Dysregulated microRNAs in type 2 diabetes and breast cancer: Potential associated molecular mechanisms.

Type 2 diabetes (T2D) is a multifaceted and heterogeneous syndrome associated with complications such as hypertension, coronary artery disease, and notably, breast cancer (BC). The connection between T2D and BC is established through processes that involve insulin resistance, inflammation and other factors. Despite this comprehension the specific cellular and molecular mechanisms linking T2D to BC, especially through microRNAs (miRNAs), remain elusive. miRNAs are regulators of gene expression at the post-transcriptional level and have the function of regulating target genes by modulating various signaling pathways and biological processes. However, the signaling pathways and biological processes regulated by miRNAs that are associated with T2D and BC have not yet been elucidated. This review aims to identify dysregulated miRNAs in both T2D and BC, exploring potential signaling pathways and biological processes that collectively contribute to the development of BC.

Increased prevalence of the null allele of the p.Arg577Ter variant in the ACTN3 gene in Brazilian long-distance athletes: A retrospective study.

INTRODUCTION: The phenotypic consequences of the p.Arg577Ter variant in the α-actinin-3 (ACTN3) gene are suggestive of a trade-off between performance traits for speed and endurance sports. Although there is a consistent association of the c.1729C allele (aka R allele) with strength/power traits, there is still a debate on whether the null allele (c.1729T allele; aka X allele) influences endurance performance. The present study aimed to test the association of the ACTN3 p.Arg577Ter variant with long-distance endurance athlete status, using previously published data with the Brazilian population. METHODS: Genotypic data from 203 long-distance athletes and 1724 controls were analysed in a case-control approach. RESULTS: The frequency of the X allele was significantly higher in long-distance athletes than in the control group (51.5% vs. 41.4%; p = 0.000095). The R/X and X/X genotypes were overrepresented in the athlete group. Individuals with the R/X genotype instead of the R/R genotype had a 1.6 increase in the odds of being a long-distance athlete (p = 0.012), whereas individuals with the X/X genotype instead of the R/R genotype had a 2.2 increase in the odds of being a long-distance athlete (p = 0.00017). CONCLUSION: The X allele, mainly the X/X genotype, was associated with long-distance athlete status in Brazilians.

Mitigation of Subsequent Ovariectomy Responses through Prior Exercise Training in Rats.

It is well known that cardiometabolic dysfunction gradually increases after menopause and the sedentary lifestyle can aggravated this condition. Therefore, we compared the effects of prior aerobic exercise training in premenopausal period and after ovariectomy (OVX) on metabolic, hemodynamic and autonomic parameters in experimental model of menopause in rats. Female rats were divided in 4 groups: control (C), sedentary OVX (SO), trained OVX (TO), and previously trained OVX (PTO). PTO trained four weeks previously+eight weeks after OVX and the TO group trained only after OVX on a motor treadmill. Autonomic modulation were evaluated and the adipose tissues (WAT) were removed, weighed and lipolysis was assessed. Citrate synthase activity was analysed in the soleus muscle. The trained groups prevented the impairment of BRS in relation to SO; however, only PTO reduced the low frequency band of pulse interval compared to SO. PTO reduced the weight of WAT compared to the other groups; the lipolysis in PTO was similar to C. PTO had preserved muscle metabolic injury in all types of fibres analysed. In conclusion, this study suggests that exercise training should be recommended in a pre-menopausal model in order to prevent cardiometabolic and autonomic menopause-induced deleterious effects.

ER stress improvement by aerobic training or enalapril differently ameliorates pathological cardiac remodeling in obese mice.

