Intramuscular Injection of miR-1 Reduces Insulin Resistance in Obese Mice

Abstract

The role of microRNAs in metabolic diseases has been recognized and modulation of them could be a promising strategy to treat obesity and obesity-related diseases. The major purpose of this study was to test the hypothesis that intramuscular miR-1 precursor replacement therapy could improve metabolic parameters of mice fed a high-fat diet. To this end, we first injected miR-1 precursor intramuscularly in high-fat diet-fed mice and evaluated glucose tolerance, insulin sensitivity, and adiposity. miR-1-treated mice did not lose weight but had improved insulin sensitivity measured by insulin tolerance test. Next, using an in vitro model of insulin resistance by treating C2C12 cells with palmitic acid (PA), we overexpressed miR-1 and measured p-Akt content and the transcription levels of a protein related to fatty acid oxidation. We found that miR-1 could not restore insulin sensitivity in C2C12 cells, as indicated by p-Akt levels and that miR-1 increased expression of Pgc1a and Cpt1b in PA-treated cells, suggesting a possible role of miR-1 in mitochondrial respiration. Finally, we analyzed mitochondrial oxygen consumption in primary skeletal muscle cells treated with PA and transfected with or without miR-1 mimic. PA-treated cells showed reduced basal respiration, oxygen consumption rate-linked ATP production, maximal and spare capacity, and miR-1 overexpression could prevent impairments in mitochondrial respiration. Our data suggest a role of miR-1 in systemic insulin sensitivity and a new function of miR-1 in regulating mitochondrial respiration in skeletal muscle.

Identification of potential miRNA-mRNA regulatory network and the key miRNAs in intramuscular and subcutaneous adipose

“…According to the order of expression, the top 10 miRNAs were taken from IMF and SCF, respectively ( Supplementary Table 2 ). Among them, miR-26, let-7, miR-27, and miR-1 families play important roles in adipogenic differentiation and lipid metabolism ( 30 , 37 – 39 ).…”

Impact of Exercise and Aging on Mitochondrial Homeostasis in Skeletal Muscle: Roles of ROS and Epigenetics

“…Russell et al [118] demonstrated that exercise not only upregulates the expression level of myomiRs, but can also increase the expression of miRNA maturation-related proteins such as Drosha, Dicer, and exportin-5. Rodrigues et al [119] demonstrated by skeletal muscle injection of miR-1 that miR-1 overexpression can activate p-AMPK, upregulate PGC-1α and carnitine palmitoyltransferase 1b protein expression, and improve skeletal muscle mitochondrial biogenesis and skeletal muscle oxidative metabolism. Nie et al [101] demonstrated that 6 weeks of endurance exercise increased the level of miR-133a and increased the expression of the mitochondrial biogenesis regulators PGC-1α, peroxisome proliferative activated receptor gamma coactivator-1β (PGC-1β), NRF1, and TFAM in skeletal muscle of wild-type mice, followed by upregulation of mitochondrial biogenesis.…”

Extracellular Vesicles as Novel Drug-Delivery Systems through Intracellular Communications

“…Lipid compositions in exosomes, which are commonly enriched with cholesterol and sphingomyelin, and minimal amounts of lecithin and phosphatidylethanolamine, primarily depend on exosome-producing cells [58][59][60][61][62]. Furthermore, it has been revealed that lean mice become insulin resistant due to the administration of exosomes isolated from the feces of obese mice that were fed a high-fat diet (HFD) and of type II diabetic patients [63][64][65]. An HFD alters the lipid composition of exosomes [63].…”