Obesity-related adipose tissue (AT) dysfunction, in particular subcutaneous AT (SCAT) lipolysis, is characterized by catecholamine resistance and impaired atrial natriuretic peptide (ANP) responsiveness. It remains unknown whether exercise training improves (non-)adrenergically mediated lipolysis in metabolically compromised conditions. We investigated the effects of local combined α-/β-adrenoceptor blockade on abdominal SCAT lipolysis in lean insulin sensitive (IS) ( n =10), obese IS ( n =10), and obese insulin resistant (IR) ( n =10) men. Obese men participated in a 12-week exercise training intervention to determine the effects on SCAT lipolysis. Abdominal SCAT extracellular glycerol concentration and blood flow (ATBF) were investigated using microdialysis, with/without locally combined α-/β-adrenoceptor blockade at rest, during low-intensity endurance-type exercise and post-exercise recovery. In obese IR men, microdialysis was repeated after exercise intervention. The exercise-induced increase in SCAT extracellular glycerol was more pronounced in obese IS compared with lean IS men, possibly resulting from lower ATBF in obese IS men. The exercise-induced increase in extracellular glycerol was blunted in obese IR compared with obese IS men, despite comparable local ATBF. Abdominal SCAT extracellular glycerol was markedly reduced (remaining ~60% of exercise-induced SCAT extracellular glycerol) following the local α-/β-adrenoceptor blockade in obese IS but not in IR men, suggesting reduced catecholamine-mediated lipolysis during exercise in obese IR men. Exercise training did not affect (non-)adrenergically mediated lipolysis in obese IR men. Our findings showed a major contribution of non-adrenergically-mediated lipolysis during exercise in male abdominal SCAT. Furthermore, catecholamine-mediated lipolysis may be blunted during exercise in obese IR men but could not be improved by exercise intervention, despite an improved metabolic profile and body composition.

During healthy pregnancy, the cardiovascular system undergoes diverse adaptations to support adequate transfer of oxygen and nutrients from mother to fetus. In order to accommodate the large expansion of blood volume and associated cardiac output, the structure, mechanics, and function of the arteries are altered. Specifically, in healthy pregnancy there is a remodeling of arteries (increased angiogenesis and vasodilation), a generalized reduction in arterial stiffness (increased compliance), and an enhanced endothelial function. The development of pregnancy complications, specifically pre-eclampsia, is associated with poor placentation (decreased angiogenesis), increased arterial stiffness, and vascular dysfunction (reduced endothelial function). Many of the positive adaptations that occur in healthy pregnancy are enhanced in response to chronic exercise. Specifically, placental angiogenesis and endothelial function have been shown to improve to a greater extent in women who are active during their pregnancy compared with those who are not. Prenatal exercise may be important in helping to reduce the risk of vascular dysfunction in pregnancy. However, our knowledge of the vascular adaptations resulting from maternal exercise is limited. This review highlights maternal vascular adaptations occurring during healthy pregnancy, and contrasts the vascular maladaptation associated with pre-eclampsia. Finally, we discuss the role of prenatal exercise on vascular function in the potential prevention of vascular complications associated with pre-eclampsia.

G551D, a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, results in impaired chloride channel function in cystic fibrosis (CF) with multiple end-organ manifestations. The effect of ivacaftor, a CFTR-potentiator, on exercise capacity in CF is unknown. Twenty G551D-CF patients were recruited to a single-centre, double-blind, placebo-controlled, 28-day crossover study of ivacaftor. Variables measured included percentage change from baseline (%Δ) of V O 2 max (maximal oxygen consumption, primary outcome) during cardiopulmonary exercise testing (CPET), relevant other CPET physiological variables, lung function, body mass index (BMI), sweat chloride and disease-specific health related quality of life (QOL) measures (CFQ-R and Alfred Wellness (AWEscore)). %Δ V O 2 max was unchanged compared with placebo as was %Δminute ventilation. However, %Δexercise time (mean 7.3, CI 0.5–14,1, P =0.0222) significantly increased as did %ΔFEV 1 (11.7%, range 5.3–18.1, P <0·005) and %ΔBMI (1.2%, range 0.1–2.3, P =0·0393) whereas sweat chloride decreased (mean −43.4; range −55.5–18.1 mmol·l −1 , P <0·005). Total and activity based domains in both CFQ-R and AWEscore also increased. A positive treatment effect on spirometry, BMI (increased), SCT (decreased) and total and activity based CF-specific QOL measures was expected. However, the lack of discernible improvement in V O 2 max and VE despite other positive changes including spirometric lung function and exercise time with a 28-day ivacaftor intervention suggests that ventilatory parameters are not the sole driver of change in exercise capacity in this study cohort. Investigation over a more prolonged period may delineate the potential interdependencies of the observed discordances over time. Trial registration number: ClinicalTrials.gov-NCT01937325.

