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Exercise Training-Induced Changes in MicroRNAs: Beneficial Regulatory Effects in Hypertension, Type 2 Diabetes, and Obesity.

ABSTRACT: MicroRNAs are small non-coding RNAs that regulate gene expression post-transcriptionally. They are involved in the regulation of physiological processes, such as adaptation to physical exercise, and also in disease settings, such as systemic arterial hypertension (SAH), type 2 diabetes mellitus (T2D), and obesity. In SAH, microRNAs play a significant role in the regulation of key signaling pathways that lead to the hyperactivation of the renin-angiotensin-aldosterone system, endothelial dysfunction, inflammation, proliferation, and phenotypic change in smooth muscle cells, and the hyperactivation of the sympathetic nervous system. MicroRNAs are also involved in the regulation of insulin signaling and blood glucose levels in T2D, and participate in lipid metabolism, adipogenesis, and adipocyte differentiation in obesity, with specific microRNA signatures involved in the pathogenesis of each disease. Many studies report the benefits promoted by exercise training in cardiovascular diseases by reducing blood pressure, glucose levels, and improving insulin signaling and lipid metabolism. The molecular mechanisms involved, however, remain poorly understood, especially regarding the participation of microRNAs in these processes. This review aimed to highlight microRNAs already known to be associated with SAH, T2D, and obesity, as well as their possible regulation by exercise training.

SUBMITTER: Improta Caria AC

PROVIDER: S-EPMC6275070 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Exercise Training-Induced Changes in MicroRNAs: Beneficial Regulatory Effects in Hypertension, Type 2 Diabetes, and Obesity.

Improta Caria Alex Cleber AC Nonaka Carolina Kymie Vasques CKV Pereira Ciro Silveira CS Soares Milena Botelho Pereira MBP Macambira Simone Garcia SG Souza Bruno Solano de Freitas BSF

International journal of molecular sciences 20181115 11

MicroRNAs are small non-coding RNAs that regulate gene expression post-transcriptionally. They are involved in the regulation of physiological processes, such as adaptation to physical exercise, and also in disease settings, such as systemic arterial hypertension (SAH), type 2 diabetes mellitus (T2D), and obesity. In SAH, microRNAs play a significant role in the regulation of key signaling pathways that lead to the hyperactivation of the renin-angiotensin-aldosterone system, endothelial dysfunct ...[more]

PMID: 30445764

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Project description:New findingsWhat is the central question of this study? Is 1 week of exercise training sufficient to reduce local and systemic inflammation? Do obesity and short-term concurrent aerobic and resistance exercise training alter skeletal muscle extracellular vesicle (EV) contents? What is the main finding and its importance? Obesity alters skeletal muscle small EV microRNAs targeting inflammatory and growth pathways. Exercise training alters skeletal muscle small EV microRNAs targeting inflammatory pathways, indicative of reduced inflammation. Our findings provide support for the hypotheses that EVs play a vital role in intercellular communication during health and disease and that EVs mediate many of the beneficial effects of exercise.AbstractObesity is associated with chronic inflammation characterized by increased levels of inflammatory cytokines, whereas exercise training reduces inflammation. Small extracellular vesicles (EVs; 30-150 nm) participate in cell-to-cell communication in part through microRNA (miRNA) post-transcriptional regulation of mRNA. We examined whether obesity and concurrent aerobic and resistance exercise training alter skeletal muscle EV miRNA content and inflammatory signalling. Vastus lateralis biopsies were obtained from sedentary individuals with (OB) and without obesity (LN). Before and after 7 days of concurrent aerobic and resistance training, muscle-derived small EV miRNAs and whole-muscle mRNAs were measured. Pathway analysis revealed that obesity alters small EV miRNAs that target inflammatory (SERPINF1, death receptor and Gαi ) and growth pathways (Wnt/β-catenin, PTEN, PI3K/AKT and IGF-1). In addition, exercise training alters small EV miRNAs in an anti-inflammatory manner, targeting the IL-10, IL-8, Toll-like receptor and nuclear factor-κB signalling pathways. In whole muscle, IL-8 mRNA was reduced by 50% and Jun mRNA by 25% after exercise training, consistent with the anti-inflammatory effects of exercise on skeletal muscle. Obesity and 7 days of concurrent exercise training differentially alter skeletal muscle-derived small EV miRNA contents targeting inflammatory and anabolic pathways.

