期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 319, 期 3, 页码 C541-C551出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00233.2020
关键词
let-7b; Lin28a; PPAR delta; skeletal muscle cells
资金
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2013/22733-0, 2016/23008-5]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [473897/2011-3, 444323/2014]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
- National Institutes of Health (National Heart, Lung, and Blood Institute) [1R01HL129191]
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.
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