Background: Exercise and citrulline (CIT) are both regulators of muscle protein metabolism. However, the combination of both has been under-studied yet may have synergistic effects on muscle metabolism and performance. Methods: Three-month-old healthy male rats were randomly assigned to be fed ad libitum for 4 weeks with either a citrulline-enriched diet (1 g·kg −1 ·day −1 ) ( CIT ) or an isonitrogenous standard diet (by addition of nonessential amino acid) ( Ctrl ) and trained (running on treadmill 5 days·week −1 ) ( ex ) or not. Maximal endurance activity and body composition were assessed, and muscle protein metabolism (protein synthesis, proteomic approach) and energy metabolism [energy expenditure, mitochondrial metabolism] were explored. Results: Body composition was affected by exercise but not by CIT supplementation. Endurance training was associated with a higher maximal endurance capacity than sedentary groups ( P <0.001), and running time was 14% higher in the CITex group than the Ctrlex group (139±4 min versus 122±6 min, P <0.05). Both endurance training and CIT supplementation alone increased muscle protein synthesis (by +27% and +33%, respectively, versus Ctrl , P <0.05) with an additive effect (+48% versus Ctrl , P <0.05). Mitochondrial metabolism was modulated by exercise but not directly by CIT supplementation. However, the proteomic approach demonstrated that CIT supplementation was able to affect energy metabolism, probably due to activation of pathways generating acetyl-CoA. Conclusion: CIT supplementation and endurance training in healthy male rats modulates both muscle protein and energy metabolisms, with synergic effects on an array of parameters, including performance and protein synthesis.

Type 2 diabetes (T2D) is characterized by insulin resistance, mitochondrial dysregulation and, in some studies, exercise resistance in skeletal muscle. Regulation of autophagy and mitochondrial dynamics during exercise and recovery is important for skeletal muscle homoeostasis, and these responses may be altered in T2D. We examined the effect of acute exercise on markers of autophagy and mitochondrial fusion and fission in skeletal muscle biopsies from patients with T2D ( n =13) and weight-matched controls ( n =14) before, immediately after and 3 h after an acute bout of exercise. Although mRNA levels of most markers of autophagy [ PIK3C , MAP1LC3B , sequestosome 1 ( SQSTM1 ), BCL-2/adenovirus E1B 19-kDa-interacting protein 3 ( BNIP3 ), BNIP3-like ( BNIP3L )] and mitochondrial dynamics [optic atrophy 1 ( OPA1 ), fission protein 1 ( FIS1 )] remained unchanged, some either increased during and after exercise ( GABARAPL1 ), decreased in the recovery period [ BECN1 , autophagy-related ( ATG ) 7, DNM1L ] or both [mitofusin ( MFN ) 2 , mitochondrial E3 ubiquitin ligase 1 ( MUL1 )]. Protein levels of ATG7, p62/SQSTM1, forkhead box O3A (FOXO3A) and MFN2 (only controls) as well as dynamin-related protein 1 (DRP1) Ser 616 phosphorylation increased in response to exercise and/or recovery, whereas microtubule-associated protein 1 light chain 3B (LC3B)-II content was reduced immediately after exercise. Exercise increased the activating Ser 555 phosphorylation and reduced the inhibitory Ser 757 phosphorylation of Unc-51-like kinase-1 (ULK1). The LC3B-II content and phosphorylation of ULK1 and DRP1 returned towards pre-exercise levels in the recovery period. Insulin sensitivity was reduced in T2D, but with no differences in the autophagic response to exercise. Our results demonstrate that initiation of autophagy and mitochondrial fission is activated by exercise in human skeletal muscle, and that these responses are intact in T2D. The exercise-induced decrease in LC3B-II could be due to increased autophagic turnover.

