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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Resistance training is accompanied by cardiac hypertrophy, but the role of the renin-angiotensin system (RAS) in this response is elusive. We evaluated this question in 36 male Wistar rats divided into six groups: control (n = 6); trained (n = 6); control + losartan (10 mg * [kg.sup.-1] * [day.sup.-1], n = 6); trained + losartan (n = 6); control + high-salt diet (1%, n = 6); and trained + high-salt diet (1%, n = 6). High salt was used to inhibit the systemic RAS and losartan to block the [AT.sub.1] receptor. The exercise protocol consisted of: 4 x 12 bouts, 5x/wk during 8 wk, with 65-75% of one repetition maximum. Left ventricle weight-to-body weight ratio increased only in trained and trained + high-salt diet groups (8.5% and 10.6%, P < 0.05) compared with control. Also, none of the pathological cardiac hypertrophy markers, atrial natriuretic peptide, and [alpha]MHC (a-myosin heavy chain)to-[beta]MHC ratio, were changed. ACE activity was analyzed by fluorometric assay (systemic and cardiac) and plasma renin activity (PRA) by RIA and remained unchanged upon resistance training, whereas PRA decreased significantly with the high-salt diet. Interestingly, using Western blot analysis and RT-PRC, no changes were observed in cardiac [AT.sub.2] receptor levels, whereas the [AT.sub.1] receptor gene (56%, P < 0.05) and protein (31%, P < 0.05) expressions were upregulated in the trained group. Also, cardiac ANG II concentration evaluated by ELISA remained unchanged (23.27 [+ or -] 2.4 vs. 22.01 [+ or -] 0.8 pg/mg, P > 0.05). Administration of a subhypotensive dose of losartan prevented left ventricle hypertrophy in response to the resistance training. Altogether, we provide evidence that resistance training-induced cardiac hypertrophy is accompanied by induction of [AT.sub.1] receptor expression with no changes in cardiac ANG II, which suggests a local activation of the RAS consistent with the hypertrophic response. [AT.sub.1] receptor; renin-angiotensin system; cardiac hypertrophy; resistance 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 (V_ O2peak), 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 (GSK3β) protein expression was lower in trained groups. Together, these molecular changes may contribute to a pronounced physiological LVH observed in high-volume aerobic training. [ABSTRACT FROM AUTHOR]

Aim: To study the relationship between the ACTN3 R577X polymorphism and oxygen uptake (VO2) before and after exercise training. Methods: Police recruits (N = 206, 25 ± 4 y) with RR (n = 75), RX (n = 97), and XX (n = 33) genotypes were selected. After baseline measures, they underwent 18 wk of running endurance training. Peak VO2 was obtained by cardiopulmonary exercise testing. Results: Baseline body weight was not different among genotypes. At baseline, XX individuals displayed higher VO2 at anaerobic threshold, respiratory compensation point, and exercise peak than did RR individuals (P < .003). Endurance training significantly increased VO2 at anaerobic threshold, respiratory compensation point, and exercise peak (P < 2 x 10-6), but the differences between XX and RR were no longer observed. Only relative peak VO2 exercise remained higher in XX than in RR genotype (P = .04). In contrast, the increase in relative peak VO2 was greater in RR than in XX individuals (12% vs 6%; P = .02). Conclusion: ACTN3 R577X polymorphism is associated with VO2. XX individuals have greater aerobic capacity. Endurance training eliminates differences in peak VO2 between XX and RR individuals. These findings suggest a ceiling-effect phenomenon, and, perhaps, trained individuals may not constitute an adequate population to explain associations between phenotypic variability and gene variations. [ABSTRACT FROM AUTHOR]

