Exercise is cardioprotective, though optimal interventions are unclear. We assessed duration dependent effects of exercise on myocardial ischemia-reperfusion (I-R) injury, kinase signaling and gene ...expression.
Responses to brief (2 day; 2EX), intermediate (7 and 14 day; 7EX and 14EX) and extended (28 day; 28EX) voluntary wheel running (VWR) were studied in male C57Bl/6 mice. Cardiac function, I-R tolerance and survival kinase signaling were assessed in perfused hearts.
Mice progressively increased running distances and intensity, from 2.4 ± 0.2 km/day (0.55 ± 0.04 m/s) at 2-days to 10.6 ± 0.4 km/day (0.72 ± 0.06 m/s) after 28-days. Myocardial mass and contractility were modified at 14–28 days VWR. Cardioprotection was not ‘dose-dependent’, with I-R tolerance enhanced within 7 days and not further improved with greater VWR duration, volume or intensity. Protection was associated with AKT, ERK1/2 and GSK3β phosphorylation, with phospho-AMPK selectively enhanced with brief VWR. Gene expression was duration-dependent: 7 day VWR up-regulated glycolytic (Pfkm) and down-regulated maladaptive remodeling (Mmp2) genes; 28 day VWR up-regulated caveolar (Cav3), mitochondrial biogenesis (Ppargc1a, Sirt3) and titin (Ttn) genes. Interestingly, I-R tolerance in 2EX/2SED groups improved vs. groups subjected to longer sedentariness, suggesting transient protection on transition to housing with running wheels.
Cardioprotection is induced with as little as 7 days VWR, yet not enhanced with further or faster running. This protection is linked to survival kinase phospho-regulation (particularly AKT and ERK1/2), with glycolytic, mitochondrial, caveolar and myofibrillar gene changes potentially contributing. Intriguingly, environmental enrichment may also protect via similar kinase regulation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Heart Foundation Research Center, School of Health Science, Griffith University, Southport, Queensland 4217, Australia
Cells of the cardiovascular system generate and release purine nucleoside ...adenosine in increasing quantities when constituent cells are "stressed" or subjected to injurious stimuli. This increased adenosine can interact with surface receptors in myocardial, vascular, fibroblast, and inflammatory cells to modulate cellular function and phenotype. Additionally, adenosine is rapidly reincorporated back into 5'-AMP to maintain the adenine nucleotide pool. Via these receptor-dependent and independent (metabolic) paths, adenosine can substantially modify the acute response to ischemic insult, in addition to generating a more sustained ischemia-tolerant phenotype (preconditioning). However, the molecular basis for acute adenosinergic cardioprotection remains incompletely understood and may well differ from more widely studied preconditioning. Here we review current knowledge and some controversies regarding acute cardioprotection via adenosine and adenosine receptor activation.
adenosine; adenosine receptor activation; ischemia; reperfusion injury
Address for reprint requests and other correspondence: J. Headrick, Heart Foundation Research Centre, Griffith Univ., Southport QLD 4217, Australia (E-mail: J.Headrick{at}griffith.edu.au ).
Background
Achilles tendinopathy is the most prevalent tendon disorder in people engaged in running and jumping sports. Aetiology of Achilles tendinopathy is complex and requires comprehensive ...research of contributing risk factors. There is relatively little research focussing on potential biomedical risk factors for Achilles tendinopathy. The purpose of this systematic review is to identify studies and summarise current knowledge of biomedical risk factors of Achilles tendinopathy in physically active people.
Methods
Research databases were searched for relevant articles followed by assessment in accordance with PRISMA statement and standards of Cochrane collaboration. Levels of evidence and quality assessment designation were implemented in accordance with OCEBM levels of evidence and Newcastle-Ottawa Quality Assessment Scale, respectively.
Results
A systematic review of the literature identified 22 suitable articles. All included studies had moderate level of evidence (2b) with the Newcastle-Ottawa score varying between 6 and 9. The majority (17) investigated genetic polymorphisms involved in tendon structure and homeostasis and apoptosis and inflammation pathways.
Overweight as a risk factor of Achilles tendinopathy was described in five included studies that investigated non-genetic factors.