Project description:Experiment protocol: Experiment was performed on 10 to 15 weeks old male NMRI mice (Harlan, Holland) housed in standard conditions (temperature 22°C, humidity 60 ± 10 %, artificial light from 8.00 am to 8.00 pm, normally 5 animals per cage). Animals had free access to tap water and food pellets (R36, Labfor, Stockholm, Sweden). Animals were randomly divided into healthy and diabetic groups. The diabetic group received a single peritoneal injection of streptozotocin (STZ, Sigma-Aldrich, France, 180 mg/kg) dissolved in sodium citrate buffer solution (0.1 mol/l, pH 4.5) to induce experimental diabetes similar to type 1. The other group received injection of an equal volume of buffer. Diabetes was confirmed 72 hours after the injection by urine glucose testing (Glukotest(r), Roche, Germany), and mice were characterized diabetic when urine glucose values were greater than 200 mg/dl. Diabetic and healthy animals were randomly assigned into 12 groups (n = 5 per group), which were sedentary or trained for one, three or five weeks. Training groups performed 1 hour per day of treadmill running at 21 m/min and 2.5° incline. After one day of familiarization on a rodent treadmill, the mice ran as described above 5 days per week. Mice were sacrificed 24 hours after the last training bout (respective sedentary controls at the same time) by cervical dislocation followed by decapitation. Calf muscles were removed, dissected free of fat and connective tissue, weighed, snap frozen in liquid nitrogen and stored at -80°C for further analysis. Total RNA extraction and sample preparation: Total RNA was extracted from the left calf muscle complex (soleus + gastrocnemius + plantaris) with Trizol Reagent (Invitrogen, Carlsbad, CA) and further purified with RNeasy columns (Qiagen, Valencia, CA) according to the manufacturers' protocols. Concentration and purity of RNA was determined by measuring absorbances at wavelengths 260 and 280 nm. Integrity of the RNA was checked with agarose gel electrophoresis. RNA samples were pooled within each group for microarray analyses. Concentration, purity and integrity of pooled RNA samples were checked as described above. Micro array analysis: Pooled RNA samples were analyzed with Affymetrix Gene Chip MG U74Av2 (Affymetrix , Inc., Santa Clara, CA) representing 6000 known genes and 6000 ESTs. Microarray analyses were performed according to the instructions of Affymetrix. Briefly, 5 µg of total pooled RNA was reverse transcribed using T7-(dT)24-primers and SuperScript II RT enzyme (Invitrogen). Single stranded cDNA was turned to double stranded cDNA using T4 DNA polymerase (Invitrogen). Produced cDNA was then purified and transcribed in vitro to biotin labeled cRNA using Enzo Bioarray High Yield RNA Transcript Labeling Kit (Enzo Diagnostics, Farmingdale, NY). RNA was purified and its quality was checked. Purity and quantity of RNA was measured with Nanodrop ND-1000 Spectrophotometer (Nanodrop Technologies, Montchanin, DE) and integrity was tested with agarose gel electrophoresis. Sample was then fragmented and hybridized to Affymetrix test chip to check the function of the hybridization cocktail and to ensure adequate representation of both 5´and 3´ends of the RNA. After testing, samples (15 µg) were hybridized to expression chips. After hybridization, chips were washed and stained in Affymetrix Fluidics Station 400. Arrays were stained first with R-Phycoerythrin Streptavidin (Molecular Probes, Eugene, OR), then with biotinylated anti-streptavidin antibody (Vector Laboratories, Burlingame, CA) and again with R-Phycoerythrin Streptavidin for signal enhancement. The chip was scanned with GeneArray Scanner G2500A (Agilent, Palo Alto, CA) Scaling and normalization of data: The array images were analyzed with Microarray Suite 5.0 (Affymetrix) software. All chips were scaled (global scaling) to target intensity of 50 to minimize differences between chips caused by physical differences in chips, hybridization efficiencies and manual laboratory work. The data was subjected to robust normalization that reduces the errors, which are caused by binding capacity and linearity differences between probe sets. Keywords: time-course

Project description:Key pointsObesity results in perilymphatic inflammation and lymphatic dysfunction. Lymphatic dysfunction in obesity is characterized by decreased lymphatic vessel density, decreased collecting lymphatic vessel pumping frequency, decreased lymphatic trafficking of immune cells, increased lymphatic vessel leakiness and changes in the gene expression patterns of lymphatic endothelial cells. Aerobic exercise, independent of weight loss, decreases perilymphatic inflammatory cell accumulation, improves lymphatic function and reverses pathological changes in gene expression in lymphatic endothelial cells.AbstractAlthough previous studies have shown that obesity markedly decreases lymphatic function, the cellular mechanisms that regulate this response remain unknown. In addition, it is unclear whether the pathological effects of obesity on the lymphatic system are reversible with behavioural modifications. The purpose of this study, therefore, was to analyse lymphatic vascular changes in obese mice and to determine whether these pathological effects are reversible with aerobic exercise. We randomized obese mice to either aerobic exercise (treadmill running for 30 min per day, 5 days a week, for 6 weeks) or a sedentary group that was not exercised and analysed lymphatic function using a variety of outcomes. We found that sedentary obese mice had markedly decreased collecting lymphatic vessel pumping capacity, decreased lymphatic vessel density, decreased lymphatic migration of immune cells, increased lymphatic vessel leakiness and decreased expression of lymphatic specific markers compared with lean mice (all P < 0.01). Aerobic exercise did not cause weight loss but markedly improved lymphatic function compared with sedentary obese mice. Exercise had a significant anti-inflammatory effect, resulting in decreased perilymphatic accumulation of inflammatory cells and inducible nitric oxide synthase expression. In addition, exercise normalized isolated lymphatic endothelial cell gene expression of lymphatic specific genes, including VEGFR-3 and Prox1. Taken together, our findings suggest that obesity impairs lymphatic function via multiple mechanisms and that these pathological changes can be reversed, in part, with aerobic exercise, independent of weight loss. In addition, our study shows that obesity-induced lymphatic endothelial cell gene expression changes are reversible with behavioural modifications.

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Exercise Training-Induced Changes in MicroRNAs: Beneficial Regulatory Effects in Hypertension, Type 2 Diabetes, and Obesity.

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Exercise Training-Induced Changes in MicroRNAs: Beneficial Regulatory Effects in Hypertension, Type 2 Diabetes, and Obesity.

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