The MicroRNA miR-696 is regulated by SNARK and reduces mitochondrial activity in mouse skeletal muscle through Pgc1α inhibition.

Autor:	Queiroz AL; Department of Biochemistry and Immunology, Ribeirão Preto Medical School, USP, Ribeirão Preto, Brazil; Research Division, Joslin Diabetes Center, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Lessard SJ; Research Division, Joslin Diabetes Center, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Ouchida AT; Department of Biochemistry and Immunology, Ribeirão Preto Medical School, USP, Ribeirão Preto, Brazil., Araujo HN; Obesity and Comorbidities Research Center, OCRC, IB, UNICAMP, Campinas, Brazil., Gonçalves DA; Department of Biochemistry and Immunology, Ribeirão Preto Medical School, USP, Ribeirão Preto, Brazil., Simões Fróes Guimarães DSP; Obesity and Comorbidities Research Center, OCRC, IB, UNICAMP, Campinas, Brazil., Teodoro BG; Department of Biochemistry and Immunology, Ribeirão Preto Medical School, USP, Ribeirão Preto, Brazil; Department of Physics and Chemistry, Faculty of Pharmaceutical Science, USP, Ribeirão Preto, Brazil., So K; Research Division, Joslin Diabetes Center, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Espreafico EM; Department of Cell Biology, Ribeirão Preto Medical School, USP, Ribeirão Preto, Brazil., Hirshman MF; Research Division, Joslin Diabetes Center, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Alberici LC; Department of Physics and Chemistry, Faculty of Pharmaceutical Science, USP, Ribeirão Preto, Brazil., Kettelhut IDC; Department of Biochemistry and Immunology, Ribeirão Preto Medical School, USP, Ribeirão Preto, Brazil., Goodyear LJ; Research Division, Joslin Diabetes Center, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: Laurie.Goodyear@joslin.harvard.edu., Silveira LR; Obesity and Comorbidities Research Center, OCRC, IB, UNICAMP, Campinas, Brazil. Electronic address: leors@unicamp.br.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2021 Sep; Vol. 51, pp. 101226. Date of Electronic Publication: 2021 Mar 31.
DOI:	10.1016/j.molmet.2021.101226
Abstrakt:	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 (Pgc1α). Of the 219 candidate miRNAs, miR-696 had one of the highest interactions at the 3'UTR of Pgc1α, suggesting that miR-696 may be involved in the regulation of Pgc1α. 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 AMPKα2 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 Pgc1α, 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 Pgc1α, reducing mitochondrial function. SNARK plays a role in this process as a metabolic stress signaling molecule inducing the expression of miR-696. (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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