Regulation of Lin28a-miRNA let-7b-5p pathway in skeletal muscle cells by peroxisome proliferator-activated receptor delta

Autor(es):Mostrar menos -

Araujo, Hygor N. ^[1] ; Lima, I, Tanes ; Guimaraes, Dimitrius Santiago P. S. F. ^[2] ; Oliveira, Andre G. ^[2] ; Favero-Santos, Bianca C. ^[2] ; Branco, Renato C. S. ^[2] ; da Silva Araujo, Rafaela Mariano ^[2] ; Dantas, Alvaro F. B. ^[2] ; Castro, Alex ^[3] ; Chacon-Mikahil, Mara Patricia T. ^[3] ; Minatel, Elaine ^[4] ; Geraldo, V, Murilo ; Carneiro, Everardo Magalhaes ^[2] ; Rodrigues, Alice C. ^[5] ; Narkar, Vihang A. ^[6] ; Silveira, Leonardo R. ^[2]

Afiliação do(s) autor(es)

^[1] Obes & Comorbid Res Ctr OCRC, Campinas - Brazil

^[2] Lima, Tanes, I, Obes & Comorbid Res Ctr OCRC, Campinas - Brazil

^[3] Univ Estadual Campinas, Sch Phys Educ, Lab Exercise Physiol, Campinas - Brazil

^[4] V, Univ Estadual Campinas, Inst Biol, Dept Struct & Funct Biol, UNICAMP, Campinas - Brazil

^[5] Univ Sao Paulo, Dept Pharmacol, Sao Paulo - Brazil

^[6] Univ Texas Hlth McGovern Med Sch, Inst Mol Med, Houston, TX 77030 - USA

• Tipo de documento: Artigo Científico
• Fonte: AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY; v. 319, n. 3, p. C541-C551, SEP 2020.
• Citações Web of Science: 0

Resumo

Lin28a/miRNA let-7b-5p pathway has emerged as a key regulators of energy homeostasis in the skeletal muscle. However, the mechanism through which this pathway is regulated in the skeletal muscle has remained unclear. We have found that 8 wk of aerobic training (Tr) markedly decreased let-7b-5p expression in murine skeletal muscle, whereas high-fat diet (Hfd) increased its expression. Conversely, Lin28a expression. a well-known inhibitor of let-7b-5p, was induced by Tr and decreased by Hfd. Similarly, in human muscle biopsies, Tr increased LIN28 expression and decreased let-76-5p expression. Bioinformatics analysis of LIN28a DNA sequence revealed that its enrichment in peroxisome proliferator-activated receptor delta (PPAR delta) binding sites, which is a well-known metabolic regulator of exercise. Treatment of primary mouse skeletal muscle cells or C2C12 cells with PPAR delta activators GW501516 and AICAR increased Lin28a expression. Lin28a and let-7b-5p expression was also regulated by PPAR delta coregulators. While PPAR gamma coactivator-1 alpha (PGC1 alpha) increased Lin28a expression. corepressor NCoR1 decreased its expression. Furthermore, PGC1 alpha markedly reduced the let-7b-5p expression. PGC1 alpha-mediated induction of Lin28a expression was blocked by the PPAR delta inhibitor GSK0660. In agreement, Lin28a expression was downregulated in PPAR delta knocked-clown cells leading to increased let-7b-5p expression. Finally, we show that modulation of the Lin28a-let-76-5p pathway in muscle cells leads to changes in mitochondrial metabolism in PGC1 alpha dependent fashion. In summary, we demonstrate that Lin28a-let-7b-5p is a direct target of PPAR delta in the skeletal muscle, where it impacts mitochondrial respiration. (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
• Processo FAPESP: 16/23008-5 - Identificação e caracterização funcional de proteína do complexo NCoR1 associada ao controle molecular do processo de biogênese mitocondrial
• Beneficiário: Leonardo dos Reis Silveira
• Modalidade de apoio: Auxílio à Pesquisa - Temático