COL5A1
genetic variants were the most extensively studied, particularly in association with genetic variants in the genes involved in regulation of cell-matrix interaction in tendon and matrix homeostasis. It is important to investigate connections and pathways whose interactions might be disrupted and therefore alter collagen structure and lead to the development of pathology. Polymorphisms in genes involved in apoptosis and inflammation, and Achilles tendinopathy did not show strong association and, however, should be considered for further investigation.
Conclusions
This systematic review suggests that biomedical risk factors are an important consideration in the future study of propensity to the development of Achilles tendinopathy. The presence of certain medical comorbidities and genetic markers should be considered when contemplating the aetiology of Achilles tendinopathy. Further elucidation of biomedical risk factors will aid in the understanding of tendon pathology and patient risk, thereby informing prevention and management strategies for Achilles tendinopathy.
Trial Registration
PROSPERO
CRD42016036558
Nearly all human complex traits and diseases exhibit some degree of sex differences, with epigenetics being one of the main contributing factors. Various tissues display sex differences in DNA ...methylation; however, this has not yet been explored in skeletal muscle, despite skeletal muscle being among the tissues with the most transcriptomic sex differences. For the first time, we investigated the effect of sex on autosomal DNA methylation in human skeletal muscle across three independent cohorts (Gene SMART, FUSION, and GSE38291) using a meta-analysis approach, totalling 369 human muscle samples (222 males and 147 females), and integrated this with known sex-biased transcriptomics. We found 10,240 differentially methylated regions (DMRs) at FDR < 0.005, 94% of which were hypomethylated in males, and gene set enrichment analysis revealed that differentially methylated genes were involved in muscle contraction and substrate metabolism. We then investigated biological factors underlying DNA methylation sex differences and found that circulating hormones were not associated with differential methylation at sex-biased DNA methylation loci; however, these sex-specific loci were enriched for binding sites of hormone-related transcription factors (with top TFs including androgen (AR), estrogen (ESR1), and glucocorticoid (NR3C1) receptors). Fibre type proportions were associated with differential methylation across the genome, as well as across 16% of sex-biased DNA methylation loci (FDR < 0.005). Integration of DNA methylomic results with transcriptomic data from the GTEx database and the FUSION cohort revealed 326 autosomal genes that display sex differences at both the epigenome and transcriptome levels. Importantly, transcriptional sex-biased genes were overrepresented among epigenetic sex-biased genes (p value = 4.6e-13), suggesting differential DNA methylation and gene expression between male and female muscle are functionally linked. Finally, we validated expression of three genes with large effect sizes (FOXO3A, ALDH1A1, and GGT7) in the Gene SMART cohort with qPCR. GGT7, involved in antioxidant metabolism, displays male-biased expression as well as lower methylation in males across the three cohorts. In conclusion, we uncovered 8420 genes that exhibit DNA methylation differences between males and females in human skeletal muscle that may modulate mechanisms controlling muscle metabolism and health.
Chronic Fatigue Syndrome (CFS) is a multifactorial disorder that affects various physiological systems including immune and neurological systems. The immune system has been substantially examined in ...CFS with equivocal results, however, little is known about the role of neutrophils and natural killer (NK) phenotypes in the pathomechanism of this disorder. Additionally the role of erythrocyte rheological characteristics in CFS has not been fully expounded. The objective of this present study was to determine deficiencies in lymphocyte function and erythrocyte rheology in CFS patients.
Flow cytometric measurements were performed for neutrophil function, lymphocyte numbers, NK phenotypes (CD56(dim)CD16(+) and CD56(bright)CD16(-)) and NK cytotoxic activity. Erythrocyte aggregation, deformability and fibrinogen levels were also assessed.
CFS patients (n = 10) had significant decreases in neutrophil respiratory burst, NK cytotoxic activity and CD56(bright)CD16(-) NK phenotypes in comparison to healthy controls (n = 10). However, hemorheological characteristic, aggregation, deformability, fibrinogen, lymphocyte numbers and CD56(dim)CD16(+) NK cells were similar between the two groups.