Overactivation of the classic arm of the renin-angiotensin system (RAS) is one of the main mechanisms involved in obesity-related cardiac remodeling, and a possible relationship between RAS and ER stress in the cardiovascular system have been described. Thus, the aim of this study is to evaluate if activating the protective arm of the RAS by ACE inhibition or aerobic exercise training could overturn diet-induced pathological cardiac hypertrophy by attenuating ER stress. Male C57BL/6 mice were fed a control (SC) or a high-fat diet (HF) for 16 weeks. In the 8th week, HF-fed animals were randomly divided into HF, enalapril treatment (HF-En), and aerobic exercise training (HF-Ex) groups. Body mass (BM), food and energy intake, plasma analyzes, systolic blood pressure (SBP), physical conditioning, and plasma ACE and ACE2 activity were evaluated. Cardiac morphology, and protein expression of hypertrophy, cardiac metabolism, RAS, and ER stress markers were assessed. Data presented as mean ± standard deviation and analyzed by one-way ANOVA with Holm-Sidak post-hoc. HF group had increased BM and SBP, and developed pathological concentric cardiac hypertrophy, with overactivation of the classic arm of the RAS, and higher ER stress. Both interventions reverted the increase in BM, and SBP, and favored the protective arm of the RAS. Enalapril treatment improved pathological cardiac hypertrophy with partial reversal of the concentric pattern, and slightly attenuated cardiac ER stress. In contrast, aerobic exercise training induced physiological eccentric cardiac hypertrophy, and fully diminished ER stress.

Resistance Training Reduces Blood Pressure: Putative Molecular Mechanisms.

Arterial hypertension is a multifactorial clinical condition characterized by higher blood pressure levels. The main treatment for controlling high blood pressure consists of drug therapy, but the scientific literature has been pointing to the efficiency of aerobic and resistance exercises acting in a therapeutic and/or preventive way to reduce and control the blood pressure levels. Resistance training is characterized by sets and repetitions on a given muscle segment that uses overload, such as machine weights, bars, and dumbbells. As it successfully affects a number of variables associated to practitioners' functional and physiological features as well as emotional and social variables, resistance training has been a crucial part of physical exercise programs. Several reports highlight the various adaptive responses it provides, with a focus on the improvement in strength, balance, and muscular endurance that enables a more active and healthy lifestyle. Resistance training programs that are acute, sub-chronic, or chronic can help people with varying ages, conditions, and pathologies reduce their arterial hypertension. However, molecular mechanisms associated with resistance training to reduce blood pressure still need to be better understood. Thus, we aimed to understand the main effects of resistance training on blood pressure as well as the associated molecular mechanisms.

Phytochemistry Profile, Antimicrobial and Antitumor Potential of the Methanolic Extract of Tabernaemontana catharinensis A DC and Eragrostis plana NEES.

Natural compounds that have the potential to act as antimicrobials and antitumors are a constant search in the field of pharmacotherapy. Eragrostis plana NEES (Poaceae) is a grass with high allelopathic potential. Allelopathy is associated with compounds generated in the primary and secondary metabolism of the plant, which act to protect it from phytopathogens. Tabernaemontana catharinensis A DC (Apocynaceae), a tree in which its leaves and bark are used for the preparation of extracts and infusions that have anti-inflammatory and antinociceptive effects, is attributed to its phytochemical constitution. The objective of this study was to elucidate the phytochemical constitution, the antibacterial potential, the toxicity against immune system cells, hemolytic potential, and antitumor effect of methanolic extracts of E. plana and T. catharinensis. The phytochemical investigation was carried out using the UHPLC-QTOF MS equipment. The antibacterial activity was tested using the broth microdilution plate assay, against Gram-negative and Gram-positive strains, and cytotoxicity assays were performed on human peripheral blood mononuclear cells (PBMC) and in vitro hemolysis. Antitumor activity was performed against the colon cancer cell line (CT26). Results were expressed as mean and standard deviation and analyzed by ANOVA. p < 0.05 was considered significant. More than 19 possible phytochemical constituents were identified for each plant, with emphasis on phenolic compounds (acids: vanillic, caffeic, and quinic) and alkaloids (alstovenine, rhyncophylline, amezepine, voacangine, and coronaridine). Both extracts showed antibacterial activity at concentrations below 500 µg/mL and were able to decrease the viability of CT26 at concentrations below 2000 µg/mL, without showing cytotoxic effect on PBMCs and in vitro hemolysis at the highest concentration tested. This is the first report of the activity of E. plana and T. catharinensis extracts against colon cancer cell line (CT26). Studies should be carried out to verify possible molecular targets involved in the antitumor effect in vivo.

MicroRNAs regulating signaling pathways in cardiac fibrosis: potential role of the exercise training.