Breast cancer (BC) survival rates have improved during the past two decades and as a result older BC survivors are at increased risk of developing heart failure (HF). Although the HF phenotype common to BC survivors has received little attention, BC survivors have a number of risk factors associated with HF and preserved ejection fraction (HFPEF) including older age, hypertension, obesity, metabolic syndrome and sedentary lifestyle. Moreover, not unlike HFPEF, BC survivors with preserved left ventricular ejection fraction (BCPEF) have reduced exercise tolerance measured objectively as decreased peak oxygen uptake (peak VO 2 ). This review summarizes the literature regarding the mechanisms of exercise intolerance and the role of exercise training to improve peak VO 2 in BCPEF.

A high demand on thermoregulatory processes may challenge homoeostasis, particularly regarding glucose regulation. This has been understudied, although it might concern millions of humans. The objective of this project was to examine the isolated and combined effects of experimental short-term mild heat exposure and metabolic level on glucoregulation. Two experimental randomized crossover studies were conducted. Ten healthy young men participated in study A, which comprises four sessions in a fasting state at two metabolic levels [rest and exercise at 60% of maximal oxygen uptake ( O 2 ) for 40 min] in two environmental temperatures (warm: 31°C and control: 22°C). Each session ended with an ad libitum meal, resulting in similar energy intake across sessions. In study B, 12 healthy young men underwent two 3 h oral glucose tolerance tests (OGTTs) in warm and control environmental temperatures. Venous blood was sampled at several time points. In study A, repeated measure ANOVAs revealed higher postprandial serum glucose and insulin levels with heat exposure. Glycaemia following the OGTT was higher in the warm temperature compared with control. The kinetics of the serum glucose response to the glucose load was also affected by the environmental temperature (temperature-by-time interaction, P =0.030), with differences between the warm and control conditions observed up to 90 min after the glucose load (all P <0.033). These studies provide evidence that heat exposure alters short-term glucoregulation. The implication of this environmental factor in the physiopathology of Type 2 diabetes has yet to be investigated.

Cerebral blood flow (CBF) regulation is an indicator of cerebrovascular health increasingly recognized as being influenced by physical activity. Although regular exercise is recommended during healthy pregnancy, the effects of exercise on CBF regulation during this critical period of important blood flow increase and redistribution remain incompletely understood. Moreover, only a few studies have evaluated the effects of human pregnancy on CBF regulation. The present work summarizes current knowledge on CBF regulation in humans at rest and during aerobic exercise in relation to healthy pregnancy. Important gaps in the literature are highlighted, emphasizing the need to conduct well-designed studies assessing cerebrovascular function before, during and after this crucial life period to evaluate the potential cerebrovascular risks and benefits of exercise during pregnancy.

Non-alcoholic fatty liver disease (NAFLD) is associated with multi-organ (hepatic, skeletal muscle, adipose tissue) insulin resistance (IR). Exercise is an effective treatment for lowering liver fat but its effect on IR in NAFLD is unknown. We aimed to determine whether supervised exercise in NAFLD would reduce liver fat and improve hepatic and peripheral (skeletal muscle and adipose tissue) insulin sensitivity. Sixty nine NAFLD patients were randomized to 16 weeks exercise supervision ( n =38) or counselling ( n =31) without dietary modification. All participants underwent MRI/spectroscopy to assess changes in body fat and in liver and skeletal muscle triglyceride, before and following exercise/counselling. To quantify changes in hepatic and peripheral insulin sensitivity, a pre-determined subset ( n =12 per group) underwent a two-stage hyperinsulinaemic euglycaemic clamp pre- and post-intervention. Results are shown as mean [95% confidence interval (CI)]. Fifty participants (30 exercise, 20 counselling), 51 years (IQR 40, 56), body mass index (BMI) 31 kg/m 2 (IQR 29, 35) with baseline liver fat/water % of 18.8% (IQR 10.7, 34.6) completed the study (12/12 exercise and 7/12 counselling completed the clamp studies). Supervised exercise mediated a greater reduction in liver fat/water percentage than counselling [Δ mean change 4.7% (0.01, 9.4); P <0.05], which correlated with the change in cardiorespiratory fitness ( r =–0.34, P =0.0173). With exercise, peripheral insulin sensitivity significantly increased (following high-dose insulin) despite no significant change in hepatic glucose production (HGP; following low-dose insulin); no changes were observed in the control group. Although supervised exercise effectively reduced liver fat, improving peripheral IR in NAFLD, the reduction in liver fat was insufficient to improve hepatic IR.