This study investigated whether regulation of the renin–angiotensin system (RAS) by enalapril and/or aerobic exercise training (AET) causes browning of the subcutaneous white adipose tissue (sWAT). C57BL/6 mice were fed either a standard chow or a high‐fat (HF) diet for 16 weeks. At Week 8, HF‐fed animals were divided into sedentary (HF), enalapril (HF‐E), AET (HF‐T), and enalapril plus AET (HF‐ET) groups. Subsequently, sWAT was extracted for morphometry, determination of RAS expression, and biomarkers of WAT browning. The HF group displayed adipocyte hypertrophy and induction of the classical RAS axis. Conversely, all interventions reduced adiposity and induced the counterregulatory RAS axis. However, only AET raised plasma irisin, increased peroxisome proliferator‐activated receptor‐γ coactivator‐1α, and uncoupling protein‐1 levels, and the expression of PR‐domain containing 16 in sWAT. Therefore, we concluded that AET‐induced sWAT browning was independent of the counterregulatory axis shifting of RAS in HF diet‐induced obesity. [ABSTRACT FROM AUTHOR]

Background: The exercise intolerance in chronic heart failure with reduced ejection fraction (HFrEF) is mostly attributed to alterations in skeletal muscle. However, the mechanisms underlying the skeletal myopathy in patients with HFrEF are not completely understood. We hypothesized that (i) aerobic exercise training (AET) and inspiratory muscle training (IMT) would change skeletal muscle microRNA‐1 expression and downstream‐associated pathways in patients with HFrEF and (ii) AET and IMT would increase leg blood flow (LBF), functional capacity, and quality of life in these patients. Methods: Patients age 35 to 70 years, left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association functional classes II–III, were randomized into control, IMT, and AET groups. Skeletal muscle changes were examined by vastus lateralis biopsy. LBF was measured by venous occlusion plethysmography, functional capacity by cardiopulmonary exercise test, and quality of life by Minnesota Living with Heart Failure Questionnaire. All patients were evaluated at baseline and after 4 months. Results: Thirty‐three patients finished the study protocol: control (n = 10; LVEF = 25 ± 1%; six males), IMT (n = 11; LVEF = 31 ± 2%; three males), and AET (n = 12; LVEF = 26 ± 2%; seven males). AET, but not IMT, increased the expression of microRNA‐1 (P = 0.02; percent changes = 53 ± 17%), decreased the expression of PTEN (P = 0.003; percent changes = −15 ± 0.03%), and tended to increase the p‐AKTser473/AKT ratio (P = 0.06). In addition, AET decreased HDAC4 expression (P = 0.03; percent changes = −40 ± 19%) and upregulated follistatin (P = 0.01; percent changes = 174 ± 58%), MEF2C (P = 0.05; percent changes = 34 ± 15%), and MyoD expression (P = 0.05; percent changes = 47 ± 18%). AET also increased muscle cross‐sectional area (P = 0.01). AET and IMT increased LBF, functional capacity, and quality of life. Further analyses showed a significant correlation between percent changes in microRNA‐1 and percent changes in follistatin mRNA (P = 0.001, rho = 0.58) and between percent changes in follistatin mRNA and percent changes in peak VO2 (P = 0.004, rho = 0.51). Conclusions: AET upregulates microRNA‐1 levels and decreases the protein expression of PTEN, which reduces the inhibitory action on the PI3K‐AKT pathway that regulates the skeletal muscle tropism. The increased levels of microRNA‐1 also decreased HDAC4 and increased MEF2c, MyoD, and follistatin expression, improving skeletal muscle regeneration. These changes associated with the increase in muscle cross‐sectional area and LBF contribute to the attenuation in skeletal myopathy, and the improvement in functional capacity and quality of life in patients with HFrEF. IMT caused no changes in microRNA‐1 and in the downstream‐associated pathway. The increased functional capacity provoked by IMT seems to be associated with amelioration in the respiratory function instead of changes in skeletal muscle. ClinicalTrials.gov (Identifier: NCT01747395) [ABSTRACT FROM AUTHOR]

