Regulation of Lin28a-miRNA let-7b-5p pathway in skeletal muscle cells by peroxisome proliferator-activated receptor delta
| Autor: | Dimitrius Santiago P.S.F. Guimarães, Leonardo R. Silveira, Hygor N. Araujo, Renato Chaves Souto Branco, Alex Castro, Tanes I. Lima, André Gustavo de Oliveira, Alice Cristina Rodrigues, Murilo Vieira Geraldo, R. Araújo, Mara Patrícia Traina Chacon-Mikahil, Alvaro F B Dantas, Bianca Cristine Favero-Santos, Vihang A. Narkar, Everardo M. Carneiro, Elaine Minatel |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Physiology Chemistry Skeletal muscle Cell Biology medicine.disease Cell biology GW501516 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure 030220 oncology & carcinogenesis microRNA medicine Myocyte Peroxisome proliferator-activated receptor delta INIBIDORES DE ENZIMAS Receptor C2C12 Corepressor |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| Popis: | 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-7b-5p expression. Bioinformatics analysis of LIN28a DNA sequence revealed that its enrichment in peroxisome proliferator-activated receptor delta (PPARδ) binding sites, which is a well-known metabolic regulator of exercise. Treatment of primary mouse skeletal muscle cells or C2C12 cells with PPARδ activators GW501516 and AICAR increased Lin28a expression. Lin28a and let-7b-5p expression was also regulated by PPARδ coregulators. While PPARγ coactivator-1α (PGC1α) increased Lin28a expression, corepressor NCoR1 decreased its expression. Furthermore, PGC1α markedly reduced the let-7b-5p expression. PGC1α-mediated induction of Lin28a expression was blocked by the PPARδ inhibitor GSK0660. In agreement, Lin28a expression was downregulated in PPARδ knocked-down cells leading to increased let-7b-5p expression. Finally, we show that modulation of the Lin28a- let-7b-5p pathway in muscle cells leads to changes in mitochondrial metabolism in PGC1α dependent fashion. In summary, we demonstrate that Lin28a- let-7b-5p is a direct target of PPARδ in the skeletal muscle, where it impacts mitochondrial respiration. |
| Databáze: | OpenAIRE |
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