Cardiovascular and metabolic diseases such as hypertension, type 2 diabetes, and obesity develop long-term fibrotic processes in the heart, promoting pathological cardiac remodeling, including after myocardial infarction, reparative fibrotic processes also occur. These processes are regulated by many intracellular signaling pathways that have not yet been completely elucidated, including those associated with microRNA (miRNA) expression. miRNAs are small RNA transcripts (18-25 nucleotides in length) that act as posttranscriptionally regulators of gene expression, inhibiting or degrading one or more target messenger RNAs (mRNAs), and proven to be involved in many biological processes such as cell cycle, differentiation, proliferation, migration, and apoptosis, directly affecting the pathophysiology of several diseases, including cardiac fibrosis. Exercise training can modulate the expression of miRNAs and it is known to be beneficial in various cardiovascular diseases, attenuating cardiac fibrosis processes. However, the signaling pathways modulated by the exercise associated with miRNAs in cardiac fibrosis were not fully understood. Thus, this review aims to analyze the expression of miRNAs that modulate signaling pathways in cardiac fibrosis processes that can be regulated by exercise training.

Aerobic exercise training mitigates tumor growth and cancer-induced splenomegaly through modulation of non-platelet platelet factor 4 expression.

Exercise training reduces the incidence of several cancers, but the mechanisms underlying these effects are not fully understood. Exercise training can affect the spleen function, which controls the hematopoiesis and immune response. Analyzing different cancer models, we identified that 4T1, LLC, and CT26 tumor-bearing mice displayed enlarged spleen (splenomegaly), and exercise training reduced spleen mass toward control levels in two of these models (LLC and CT26). Exercise training also slowed tumor growth in melanoma B16F10, colon tumor 26 (CT26), and Lewis lung carcinoma (LLC) tumor-bearing mice, with minor effects in mammary carcinoma 4T1, MDA-MB-231, and MMTV-PyMT mice. In silico analyses using transcriptome profiles derived from these models revealed that platelet factor 4 (Pf4) is one of the main upregulated genes associated with splenomegaly during cancer progression. To understand whether exercise training would modulate the expression of these genes in the tumor and spleen, we investigated particularly the CT26 model, which displayed splenomegaly and had a clear response to the exercise training effects. RT-qPCR analysis confirmed that trained CT26 tumor-bearing mice had decreased Pf4 mRNA levels in both the tumor and spleen when compared to untrained CT26 tumor-bearing mice. Furthermore, exercise training specifically decreased Pf4 mRNA levels in the CT26 tumor cells. Aspirin treatment did not change tumor growth, splenomegaly, and tumor Pf4 mRNA levels, confirming that exercise decreased non-platelet Pf4 mRNA levels. Finally, tumor Pf4 mRNA levels are deregulated in The Cancer Genome Atlas Program (TCGA) samples and predict survival in multiple cancer types. This highlights the potential therapeutic value of exercise as a complementary approach to cancer treatment and underscores the importance of understanding the exercise-induced transcriptional changes in the spleen for the development of novel cancer therapies.

Resistance exercise training benefits pulmonary, cardiac, and muscular structure and function in rats with stable pulmonary artery hypertension.

AIM: We tested the effects of low- to moderate-intensity resistance exercise training (RT) on the structure and function of pulmonary, right ventricle (RV), and skeletal muscle tissues in rats with stable pulmonary artery hypertension (PAH). MAIN METHODS: After the first monocrotaline (MCT; 20 mg/kg) injection, male rats were submitted to a RT program (Ladder climbing; 55-65 % intensity), 5 times/week. Seven days later rats received the second MCT dose. Physical effort tolerance test and echocardiographic examination were performed. After euthanasia, lung, heart, and biceps brachii were processed for histological, single myocyte, and biochemical analysis. KEY FINDINGS: RT improved survival and physical effort tolerance (i.e., maximum carrying load), mitigated the pulmonary artery resistance increase (i.e., TA/TE), and preserved cardiac function (i.e., fractional shortening, ejection fraction, stroke volume and TAPSE). RT counteracted oxidative stress (i.e., CAT, SOD, GST, MDA and NO) and adverse remodeling in lung (i.e., collapsed alveoli) and in biceps brachii (i.e., atrophy and total collagen) tissues. RT delayed RV adverse remodeling (i.e., hypertrophy, extracellular matrix, collagen types I and III, and fibrosis) and impairments in single RV myocyte contractility (i.e., amplitude and velocity to peak and relaxation). RT improved the expression of gene (i.e., miRNA 214) and intracellular Ca2+ cycling regulatory proteins (i.e., PLBser16); and of pathological (i.e., α/ß-MHC and Foxo3) and physiological (i.e., Akt, p-Akt, mTOR, p-mTOR, and Bcl-xL) hypertrophy pathways markers in RV tissue. SIGNIFICANCE: Low- to moderate-intensity RT benefits the structure and function of pulmonary, RV, and skeletal muscle tissues in rats with stable pulmonary artery hypertension.