Exercise training not only improves the plasma lipid profile but also reduces risk of developing coronary heart disease. We investigate whether plasma lipids and high density lipoprotein (HDL) metabolism are affected by aerobic training and whether the high‐density lipoprotein cholesterol (HDL‐C) levels at baseline influence exercise‐induced changes in HDL. Seventy‐one male sedentary volunteers were evaluated and allocated in two subgroups, according to the HLD‐C levels (< or >40 mg/dL). Participants underwent an 18‐week aerobic training period. Blood was sampled before and after training for biochemical analysis. Plasma lipids, apolipoproteins, HDL diameter, and VO2 peak were determined. Lipid transfers to HDL were determined in vitro by incubating plasma samples with a donor lipid artificial nanoemulsion. After the 18‐week period of aerobic training, the VO2 peak increased, while the mean body mass index (BMI) decreased. HDL‐C concentration was higher after the training period, but low‐density lipoprotein cholesterol (LDL‐C) and non‐HDL‐C did not change. The transfer of esterified cholesterol and phospholipids was greater after exercise training, but the triacylglycerol and unesterified cholesterol transfers were unchanged. The HDL particle diameter increased after aerobic training in all participants. When the participants were separated in low‐HDL and normal‐HDL groups, the postaerobic exercise increment in HDL‐C was higher in the low‐HDL group, while the transfer of esterified cholesterol was lower. In conclusion, aerobic exercise training increases the lipid transfers to HDL, as measured by an in vitro method, which possibly contributes to the classical elevation of the HDL‐C associated with training. [ABSTRACT FROM AUTHOR]

Hypertension is a difficult disease to control and exercise training plays a key role in hypertension control. Some individuals are not responsive to exercise training, so we highlight the polymorphism of angiotensin I converting enzyme, as a factor responsible for this lack of responsiveness. The aim of this study was to evaluate the influence of ACE (I/D) genotypes on effects of resistance training on blood pressure and chronic inflammation. Eighty-six hypertensive volunteers, aged between 60 and 80, were evaluated. They performed 16 weeks of resistance training at 50% of 1 maximal repetition. The greatest benefits were seen on homozygous of the Insertion allele, whom presented reduction of systolic blood pressure (SBP: 129.31±13.34 vs. 122.56±9.68 mmHg, p<0.001) and diastolic blood pressure (DBP: 79.18±8.05 vs. 70.12±7.71 mmHg, p<0.01) during daytime period, and in 24h period (SBP: 127.12±13.65 vs. 121.06±9.68 mmHg, p<0.001 and DBP: 71.87±8.39 vs. 68.75±8.72 mmHg, p<0.05) and also increased circulating adiponectin levels (4.04±1.79 vs. 6.00±2.81 ng/mL, p<0.01). Other genotypes showed no changes in blood pressure and biochemical parameters. Our results suggest a cardio protective factor of I allele, since only those homozygous showed reductions in blood pressure and increases in adiponectin. [ABSTRACT FROM AUTHOR]

Moderate physical exercise acts at molecular and behavioural levels, such as interfering in neuroplasticity, cell death, neurogenesis, cognition and motor functions. Therefore, the aim of this study is to analyse the cellular effects of moderate treadmill running upon substantia nigra during early neurodegeneration. Aged male Lewis rats (9-month-old) were exposed to rotenone 1mg/kg/day (8 weeks) and 6 weeks of moderate treadmill running, beginning 4 weeks after rotenone exposure. Substantia nigra was extracted and submitted to proteasome and antioxidant enzymes activities, hydrogen peroxide levels and Western blot to evaluate tyrosine hydroxylase (TH), alpha-synuclein, Tom-20, PINK1, TrkB, SLP1, CRMP-2, Rab-27b, LC3II and Beclin-1 level. It was demonstrated that moderate treadmill running, practiced during early neurodegeneration, prevented the increase of alpha-synuclein and maintained the levels of TH unaltered in substantia nigra of aged rats. Physical exercise also stimulated autophagy and prevented impairment of mitophagy, but decreased proteasome activity in rotenone-exposed aged rats. Physical activity also prevented H2O2 increase during early neurodegeneration, although the involved mechanism remains to be elucidated. TrkB levels and its anterograde trafficking seem not to be influenced by moderate treadmill running. In conclusion, moderate physical training could prevent early neurodegeneration in substantia nigra through the improvement of autophagy and mitophagy. [ABSTRACT FROM AUTHOR]