Influência do análogo de GLP-1 na musculatura esquelética de ratos tratados agudamente com doxorrubicina
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Data
2023-04-27
Autores
Luciano, Danilo Malmonge Barbosa
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Universidade Estadual Paulista (Unesp)
Resumo
A Doxorrubicina é um quimioterápico altamente efetivo no tratamento de tumores hematológicos e sólidos. No entanto, apresenta efeitos colaterais no sistema cardíaco e na musculatura esquelética, condição resultante de inúmeras alterações, dentre elas, o aumento do estresse oxidativo, da inflamação e disfunções mitocondriais. Análogos de GLP-1 podem prevenir a degeneração muscular, atenuar a inflamação, modular o metabolismo e reduzir a atrofia muscular. O objetivo do estudo foi avaliar a influência da administração análogo de GLP-1 liraglutida na musculatura esquelética de ratos tratados agudamente com doxorrubicina. Para isso, foram utilizados 60 ratos Wistar machos, divididos em 4 grupos com 15 animais cada: Controle (C), Doxorrubicina (D), administração de liraglutida (análogo de GLP-1) (LG) e Doxorrubicina + administração de liraglutida (DLG). Os grupos LG e DL receberam liraglutida 0,6mg/kg, subcutâneo, diariamente por 14 dias, e os grupos C e D receberam soro fisiológico. Após 12 dias, os grupos D e DLG receberam injeção intraperitoneal de doxorrubicina 20mg/kg, dose única, e os grupos C e LG receberam soro fisiológico. Após 48 horas da injeção de doxorrubicina, os animais foram submetidos à eutanásia e foram coletados músculo sóleo e gastrocnêmio (porção branca e vermelha). Foram avaliados na musculatura esquelética o estresse oxidativo, e quantificação das proteínas Sirt1, PGC1-α e PPARϫ (envolvidas na biogênese mitocondrial), e também NF-kB, GLUT-4 e Troponina T por Western blot. Os resultados foram analisados por ANOVA de uma via e foi considerado o nível de significância estatística de 5%. Observamos menor ingestão de ração e ganho de peso nos animais que receberam liraglutida. Após a injeção de doxorrubicina, os animais que receberam o quimioterápico também tiveram redução da ingestão de ração e do peso corporal. Em relação ao estresse oxidativo, os grupos D e DLG apresentaram maior atividade da catalase no tecido muscular quando comparados ao grupo C e o grupo DLG apresentou menor carbonilação proteica que o grupo C. Não observamos diferenças na expressão proteica de Sirt1, PGC1-α, PPARϫ, NF-kB, GLUT-4 e Troponina T, apesar de observarmos tendência de diminuição de troponina T no grupo D em relação aos outros grupos. Em conclusão, a doxorrubicina não foi capaz de aumentar o estresse oxidativo na musculatura esquelética periférica e não modificou a quantidade de proteínas relacionadas ao funcionamento mitocondrial em ratos tratados com o quimioterápico. Portanto, o efeito da liraglutida na atenuação do dano ao músculo periférico induzido pela doxorrubicina permanece por ser esclarecido.