Irisin: An anti-inflammatory exerkine in aging and redox-mediated comorbidities.

Human beings lead largely sedentary lives. From an evolutionary perspective, such lifestyle is not beneficial to health. Exercise can promote many enabling pathways, particularly through circulating exerkines, to optimize individual health and quality of life. Such benefits might explain the protective effects of exercise against aging and noncommunicable diseases. Nevertheless, the miRNA-mediated molecular mechanisms and exerkine interorgan crosstalk that underlie the beneficial effects of exercise remain poorly understood. In this mini review, we focused on the exerkine, irisin, mainly produced by muscle contraction during adaptation to exercise and its beneficial effects on body homeostasis. Herein, the complex role of irisin in metabolism and inflammation is described, including its subsequent effects on thermogenesis through browning to control obesity and improve glycemic regulation for diabetes mellitus control, its potential to improve cognitive function (via brain derived neurotrophic factor), and its pathways of action and role in aging.

mt-Ty 5'tiRNA regulates skeletal muscle cell proliferation and differentiation.

In this study, we sought to determine the role of tRNA-derived fragments in the regulation of gene expression during skeletal muscle cell proliferation and differentiation. We employed cell culture to examine the function of mt-Ty 5' tiRNAs. Northern blotting, RT-PCR as well as RNA-Seq, were performed to determine the effects of mt-Ty 5' tiRNA loss and gain on gene expression. Standard and transmission electron microscopy (TEM) were used to characterize cell and sub-cellular structures. mt-Ty 5'tiRNAs were found to be enriched in mouse skeletal muscle, showing increased levels in later developmental stages. Gapmer-mediated inhibition of tiRNAs in skeletal muscle C2C12 myoblasts resulted in decreased cell proliferation and myogenic differentiation; consistent with this observation, RNA-Seq, transcriptome analyses, and RT-PCR revealed that skeletal muscle cell differentiation and cell proliferation pathways were also downregulated. Conversely, overexpression of mt-Ty 5'tiRNAs in C2C12 cells led to a reversal of these transcriptional trends. These data reveal that mt-Ty 5'tiRNAs are enriched in skeletal muscle and play an important role in myoblast proliferation and differentiation. Our study also highlights the potential for the development of tiRNAs as novel therapeutic targets for muscle-related diseases.

Circular RNAs as a Diagnostic and Therapeutic Target in Cardiovascular Diseases.

Circular RNAs (circRNAs) are a family of noncoding RNAs (ncRNAs) that are endogenous and widely distributed in different species, performing several functions, mainly their association with microRNAs (miRNAs) and RNA-binding proteins. CVDs remain the leading cause of death worldwide; therefore, the development of new therapies and strategies, such as gene therapies or nonpharmacological therapies, with low cost, such as physical exercise, to alleviate these diseases is of extreme importance for society. With increasing evidence of ncRNA participating in the progression of CVDs, several studies have reported these RNAs as promising targets for diagnosis and treatment. There are several studies of CVDs and the role of miRNAs and lncRNAs; however, little is known about the new class of RNAs, called circRNAs, and CVDs. In this mini review, we focus on the mechanisms of circRNAs and CVDs.

Comparison between aerobic exercise training and enalapril treatment as tools to improve diet-induced metabolic-associated fatty liver disease: Effects on endoplasmic reticulum stress markers.