Although lifestyle changes encompassing weight loss and exercise remain the cornerstone of non-alcoholic fatty liver disease (NAFLD) management, the effect of different types of exercise on NAFLD is unknown. This study defines the effect of modified high-intensity interval training (HIIT) on liver fat, cardiac function and metabolic control in adults with NAFLD. Twenty-three patients with NAFLD [age 54±10 years, body mass index (BMI) 31±4 kg/m 2 , intra-hepatic lipid >5%) were assigned to either 12 weeks HIIT or standard care (controls). HIIT involved thrice weekly cycle ergometry for 30–40 min. MRI and spectroscopy were used to assess liver fat, abdominal fat and cardiac structure/function/energetics. Glucose control was assessed by oral glucose tolerance test and body composition by air displacement plethysmography. Relative to control, HIIT decreased liver fat (11±5% to 8±2% compared with 10±4% to 10±4% P =0.019), whole-body fat mass (35±7 kg to 33±8 kg compared with 31±9 kg to 32±9 kg, P =0.013), alanine (52±29 units/l to 42±20 units/l compared with 47±22 units/l to 51±24 units/l, P =0.016) and aspartate aminotransferase (AST; 36±18 units/l to 33±15 units/l compared with 31±8 units/l to 35±8 units/l, P =0.017) and increased early diastolic filling rate (244±84 ml/s to 302±107 ml/s compared with 255±82 ml/s to 251±82 ml/s, P =0.018). There were no between groups differences in glucose control. Modified HIIT reduces liver fat and improves body composition alongside benefits to cardiac function in patients with NAFLD and should be considered as part of the broader treatment regimen by clinical care teams. ISRCTN trial ID: ISRCTN78698481.

Compared with eumenorrhoeic women, exercise-trained women with functional hypothalamic amenorrhoea (ExFHA) exhibit low heart rates (HRs) and absent reflex renin–angiotensin-system activation and augmentation of their muscle sympathetic nerve response to orthostatic stress. To test the hypothesis that their autonomic HR modulation is altered concurrently, three age-matched (pooled mean, 24±1 years; mean ± S.E.M.) groups of women were studied: active with either FHA (ExFHA; n =11) or eumenorrhoeic cycles (ExOv; n =17) and sedentary with eumenorrhoeic cycles (SedOv; n =17). Blood pressure (BP), HR and HR variability (HRV) in the frequency domain were determined during both supine rest and graded lower body negative pressure (LBNP; −10, −20 and −40 mmHg). Very low (VLF), low (LF) and high (HF) frequency power spectra (ms 2 ) were determined and, owing to skewness, log 10 -transformed. LF/HF ratio and total power (VLF + LF + HF) were calculated. At baseline, HR and systolic BP (SBP) were lower ( P <0.05) and HF and total power were higher ( P <0.05) in ExFHA than in eumenorrhoeic women. In all groups, LBNP decreased ( P <0.05) SBP, HF and total power and increased ( P <0.05) HR and LF/HF ratio. However, HF and total power remained higher ( P <0.05) and HR, SBP and LF/HF ratio remained lower ( P <0.05) in ExFHA than in eumenorrhoeic women, in whom measures did not differ ( P >0.05). At each stage, HR correlated inversely ( P <0.05) with HF. In conclusion, ExFHA women demonstrate augmented vagal yet unchanged sympathetic HR modulation, both at rest and during orthostatic stress. Although the role of oestrogen deficiency is unclear, these findings are in contrast with studies reporting decreased HRV in hypoestrogenic post-menopausal women.