Doxorubicin is a highly effective chemotherapeutic in the treatment of hematological and solid tumors. However, it has side effects on the cardiac system and skeletal muscles, a condition resulting from numerous changes, including increased oxidative stress, inflammation and mitochondrial dysfunction. GLP-1 analogues can prevent muscle degeneration, attenuate inflammation, modulate metabolism and reduce muscle atrophy. The aim of the study was to evaluate the influence of the administration of the GLP-1 analogue liraglutide in the skeletal muscles of rats acutely treated with doxorubicin. For this, 60 male Wistar rats were divided into 4 groups (15 rats each group): Control (C), Doxorubicin (D), administration of Liraglutide (LG) and Doxorubicin + administration of Liraglutide (DLG). LG and DL groups received liraglutide 0.6mg/kg, subcutaneously, daily for 14 days, and groups C and D received saline solution. After 12 days, groups D and DLG received intraperitoneal injection of doxorubicin 20mg/kg, single dose, and groups C and LG received saline solution. After 48 hours of doxorubicin injection, the animals were euthanized and soleus and gastrocnemius muscle (white and red portion) were collected. Oxidative stress and quantification of Sirt1, PGC1-α, PPARϫ, NF-kB, GLUT-4 and Troponin T by Western blot were evaluated in skeletal muscle. The results were analyzed by one-way ANOVA and a statistical significance level of 5% was considered. We observed a decrease in chow intake and weight gain in the animals treated with liraglutide. After doxorubicin administration, animals that received the drug decreased body weight and chow ingestion too. Regarding oxidative stress, the D and DLG groups showed higher catalase activity in muscle tissue when compared to the C group and the DLG group showed less protein carbonylation than the C group. We did not observe differences in Sirt1, PGC1-α, PPARϫ, NF-kB, GLUT-4 and Troponin T protein expression, although we observed a trend towards a decrease in troponin T in group D compared to the other groups. In conclusion, doxorubicin was not able to increase oxidative stress in peripheral skeletal muscles and did not modify the proteins related to mitochondrial functioning in rats treated with chemotherapy. Therefore, the effect of liraglutide in attenuating peripheral muscle damage induced by doxorubicin remains to be clarified. Keywords: doxorubicin, GLP-1 analogue, mitochondria, skeletal muscle
Doxorubicin is a highly effective chemotherapeutic in the treatment of hematological and solid tumors. However, it has side effects on the cardiac system and skeletal muscles, a condition resulting from numerous changes, including increased oxidative stress, inflammation and mitochondrial dysfunction. GLP-1 analogues can prevent muscle degeneration, attenuate inflammation, modulate metabolism and reduce muscle atrophy. The aim of the study was to evaluate the influence of the administration of the GLP-1 analogue liraglutide in the skeletal muscles of rats acutely treated with doxorubicin. For this, 60 male Wistar rats were divided into 4 groups (15 rats each group): Control (C), Doxorubicin (D), administration of Liraglutide (LG) and Doxorubicin + administration of Liraglutide (DLG). LG and DL groups received liraglutide 0.6mg/kg, subcutaneously, daily for 14 days, and groups C and D received saline solution. After 12 days, groups D and DLG received intraperitoneal injection of doxorubicin 20mg/kg, single dose, and groups C and LG received saline solution. After 48 hours of doxorubicin injection, the animals were euthanized and soleus and gastrocnemius muscle (white and red portion) were collected. Oxidative stress and quantification of Sirt1, PGC1-α, PPARϫ, NF-kB, GLUT-4 and Troponin T by Western blot were evaluated in skeletal muscle. The results were analyzed by one-way ANOVA and a statistical significance level of 5% was considered. We observed a decrease in chow intake and weight gain in the animals treated with liraglutide. After doxorubicin administration, animals that received the drug decreased body weight and chow ingestion too. Regarding oxidative stress, the D and DLG groups showed higher catalase activity in muscle tissue when compared to the C group and the DLG group showed less protein carbonylation than the C group. We did not observe differences in Sirt1, PGC1-α, PPARϫ, NF-kB, GLUT-4 and Troponin T protein expression, although we observed a trend towards a decrease in troponin T in group D compared to the other groups. In conclusion, doxorubicin was not able to increase oxidative stress in peripheral skeletal muscles and did not modify the proteins related to mitochondrial functioning in rats treated with chemotherapy. Therefore, the effect of liraglutide in attenuating peripheral muscle damage induced by doxorubicin remains to be clarified. Keywords: doxorubicin, GLP-1 analogue, mitochondria, skeletal muscle
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Palavras-chave
Doxorrubicina, Análogo GLP-1, Mitocôndria, Músculo esquelético, Estresse oxidativo