AIMS: Endoplasmic reticulum (ER) stress poses a new pathological mechanism for metabolic-associated fatty liver disease (MAFLD). MAFLD treatment has encompassed renin-angiotensin system (RAS) blockers and aerobic exercise training, but their association with hepatic ER stress is not well known. Therefore, we aimed to compare the effects of hepatic RAS modulation by enalapril and/or aerobic exercise training over ER stress in MAFLD caused by a diet-induced obesity model. MAIN METHODS: C57BL/6 mice were fed a standard-chow (CON, n = 10) or a high-fat (HF, n = 40) diet for 8 weeks. HF group was then randomly divided into: HF (n = 10), HF + Enalapril (EN, n = 10), HF + Aerobic exercise training (AET, n = 10), and HF + Enalapril+Aerobic exercise training (EN + AET, n = 10) for 8 more weeks. Body mass (BM) and glucose profile were evaluated. In the liver, ACE and ACE2 activity, morphology, lipid profile, and protein expression of ER stress and metabolic markers were assessed. KEY FINDINGS: Both enalapril and aerobic exercise training provided comparable efficacy in improving diet-induced MAFLD through modulation of RAS and ER stress, but the latter was more efficient in improving ER stress, liver damage and metabolism. SIGNIFICANCE: This is the first study to evaluate pharmacological (enalapril) and non-pharmacological (aerobic exercise training) RAS modulators associated with ER stress in a diet-induced MAFLD model.

Angiotensin II Promotes Skeletal Muscle Angiogenesis Induced by Volume-Dependent Aerobic Exercise Training: Effects on miRNAs-27a/b and Oxidant-Antioxidant Balance.

Aerobic exercise training (ET) produces beneficial adaptations in skeletal muscles, including angiogenesis. The renin-angiotensin system (RAS) is highly involved in angiogenesis stimuli. However, the molecular mechanisms underlying capillary growth in skeletal muscle induced by aerobic ET are not completely understood. This study aimed to investigate the effects of volume-dependent aerobic ET on skeletal muscle angiogenesis involving the expression of miRNAs-27a and 27b on RAS and oxidant-antioxidant balance. Eight-week-old female Wistar rats were divided into three groups: sedentary control (SC), trained protocol 1 (P1), and trained protocol 2 (P2). P1 consisted of 60 min/day of swimming, 5×/week, for 10 weeks. P2 consisted of the same protocol as P1 until the 8th week, but in the 9th week, rats trained 2×/day, and in the 10th week, trained 3×/day. Angiogenesis and molecular analyses were performed in soleus muscle samples. Furthermore, to establish ET-induced angiogenesis through RAS, animals were treated with an AT1 receptor blocker (losartan). Aerobic ET promoted higher VO2 peak and exercise tolerance values. In contrast, miRNA-27a and -27b levels were reduced in both trained groups, compared with the SC group. This was in parallel with an increase in the ACE1/Ang II/VEGF axis, which led to a higher capillary-to-fiber ratio. Moreover, aerobic ET induced an antioxidant profile increasing skeletal muscle SOD2 and catalase gene expression, which was accompanied by high nitrite levels and reduced nitrotyrosine concentrations in the circulation. Additionally, losartan treatment partially re-established the miRNAs expression and the capillary-to-fiber ratio in the trained groups. In summary, aerobic ET promoted angiogenesis through the miRNA-27a/b-ACE1/Ang II/VEGF axis and improved the redox balance. Losartan treatment demonstrates the participation of RAS in ET-induced vascular growth. miRNAs and RAS components are promising potential targets to modulate angiogenesis for combating vascular diseases, as well as potential biomarkers to monitor training interventions and physical performance.

MicroRNAs in Obesity-Associated Disorders: The Role of Exercise Training.

Obesity is a worldwide epidemic affecting over 13% of the adult population and is defined by an excess of body fat that predisposes comorbidities. It is considered a multifactorial disease in which environmental and genetic factors interact, and it is a risk marker for cardiovascular disease. Lifestyle modifications remain the mainstay of treatment for obesity based on adequate diet and physical exercise. In addition, obesity is related to cardiovascular and skeletal muscle disorders, such as cardiac hypertrophy, microvascular rarefaction, and skeletal muscle atrophy. The discovery of obesity-involved molecular pathways is an important step to improve both the prevention and management of this disease. MicroRNAs (miRNAs) are a class of gene regulators which bind most commonly, but not exclusively, to the 3'-untranslated regions of messenger RNAs of protein-coding genes and negatively regulate their expression. Considerable effort has been made to identify miRNAs and target genes that predispose to obesity. Besides their intracellular function, recent studies have demonstrated that miRNAs can be exported or released by cells and circulate within the blood in a remarkably stable form. The discovery of circulating miRNAs opens up intriguing possibilities for the use of circulating miRNA patterns as biomarkers for obesity and cardiovascular diseases. The aim of this review is to provide an overview of the recent discoveries of the role played by miRNAs in the obese phenotype and associated comorbidities. Furthermore, we will discuss the role of exercise training on regulating miRNAs, indicating the mechanisms related to these alterations.