Skeletal muscle metabolism is highly dependent on mitochondrial function, with impaired mitochondrial biogenesis associated with the development of metabolic diseases such as insulin resistance and type 2 diabetes. Mitochondria display substantial plasticity in skeletal muscle, and are highly sensitive to levels of physical activity. It is thought that physical activity promotes mitochondrial biogenesis in skeletal muscle through increased expression of genes encoded in both the nuclear and the mitochondrial genome; however, how this process is co-ordinated at the cellular level is poorly understood. Nuclear receptors (NRs) are key signalling proteins capable of integrating environmental factors and mitochondrial function, thereby providing a potential link between exercise and mitochondrial biogenesis. The aim of this review is to highlight the function of NRs in skeletal muscle mitochondrial biogenesis and discuss the therapeutic potential of NRs for the management and treatment of chronic metabolic disease.

Exercise and hypoxia paradoxically modulate vascular thrombotic risks. The shedding of procoagulant-rich microparticles from monocytes may accelerate the pathogenesis of atherothrombosis. The present study explores the manner in which normoxic and hypoxic exercise regimens affect procoagulant monocyte-derived microparticle (MDMP) formation and monocyte-promoted thrombin generation (TG). Forty sedentary healthy males were randomized to perform either normoxic (NET; 21% O 2 , n =20) or hypoxic (HET; 15% O 2 , n =20) exercise training (60% V O 2max ) for 30 min/day, 5 days/week for 5 weeks. At rest and immediately after HET (100 W under 12% O 2 for 30 min), the MDMP characteristics and dynamic TG were measured by flow cytometry and thrombinography respectively. The results demonstrated that acute 12% O 2 exercise (i) increased the release of coagulant factor V (FV)/FVIII-rich, phosphatidylserine (PS)-exposed and tissue factor (TF)-expressed microparticles from monocytes, (ii) enhanced the peak height and rate of TG in monocyte-rich plasma (MRP) and (iii) elevated concentrations of norepinephrine/epinephrine, myeloperoxidase (MPO) and interleukin-6 (IL-6) in plasma. Following the 5-week intervention, HET exhibited higher enhancements of peak work-rate and cardiopulmonary fitness than NET did. Moreover, both NET and HET decreased the FV/FVIII-rich, PS-exposed and TF-expressed MDMP counts and the peak height and rate of TG in MRP following the HET. However, HET elicited more suppression for the HE (hypoxic exercise)-enhanced procoagulant MDMP formation and dynamic TG in MPR and catecholamine/peroxide/pro-inflammatory cytokine levels in plasma than NET. Hence, we conclude that HET is superior to NET for enhancing aerobic capacity. Furthermore, HET effectively suppresses procoagulant MDMP formation and monocyte-mediated TG under severe hypoxic stress, compared with NET.

Acute hypoxic exposure increases vascular thrombotic risk. The release of procoagulant-rich microparticles from neutrophils accelerates the pathogenesis of inflammatory thrombosis. The present study explicates the manner in which interval and continuous exercise regimens affect neutrophil-derived microparticle (NDMP) formation and neutrophil/NDMP-mediated thrombin generation (TG) under hypoxic condition. A total of 60 sedentary males were randomized to perform either aerobic interval training [AIT; 3-min intervals at 40% and 80% V ̇ O 2max (maximal O 2 consumption)] or moderate continuous training (MCT; sustained 60% V ̇ O 2max ) for 30 min/day, 5 days/week for 5 weeks, or to a control (CTL) group who did not receive any form of training. At rest and immediately after hypoxic exercise test (HE, 100 W under 12% O 2 for 30 min), the NDMP characteristics and dynamic TG were measured by flow cytometry and thrombinography respectively. Before the intervention, HE (i) elevated coagulant factor VIII/fibrinogen concentrations and shortened activated partial thromboplastin time (aPTT), (ii) increased total and tissue factor (TF)-rich/phosphatidylserine (PS)-exposed NDMP counts and (iii) enhanced the peak height and rate of TG promoted by neutrophils/NDMPs. Following the 5-week intervention, AIT exhibited higher enhancement of V ̇ O 2max than did MCT. Notably, both MCT and AIT attenuated the extents of HE-induced coagulant factor VIII/fibrinogen elevations and aPTT shortening. Furthermore, the two exercise regimens significantly decreased TF-rich/PS-exposed NDMP formation and depressed neutrophil/NDMP-mediated dynamic TG at rest and following HE. Hence, we conclude that AIT is superior to MCT for enhancing aerobic capacity. Moreover, either AIT or MCT effectively ameliorates neutrophil/NDMP-promoted TG by down-regulating expression of procoagulant factors during HE, which may reduce thrombotic risk evoked by hypoxia. Moreover, either AIT or MCT effectively ameliorates neutrophil/NDMP-promoted TG by down-regulating expression of procoagulant factors during HE, which may reduce thrombotic risk evoked by hypoxia.

