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.
Highlights
An imbalance between energy intake and energy expenditure can lead to obesity, which presents adipose tissue expansion and fat accumulation in non-adipose tissues, such as skeletal muscle, leading to the development of insulin resistance (IR) in this tissue [1]
Mice fed with high-fat diet (HFD) showed augment of body weight gain, weights of adipose depots, fasting insulin levels, HOMA-IR, constant of glucose disapearance (Kitt), the area under the curve (AUC) of Glucose tolerance test (GTT), and so IR and glucose intolerance conditions were established already after 4 weeks (Table 2; Figures 1A,B)
Glucose metabolism and insulin responsiveness were investigated in soleus muscle that is rich in oxidative (I and IIa type) fibers [26] (Figures 1C–L)
Summary
An imbalance between energy intake and energy expenditure can lead to obesity, which presents adipose tissue expansion and fat accumulation in non-adipose tissues, such as skeletal muscle, leading to the development of insulin resistance (IR) in this tissue [1]. MyomiRs, Myogenesis, and Insulin Resistance muscle constitutes about 40% of total body weight and accounts for about 80% of the insulin-stimulated postprandial glucose utilization [2], this tissue is the major player in the development of IR and type 2 diabetes [3]. The treatment with insulin sensitizer can attenuate or even prevent the progressive loss of skeletal muscle mass and the establishment of sarcopenia in type 2 diabetic patients [4]. The myogenic regulatory factors (MRFs) that include myogenin, Murf, Myf, and MyoD, and members of the MEF2 family, essentially control skeletal muscle development (myogenesis) process. Various extracellular stimuli and distinct signaling pathways modulate expression of the MRFs. the insulin-growth factor (IGF)-1/phosphatidylinositol 3-kinase (PI3K)/AKT/MTOR is the main signaling pathway involved in skeletal differentiation and growth [5]. The IGF-1R signaling pathway plays a central role in muscle cell development
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