MicroRNAs in type 2 diabetes mellitus: potential role of physical exercise.

Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disease, and its prevalence has grown worldwide. Several pathophysiological processes contribute to the development, progression and aggravating of the disease, for example, decreased insulin synthesis and secretion, insulin resistance, inflammation, and apoptosis, all these processes are regulated by various epigenetic factors, including microRNAs (miRNAs). MiRNAs are small non-coding RNAs, which are around 20 nucleotides in length and are regulators of gene expression at the post-transcriptional level, have a specific function of inhibiting or degrading a messenger RNA target. Thus, miRNAs modulate the expression of many associated genes with the pathophysiological processes in T2DM. On the other hand, miRNAs are also modulated through physical exercise (PE), which induces a change in their expression pattern during and after exercise. Some scientific evidence shows that PE modulates miRNAs beneficially and improves the signaling pathway of insulin resistance, however, little is known about the function of PE modulating miRNAs associated with the processes of insulin secretion, inflammation, and apoptosis. Thus, the objective of this review is to identify the miRNAs expression pattern in T2DM and compare it with the exercise-induced miRNAs expression pattern, identifying the signaling pathways that these miRNAs are regulating in the processes of insulin secretion, insulin resistance, inflammation, and apoptosis in T2DM, and how PE may have a potential role in modulating these signal transduction pathways, promoting benefits for patients with T2DM.

mTOR signaling-related microRNAs as cardiac hypertrophy modulators in high-volume endurance training.

Aerobic exercise training (ET) promotes cardiovascular adaptations, including physiological left ventricular hypertrophy (LVH). However, the molecular mechanisms underlying these changes are unclear. The study aimed to elucidate specific microRNAs (miRNAs) and target genes involved with the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling in high-volume ET-induced LVH. Eight-week-old female Wistar rats were assigned to three groups: sedentary control (SC), trained protocol 1 (P1), and trained protocol 2 (P2). P1 consisted of 60 min/day of swimming, 5 times/wk, for 10 wk. P2 consisted of the same protocol as P1 until the 8th week; in the 9th week rats trained 2 times/day, and in the 10th week they trained 3 times/day. Subsequently, structure and molecular parameters were evaluated in the heart. Trained groups demonstrate higher values of peak oxygen uptake ([Formula: see text]), exercise tolerance, and LVH in a volume-dependent manner. The miRNA-26a-5p levels were higher in P1 and P2 compared with the SC group (150 ± 15%, d = 1.8; 148 ± 16%, d = 1.7; and 100 ± 7%, respectively; P < 0.05). In contrast, miRNA-16-5p levels were lower in P1 and P2 compared with the SC group (69 ± 5%, d = 2.3, P < 0.01; 37 ± 4%, d = 5.6, P < 0.001; and 100 ± 6%, respectively). Additionally, miRNA-16-5p knockdown and miRNA-26a-5p overexpression significantly promoted cardiomyocyte hypertrophy in neonatal rat cardiomyocytes. Both miRNAs were selected, with the DIANA Tools bioinformatics website, for acting in the mTOR signaling pathway. The protein expression of AKT, MTOR, ribosomal protein S6 kinase beta-1 (P70S6K), and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) were greater in P1 and even more pronounced in P2. Nonetheless, glycogen synthase kinase 3 beta (GSK3ß) protein expression was lower in trained groups. Together, these molecular changes may contribute to a pronounced physiological LVH observed in high-volume aerobic training.NEW & NOTEWORTHY Physiological hypertrophic growth of the heart as a compensatory response to exercise training (ET) is coupled with recent progress in dissecting the microRNA (miRNA)-mediated molecular basis of hypertrophy. Aerobic ET seems to reduce miRNA-16-5p and increase miRNA-26a-5p expression in a volume-dependent mode, activating protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathways, and likely produces an enhanced left ventricular hypertrophy (LVH) in high-volume endurance training. New insight into these mechanisms can be useful in understanding physiological LVH and how it might be harnessed as a therapeutic application.