Habitual aerobic exercise prevents age-related impairments in endothelium-dependent dilation (EDD). We have hypothesized that the pro-inflammatory transcription factor nuclear factor κB (NF-κB) impairs EDD with sedentary aging, and habitual aerobic exercise prevents this age-related suppression of EDD by NF-κB. To test this hypothesis, we have inhibited NF-κB signalling via oral salsalate administration in healthy older aerobic exercise-trained adults (OT, n =14, 58±2 years), older non-exercising adults (ON, n =16, 61±1 years) and young non-exercising controls (YN, n =8, 23±1 years). Salsalate reduced endothelial cell expression of NF-κB p65 by ~25% in ON ( P <0.05) but did not significantly change expression in OT or YN ( P >0.05). EDD, assessed by brachial artery flow-mediated dilation (FMD), was improved by salsalate in ON (4.0±0.7% compared with 6.8±0.7%, placebo compared with salsalate, P <0.001) but did not change with salsalate in OT or YN (OT: 7.2±0.7% compared with 7.7±0.6%; YN: 7.6±0.9% compared with 8.1±0.8%; placebo compared with salsalate, P >0.05). Endothelium-independent dilation was not affected by salsalate in any group ( P >0.05). In ON, vitamin C infusion improved FMD by ~30% during placebo ( P <0.001) but had no affect during salsalate ( P >0.05). In OT and YN, vitamin C infusion did not affect FMD during either placebo or salsalate ( P >0.05). Salsalate reduced endothelial cell nitrotyrosine content by ~25% and NADPH oxidase p47 phox expression by ~30% in ON ( P <0.05) but had no effect in OT or YN ( P >0.05). Our results suggest that endothelial NF-κB signalling is associated with oxidative stress-related impairment of EDD in healthy non-exercising but not aerobically exercising older adults. This may be a key mechanism by which regular aerobic exercise preserves endothelial function and reduces cardiovascular risk with aging.

Variation in genes encoding the β 2 -adrenergic receptor ( ADRB2 ) and angiotensin-converting enzyme ( ACE ) may influence Q ̇ (cardiac output). The 46G>A (G16R) SNP (single nucleotide polymorphism) has been associated with β 2 -mediated vasodilation, but the effect of ADRB2 haplotypes on Q ̇ has not been studied. Five SNPs within ADRB2 (46G>A, 79C>G, 491C>T, 523C>A and 1053G>C by a pairwise tagging principle) and the I/D (insertion/deletion) polymorphism in ACE were genotyped in 143 subjects. Cardiovascular variables were evaluated by the Model flow method at rest and during incremental cycling exercise. Only the G16R polymorphism was associated with Q ̇. In carriers of the Arg 16 allele, Q ̇ rest (resting Q ̇) was 0.4 [95% CI (confidence interval), 0.0–0.7] l/min lower than in G16G homozygotes ( P =0.048). During exercise, the increase in Q ̇ was by 4.7 (95% CI, 4.3–5.2) l/min per litre increase in pulmonary V ̇ O 2 (oxygen uptake) in G16G subjects, but the increase was 0.5 (0.0–0.9) l/min lower in Arg 16 carriers ( P =0.035). A similar effect size was observed for the Arg 16 haplotypes ACCCG and ACCCC. No interaction was found between ADRB2 and ACE polymorphisms. During exercise, the increase in Q ̇ was 0.5 (CI, 0.0 –1.0) l/min greater in ACE I/I carriers compared with I/D and D/D subjects ( P =0.054). In conclusion, the ADRB2 Arg 16 allele in humans is associated with a lower Q ̇ both at rest and during exercise, overriding the effects of haplotypes.