These results indicate immune dysfunction as potential contributors to the mechanism of CFS, as indicated by decreases in neutrophil respiratory burst, NK cell activity and NK phenotypes. Thus, immune cell function and phenotypes may be important diagnostic markers for CFS. The absence of rheological changes may indicate no abnormalities in erythrocytes of CFS patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background: It is currently inconclusive whether different intracytoplasmic sperm injection (ICSI) timings post oocyte retrieval (POR) lead to altered chance of clinical pregnancy and live birth ...following in vitro fertilization (IVF) treatment. This study, therefore, aimed to synthesize literature-based evidence for better clinical guidance regarding ICSI practice. Methods: A systematic review and meta-analysis were performed according to PRISMA guidelines. Studies were searched for in PubMed, MEDLINE, EMBASE, and the Cochrane Library. Outcome endpoints included clinical pregnancy and live birth rates (LBRs). Results: A total of 605 records were retrieved in the initial search. After exclusion, 30 articles were included for further screening for eligibility. For meta-analysis, 1 prospective and 5 retrospective cohort studies were included for pooled analysis, from which clinical pregnancy rates (CPRs) were evaluated in 6 studies while LBRs were evaluated in 3 studies. CPRs were comparable when ICSI was performed at (a) Formula: see text hours POR (risk ratio or RR = 1.00, Formula: see text confidence interval CI 0.94–1.08) vs Formula: see text hours, (b) Formula: see text hours (RR = 1.01, Formula: see text CI 0.88–1.16) vs Formula: see text hours, (c) Formula: see text hours (RR = 0.99, Formula: see text CI 0.93–1.05) vs Formula: see text hours, (d) Formula: see text hours (RR = 0.98, Formula: see text CI 0.93–1.02) vs Formula: see text hours, and (e) Formula: see text hours (RR = 1.05, Formula: see text CI 0.90–1.23) vs Formula: see text hours. However, LBR was reduced when ICSI was performed Formula: see text hours POR vs Formula: see text hours (RR = 0.94, Formula: see text CI 0.89–0.99), but such reduction disappeared when comparing Formula: see text hours POR (RR = 1.09, Formula: see text CI 0.85–1.38) vs Formula: see text hours. Conclusions: CPRs remain comparable when ICSI is performed at a range of timings up to 6-hour POR. However, LBR may benefit slightly by scheduling ICSI between 5- and 6-hour POR.
Cholesterol-rich caveolar microdomains and associated caveolins influence sarcolemmal ion channel and receptor function and protective stress signaling. However, the importance of membrane ...cholesterol content to cardiovascular function and myocardial responses to ischemia-reperfusion (I/R) and cardioprotective stimuli are unclear. We assessed the effects of graded cholesterol depletion with methyl-β-cyclodextrin (MβCD) and lifelong knockout (KO) or overexpression (OE) of caveolin-3 (Cav-3) on cardiac function, I/R tolerance, and opioid receptor (OR)-mediated protection. Langendorff-perfused hearts from young male C57Bl/6 mice were untreated or treated with 0.02-1.0 mM MβCD for 25 min to deplete membrane cholesterol and disrupt caveolae. Hearts were subjected to 25-min ischemia/45-min reperfusion, and the cardioprotective effects of morphine applied either acutely or chronically sustained ligand-activated preconditioning (SLP) were assessed. MβCD concentration dependently reduced normoxic contractile function and postischemic outcomes in association with graded (10-30%) reductions in sarcolemmal cholesterol. Cardioprotection with acute morphine was abolished with ≥20 μM MβCD, whereas SLP was more robust and only inhibited with ≥200 μM MβCD. Deletion of Cav-3 also reduced, whereas Cav-3 OE improved, myocardial I/R tolerance. Protection via SLP remained equally effective in Cav-3 KO mice and was additive with innate protection arising with Cav-3 OE. These data reveal the membrane cholesterol dependence of normoxic myocardial and coronary function, I/R tolerance, and OR-mediated cardioprotection in murine hearts (all declining with cholesterol depletion). In contrast, baseline function appears insensitive to Cav-3, whereas cardiac I/R tolerance parallels Cav-3 expression. Novel SLP appears unique, being less sensitive to cholesterol depletion than acute OR protection and arising independently of Cav-3 expression.
New Findings
What is the central question of this study?