Walking Training Increases microRNA-126 Expression and Muscle Capillarization in Patients with Peripheral Artery Disease.

Patients with peripheral artery disease (PAD) have reduced muscle capillary density. Walking training (WT) is recommended for PAD patients. The goal of the study was to verify whether WT promotes angiogenesis in PAD-affected muscle and to investigate the possible role of miRNA-126 and the vascular endothelium growth factor (VEGF) angiogenic pathways on this adaptation. Thirty-two men with PAD were randomly allocated to two groups: WT (n = 16, 2 sessions/week) and control (CO, n = 16). Maximal treadmill tests and gastrocnemius biopsies were performed at baseline and after 12 weeks. Histological and molecular analyses were performed by blinded researchers. Maximal walking capacity increased by 65% with WT. WT increased the gastrocnemius capillary-fiber ratio (WT = 109 ± 13 vs. 164 ± 21 and CO = 100 ± 8 vs. 106 ± 6%, p < 0.001). Muscular expression of miRNA-126 and VEGF increased with WT (WT = 101 ± 13 vs. 130 ± 5 and CO = 100 ± 14 vs. 77 ± 20%, p < 0.001; WT = 103 ± 28 vs. 153 ± 59 and CO = 100 ± 36 vs. 84 ± 41%, p = 0.001, respectively), while expression of PI3KR2 decreased (WT = 97 ± 23 vs. 75 ± 21 and CO = 100 ± 29 vs. 105 ± 39%, p = 0.021). WT promoted angiogenesis in the muscle affected by PAD, and miRNA-126 may have a role in this adaptation by inhibiting PI3KR2, enabling the progression of the VEGF signaling pathway.

Effects of Aerobic Exercise Training on MyomiRs Expression in Cachectic and Non-Cachectic Cancer Mice.

We investigated the effects of AET on myomiRs expression in the skeletal muscle and serum of colon cachectic (CT26) and breast non-cachectic (MMTV-PyMT) cancer mice models. Colon cancer decreased microRNA-486 expression, increasing PTEN in tibialis anterior muscle (TA), decreasing the PI3K/mTOR protein pathway, body and muscle wasting, fibers' cross-sectional area and muscle dysfunction, that were not preserved by AET. In contrast, breast cancer decreased those muscle functions, but were preserved by AET. In circulation, the downregulation of microRNA-486 and -206 in colon cancer, and the downregulation of microRNA-486 and upregulation of microRNA-206 expression in breast cancer might be good cancer serum biomarkers. Since the microRNA-206 is skeletal muscle specific, their expression was increased in the TA, serum and tumor in MMTV, suggesting a communication among these three compartments. The AET prevents these effects on microRNA-206, but not on microRNA-486 in MMTV. In conclusion, cancer induced a downregulation of microRNA-486 expression in TA and serum of CT26 and MMTV mice and these effects were not prevented by AET; however, to MMTV, the trained muscle function was preserved, probably sustained by the downregulation of microRNA-206 expression. Serum microRNA-206 is a potential biomarker for colon (decreased) and breast (increased) cancer to monitor the disease evolution and the effects promoted by the AET.

Long Non-Coding RNAs in Cardiovascular Diseases: Potential Function as Biomarkers and Therapeutic Targets of Exercise Training.

Despite advances in treatments and therapies, cardiovascular diseases (CVDs) remain one of the leading causes of death worldwide. The discovery that most of the human genome, although transcribed, does not encode proteins was crucial for focusing on the potential of long non-coding RNAs (lncRNAs) as essential regulators of cell function at the epigenetic, transcriptional, and post-transcriptional levels. This class of non-coding RNAs is related to the pathophysiology of the cardiovascular system. The different expression profiles of lncRNAs, in different contexts of CVDs, change a great potential in their use as a biomarker and targets of therapeutic intervention. Furthermore, regular physical exercise plays a protective role against CVDs; on the other hand, little is known about its underlying molecular mechanisms. In this review, we look at the accumulated knowledge on lncRNAs and their functions in the cardiovascular system, focusing on the cardiovascular pathology of arterial hypertension, coronary heart disease, acute myocardial infarction, and heart failure. We discuss the potential of these molecules as biomarkers for clinical use, their limitations, and how the manipulation of the expression profile of these transcripts through physical exercise can begin to be suggested as a strategy for the treatment of CVDs.