MyomiRs as Markers of Insulin Resistance and Decreased Myogenesis in Skeletal Muscle of Diet-Induced Obese Mice

Abstract

High-fat diet (HFD) feeding causes insulin resistance (IR) in skeletal muscle of mice, which affects skeletal muscle metabolism and function. The involvement of muscle-specific microRNAs in the evolution of skeletal muscle IR during 4, 8, and 12 weeks in HFD-induced obese mice was investigated. After 4 weeks in HFD, mice were obese, hyperglycemic, and hyperinsulinemic; however, their muscles were responsive to insulin stimuli. Expressions of MyomiRs (miR-1, miR-133a, and miR-206) measured in soleus muscles were not different from those found in control mice. After 8 weeks of HFD feeding, glucose uptake was lower in skeletal muscle from obese mice compared to control mice, and we observed a significant decrease in miR-1a in soleus muscle when compared to HFD for 4 weeks. miR-1a expression continued to decay within time. After 12 weeks of HFD, miR-133a expression was upregulated when compared to the control group. Expression of miR-1a was negatively correlated with glycemia and positively correlated with the constant rate of plasma glucose disappearance. Pioglitazone treatment could not reverse decreases of miR-1a levels induced by HFD. Targets of myomiRs involved in insulin-growth factor (IGF)-1 pathway, such as Igf-1, Irs-1, Rheb, and follistatin, were reduced after 12 weeks in HFD and Mtor increased, when compared to the control or HFD for 4 or 8 weeks. These findings suggest for the first time that miR-1 may be a marker of the development of IR in skeletal muscle. Evidence was also presented that impairment in myomiRs expression contributes to decreased myogenesis and skeletal muscle growth reported in diabetes.

Fenofibrate reverses changes induced by high‐fat diet on metabolism in mice muscle and visceral adipocytes

“…Next, as an attempt to understand post‐transcriptional regulation affecting glucose and fatty acids metabolism signaling paths, we decided to evaluate microRNAs expression proposed to play a role in insulin signaling (let‐7b, miR‐29b, and miR‐23b) and obesity (miR‐143). As well as myomiRs (miR‐1a, miR‐206, and miR‐133a/b), previously found to be downregulated in soleus muscle of high‐fat diet fed mice (Frias Fde et al, ).…”

“…MicroRNAs expression were performed by Stem Loop RT‐qPCR technique using TaqMan microRNA Assays (Thermo Fisher Scientific): hsa‐miR‐1 (002222), hsa‐miR‐206 (000510), hsa‐miR‐133a (002246), hsa‐miR‐133b (002247), hsa‐let‐7b (002619), hsa‐miR‐29b (000413), has‐miR‐23b (000400), hsa‐miR‐143 (002249), hsa‐miR‐103 (00439), snoRNA‐202 (001232), and snoRNA‐234 (001234). Transcript levels were measured by RT‐qPCR, as previously described (Frias Fde et al, ). Primer sequences are available in Supplementary Table S1.…”

Role of microRNAs on the Regulation of Mitochondrial Biogenesis and Insulin Signaling in Skeletal Muscle

“…Muscle‐specific knockout mice for Lin28a and transgenic mice overexpressing miRlet‐7, showed severe glucose intolerance suggesting that the Lin28/let‐7 pathway plays an important role in regulating the glucose metabolism in the skeletal muscle (Zhu et al, ). Frias Fde et al () investigating the effect of HFD feeding over insulin response and metabolism in the skeletal muscle of diet‐induced obese mice observed a significant decrease in miR‐1a and increase in miR‐133a expression in the soleus muscle compared to the controls. More interestingly, miR‐1a was negatively correlated with glycemia and targets of miR‐1a including IGF‐1, IRS‐1, Rheb, and follistatin, were markedly reduced suggesting that miR‐1 may be a marker for the development of IR in skeletal muscles.…”

“…This role of Lin28a is, at least in part, due to reduced let-7 expression and increased insulin-PI3K-mTOR signaling. Muscle-specific knockout mice for Lin28a and transgenic mice overexpressing miRlet-7, showed severe glucose intolerance suggesting that the Lin28/ let-7 pathway plays an important role in regulating the glucose metabolism in the skeletal muscle (Zhu et al, 2011). Frias Fde et al (2016 investigating the effect of HFD feeding over insulin response and metabolism in the skeletal muscle of diet-induced obese mice observed a significant decrease in miR-1a and increase in miR-133a expression in the soleus muscle compared to the controls.…”

Regulation of Gene Expression by Exercise-Related Micrornas

“…MiR-7 has been suggested to be involved in the pathogenesis of myocardial infarction and heart failure [59], miR-155 in the inflammatory process of the atherosclerosis via SOCS-1 activation in macrophages [60], and miR-378 in the cytokine-induced inflammation through SREBP and C/EBP pathaway in adipose tissue [61]. MiR-103 and miR-107 negatively regulate insulin sensitivity in liver from animal experimental models and patients with insulin resistance [62,63], whereas miR-1 has been positively related to the insulin sensitivity and miR-106b, -27a, and -30d negatively to the GLUT-4 expression in skeletal muscle cells from animal and cellular models [64,65]. MiRs also play an important role in skeletal muscle function [66,67].…”