Busca avançada
Ano de início
Entree
(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

The MicroRNA miR-696 is regulated by SNARK and reduces mitochondrial activity in mouse skeletal muscle through Pgc1 alpha inhibition

Texto completo
Autor(es):
Mostrar menos -
Queiroz, Andre L. [1, 2, 3] ; Lessard, Sarah J. [2, 3] ; Ouchida, Amanda T. [1] ; Araujo, Hygor N. [4] ; Goncalves, Dawit A. [1] ; Guimaraes, Dimitrius Santiago P. Simoes Frees [4] ; Teodoro, Bruno G. [1, 5] ; So, Kawai [2, 3] ; Esprea, Enilza M. [6] ; Hirshman, Michael F. [2, 3] ; Alberici, Luciane C. [5] ; Kettelhut, Isis do Carmo [1] ; Goodyear, Laurie J. [2, 3] ; Silveira, Leonardo R. [4]
Número total de Autores: 14
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, Ribeirao Preto - Brazil
[2] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 - USA
[3] Harvard Med Sch, Brigham & Womens Hosp, Joslin Diabet Ctr, Res Div, Boston, MA 02115 - USA
[4] Univ Estadual Campinas, Obes & Comorbid Res Ctr, OCRC, IB, Campinas - Brazil
[5] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Phys & Chem, Ribeirao Preto - Brazil
[6] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Cell Biol, Ribeirao Preto - Brazil
Número total de Afiliações: 6
Tipo de documento: Artigo Científico
Fonte: MOLECULAR METABOLISM; v. 51, SEP 2021.
Citações Web of Science: 0
Resumo

Objective: MicroRNAs (miRNA) are known to regulate the expression of genes involved in several physiological processes including metabolism, mitochondrial biogenesis, proliferation, differentiation, and cell death. Methods: Using ``in silico{''} analyses, we identified 219 unique miRNAs that potentially bind to the 3'UTR region of a critical mitochondrial regulator, the peroxisome proliferator-activated receptor gamma coactivator (PGC) 1 alpha (Pgc1 alpha). Of the 219 candidate miRNAs, miR-696 had one of the highest interactions at the 3'UTR of Pgc1 alpha, suggesting that miR-696 may be involved in the regulation of Pgc1 alpha. Results: Consistent with this hypothesis, we found that miR-696 was highly expressed in the skeletal muscle of STZ-induced diabetic mice and chronic high-fat-fed mice. C2C12 muscle cells exposed to palmitic acid also exhibited a higher expression of miR-696. This increased expression corresponded with a reduced expression of oxidative metabolism genes and reduced mitochondrial respiration. Importantly, reducing miR-696 reversed decreases in mitochondrial activity in response to palmitic acid. Using C2C12 cells treated with the AMP-activated protein kinase (AMPK) activator AICAR and skeletal muscle from AMPK alpha 2 dominant-negative (DN) mice, we found that the signaling mechanism regulating miR-696 did not involve AMPK. In contrast, overexpression of SNF1-AMPK-related kinase (SNARK) in C2C12 cells increased miR-696 transcription while knockdown of SNARK significantly decreased miR-696. Moreover, muscle-specific transgenic mice overexpressing SNARK exhibited a lower expression of Pgc1 alpha, elevated levels of miR-696, and reduced amounts of spontaneous activity. Conclusions: Our findings demonstrate that metabolic stress increases miR-696 expression in skeletal muscle cells, which in turn inhibits Pgc1 alpha, reducing mitochondrial function. SNARK plays a role in this process as a metabolic stress signaling molecule inducing the expression of miR-696. (C) 2021 The Authors. Published by Elsevier GmbH. (AU)

Processo FAPESP: 13/22733-0 - Controle da função mitocondrial por micro-RNAs em células musculares resistentes a insulina: efeito da superexpressão e inibição do miR-696 e miR-let7b
Beneficiário:Leonardo dos Reis Silveira
Modalidade de apoio: Auxílio à Pesquisa - Regular