIRA, LOREANA; MELLO ANTUNES, BARBARA DE MOURA; ARAUJO MINARI, ANDRE LUIS; THOMATIELI DOS SANTOS, RONALDO VAGNER; ROSA NETO, JOSE CESAR; LIRA, FABIO SANTOS. Macrophage Polarization: Implications on Metabolic Diseases and the Role of Exercise. CRITICAL REVIEWS IN EUKARYOTIC GENE EXPRESSION, v. 26, n. 2, p. 115-132, 2016. (14/08003-1, 13/25310-2, 13/09367-4, 14/01246-6)

BATATINHA, HELENA A. P.; LIMA, EDSON A.; TEIXEIRA, ALEXANDRE A. S.; SOUZA, CAMILA O.; BIONDO, LUANA A.; SILVEIRA, LOREANA S.; LIRA, FABIO S.; ROSA NETO, JOSE C.. Association Between Aerobic Exercise and Rosiglitazone Avoided the NAFLD and Liver Inflammation Exacerbated in PPAR-alpha Knockout Mice. Journal of Cellular Physiology, v. 232, n. 5, p. 1008-1019, MAY 2017. (13/25310-2, 13/09367-4, 14/01246-6)

BIONDO, LUANA A.; BATATINHA, HELENA A.; SOUZA, CAMILA O.; TEIXEIRA, ALEXANDRE A. S.; SILVEIRA, LOREANA S.; ALONSO-VALE, MARIA I.; OYAMA, LILA M.; ALVES, MICHELE J.; SEELAENDER, MARILIA; NETO, JOSE C. R.. Metformin Mitigates Fibrosis and Glucose Intolerance Induced by Doxorubicin in Subcutaneous Adipose Tissue. FRONTIERS IN PHARMACOLOGY, v. 9, MAY 8 2018. (12/50079-0, 13/09367-4)

ALVES DE LIMA, JR., EDSON; TEIXEIRA, ALEXANDRE ABILIO DE SOUZA; BIONDO, LUANA AMORIM; DINIZ, TIEGO APARECIDO; SILVEIRA, LOREANA SANCHES; COLETTI, DARIO; BUSQUETS RIUS, SILVIA; ROSA NETO, JOSE CESAR. Exercise Reduces the Resumption of Tumor Growth and Proteolytic Pathways in the Skeletal Muscle of Mice Following Chemotherapy. CANCERS, v. 12, n. 11, NOV 2020. (15/17068-2, 13/09367-4, 19/01244-7, 19/09854-9)

SILVEIRA, LOREANA S.; PIMENTEL, GUSTAVO D.; SOUZA, CAMILA O.; BIONDO, LUANA A.; TEIXEIRA, ALEXANDRE ABILIO S.; LIMA, EDSON A.; BATATINHA, HELENA A. P.; ROSA NETO, JOSE C.; LIRA, FABIO S.. Effect of an acute moderate-exercise session on metabolic and inflammatory profile of PPAR- knockout mice. Cell Biochemistry and Function, v. 35, n. 8, p. 510-517, DEC 2017. (13/09367-4, 14/01246-6, 13/10861-3, 13/04765-1, 13/25310-2)

LIRA, FABIO SANTOS; ESTEVES, ANDREA MACULANO; PIMENTEL, GUSTAVO DUARTE; ROSA, JOSE CESAR; FRANK, MIRIAM KANNEBLEY; MARIANO, MELISE OLIVEIRA; BUDNI, JOSIANE; QUEVEDO, JOAO; DOS SANTOS, RONALDO VAGNER; DE MELLO, MARCO TULIO. Sleep pattern and locomotor activity are impaired by doxorubicin in non-tumor-bearing rats. SLEEP SCIENCE, v. 9, n. 3, p. 232-235, JUL-SEP 2016. (13/09367-4)

DE LIMA, JR., EDSON A.; DE SOUSA, LUIS G. O.; TEIXEIRA, ALEXANDRE ABILIO DE S.; MARSHALL, ANDREA G.; ZANCHI, NELO E.; ROSA NETO, JOSE C.. Aerobic exercise, but not metformin, prevents reduction of muscular performance by AMPk activation in mice on doxorubicin chemotherapy. Journal of Cellular Physiology, v. 233, n. 12, p. 9652-9662, DEC 2018. (13/09367-4, 15/17068-2)

TEIXEIRA, ALEXANDRE ABILIO DE S.; LIRA, FABIO S.; PIMENTEL, GUSTAVO D.; DE SOUZA, CAMILA OLIVEIRA; BATATINHA, HELENA; BIONDO, LUANA A.; YAMASHITA, ALEX S.; LIMA JUNIOR, EDSON A.; ROSA NETO, JOSE C.. Aerobic Exercise Modulates the Free Fatty Acids and Inflammatory Response During Obesity and Cancer Cachexia. CRITICAL REVIEWS IN EUKARYOTIC GENE EXPRESSION, v. 26, n. 3, p. 187-198, 2016. (13/09367-4, 13/25310-2)

DE LIMA JUNIOR, EDSON ALVES; YAMASHITA, ALEX SHIMURA; PIMENTEL, GUSTAVO DUARTE; DE SOUSA, LUIS G. O.; SANTOS, RONALDO VAGNER T.; GONCALVES, CINARA LUDVIG; STRECK, EMILIO LUIZ; DE LIRA, FABIO SANTOS; ROSA NETO, JOSE CESAR. Doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscle. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, v. 7, n. 5, p. 615-625, DEC 2016. (13/09367-4)

DE SOUZA TEIXEIRA, ALEXANDRE ABILIO; SOUZA, CAMILA O.; BIONDO, LUANA A.; SILVEIRA, LOREANA SANCHES; LIMA, EDSON A.; BATATINHA, HELENA A.; ARAUJO, ADRIANE PEREIRA; ALVES, MICHELE JOANA; HIRABARA, SANDRO MASSAO; CURI, RUI; et al. Short-term treatment with metformin reduces hepatic lipid accumulation but induces liver inflammation in obese mice. INFLAMMOPHARMACOLOGY, v. 26, n. 4, p. 1103-1115, AUG 2018. (15/16777-0, 13/09367-4, 16/01409-8)

BIONDO, LUANA AMORIM; LIMA JUNIOR, EDSON ALVES; SOUZA, CAMILA OLIVEIRA; CRUZ, MAYSA MARIANA; CUNHA, ROBERTA D. C.; ALONSO-VALE, MARIA ISABEL; OYAMA, LILA MISSAE; OLLER NASCIMENTO, CLAUDIA M.; PIMENTEL, GUSTAVO DUARTE; DOS SANTOS, RONALDO V. T.; et al. Impact of Doxorubicin Treatment on the Physiological Functions of White Adipose Tissue. PLoS One, v. 11, n. 3, MAR 25 2016. (13/09367-4)