The extent to which genetics determines adaptation to endurance versus resistance exercise is unclear. Previously, a divergent selective ...breeding rat model showed that genetic factors play a major role in the response to aerobic training. Here, we asked: do genetic factors that underpin poor adaptation to endurance training affect adaptation to functional overload?
What is the main finding and its importance?
Our data show that heritable factors in low responders to endurance training generated differential gene expression that was associated with impaired skeletal muscle hypertrophy. A maladaptive genotype to endurance exercise appears to dysregulate biological processes responsible for mediating exercise adaptation, irrespective of the mode of contraction stimulus.
Divergent skeletal muscle phenotypes result from chronic resistance‐type versus endurance‐type contraction, reflecting the principle of training specificity. Our aim was to determine whether there is a common set of genetic factors that influence skeletal muscle adaptation to divergent contractile stimuli. Female rats were obtained from a genetically heterogeneous rat population and were selectively bred from high responders to endurance training (HRT) or low responders to endurance training (LRT; n = 6/group; generation 19). Both groups underwent 14 days of synergist ablation to induce functional overload of the plantaris muscle before comparison to non‐overloaded controls of the same phenotype. RNA sequencing was performed to identify Gene Ontology biological processes with differential (LRT vs. HRT) gene set enrichment. We found that running distance, determined in advance of synergist ablation, increased in response to aerobic training in HRT but not LRT (65 ± 26 vs. −6 ± 18%, mean ± SD, P < 0.0001). The hypertrophy response to functional overload was attenuated in LRT versus HRT (20.1 ± 5.6 vs. 41.6 ± 16.1%, P = 0.015). Between‐group differences were observed in the magnitude of response of 96 upregulated and 101 downregulated pathways. A further 27 pathways showed contrasting upregulation or downregulation in LRT versus HRT in response to functional overload. In conclusion, low responders to aerobic endurance training were also low responders for compensatory hypertrophy, and attenuated hypertrophy was associated with differential gene set regulation. Our findings suggest that genetic factors that underpin aerobic training maladaptation might also dysregulate the transcriptional regulation of biological processes that contribute to adaptation to mechanical overload.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Mildly elevated circulating unconjugated bilirubin (UCB) is associated with protection against hypertension and ischemic heart disease. We assessed whether endogenously elevated bilirubin in Gunn ...rats modifies cardiovascular function and resistance to ischemic insult. Hearts were assessed ex vivo (Langendorff perfusion) and in vivo (Millar catheterization and echocardiography), and left ventricular myocardial gene expression was measured via quantitative real-time PCR. Ex vivo analysis revealed reduced intrinsic contractility in the Gunn myocardium (+dP/dt: 1,976 ± 622 vs. 2,907 ± 334 mmHg/s, P < 0.01; -dP/dt: -1,435 ± 372 vs. -2,234 ± 478 mmHg/s, P < 0.01), which correlated positively with myocardial UCB concentration (P < 0.05). In vivo analyses showed no changes in left ventricular contractile parameters and ejection (fractional shortening and ejection fraction). However, Gunn rats exhibited reductions in the rate of aortic pressure development (3,008 ± 461 vs. 4,452 ± 644 mmHg/s, P < 0.02), mean aortic velocity (439 ± 64 vs. 644 ± 62 mm/s, P < 0.01), and aortic volume time integral pressure gradient (2.32 ± 0.65 vs. 5.72 ± 0.74 mmHg, P < 0.01), in association with significant aortic dilatation (12-24% increase in aortic diameter, P < 0.05). Ex vivo Gunn hearts exhibited improved ventricular function after 35 min of ischemia and 90 min of reperfusion (63 ± 14 vs. 35 ± 12%, P < 0.01). These effects were accompanied by increased glutathione peroxidase and reduced superoxide dismutase and phospholamban gene expression in Gunn rat myocardium (P < 0.05). These data collectively indicate that hyperbilirubinemia in Gunn rats 1) reduces intrinsic cardiac contractility, which is compensated for in vivo; 2) induces aortic dilatation, which may beneficially influence aortic ejection velocities and pressures; and 3) may improve myocardial stress resistance in association with beneficial transcriptional changes. These effects may contribute to protection from cardiovascular disease with elevated bilirubin.