Autonomic dysfunction has been reported in patients with NAFLD (non-alcoholic fatty liver disease) and is associated with clinical presentations. To date, there are no therapies to improve autonomic regulation in people with NAFLD. The present study defines the impact of a short-term exercise programme on cardiac autonomic and haemodynamic regulation in patients with NAFLD. A total of 17 patients with clinically defined NAFLD [age, 55±12 years; BMI (body mass index), 33±5 kg/m 2 ; liver fat, 17±9%] were randomized to 8 weeks of resistance exercise or a control group to continue standard care. Resting and submaximal exercise (50% of peak oxygen consumption) autonomic and cardiac haemodynamic measures were assessed before and after the intervention. Resistance exercise resulted in a 14% reduction in HR (heart rate) and 7% lower SBP (systolic blood pressure) during submaximal exercise (16 beats/min, P =0.03 and 16 mmHg, P =0.22). Sympathovagal balance, expressed as LF/HF (low-frequency/high-frequency) ratio of the mean HR beat-to-beat (R–R) interval, was reduced by 37% ( P =0.26). Similarly sympathovagal balance of DBP (diastolic blood pressure) and SBP variability decreased by 29% ( P =0.33) and 19% ( P =0.55), respectively in the exercise group only. BRS (baroreflex sensitivity) increased by 31% ( P =0.08) following exercise. The mean R–R interval increased by 23% (159 ms, P =0.09). Parasympathetic regulation was decreased by 17% ( P =0.05) and overall sympathovagal balance in BP regulation (LF/HF ratio) increased by 26% ( P =0.02) following resistance exercise. Resting haemodynamic measures remained similar between groups. Resistance exercise therapy seems to improve autonomic and submaximal exercise haemodynamic regulation in NAFLD. Further studies are required to define its role in clinical management of the condition.

The cytotoxic functions of NKs (natural killer cells) are critical in enabling the immune system to cope efficiently with malignancy. In the present study, we compared how various exercise regimens without/with hypoxia influence phenotypic characteristics of NK subsets and cytotoxicity of NKs to NPCs (nasopharyngeal carcinoma cells). A total of 60 sedentary males were randomly divided into five groups. Each group ( n =12) underwent one of five regimens: normoxic (21% O 2 ) control (N-C), hypoxic (15% O 2 ) control (H-C), normoxic exercise (50% maximal work rate under 21% O 2 ; N-E), hypoxic relative exercise (50% maximal heart rate reserve under 15% O 2 ; H-RE) or hypoxic absolute exercise (50% maximal work rate under 15% O 2 ; H-AE) for 30 min/day, 5 days/week for 4 weeks. The results showed that hypoxic exercise regimens increased pulmonary ventilation and tissue oxygen utilization. Moreover, the H-RE regimen resulted in enhanced aerobic fitness at a less intensive training workload in the H-AE regimen. Before each regimen, strenuous exercise elevated NK perforin/granzyme B content and promoted cytotoxicity of NKs to NPCs. However, the percentage of NKs expressing homing (CD11a)/terminally differentiated (CD57)/inhibitory [KLRG1 (killer cell lectin-like receptor G1)] molecules that entered the bloodstream from peripheral tissues increased following this exercise. After 4 weeks, both the H-AE and H-RE regimens produced an up-regulated expression of memory (CD45RO)/activating (NKG2D) molecules and was accompanied by a decrease in CD57/KLRG1 levels on NKs at rest and after strenuous exercise. Furthermore, the two regimens increased resting and exercise NK perforin/granzyme B content and NK-induced phosphatidylserine exposure of NPCs. In contrast, no significant change in the phenotypic characteristics of blood NK subsets or NK-induced NPC apoptosis was observed in the N-C, H-C and N-E regimens. Therefore we conclude that 15% O 2 exercise training reduces terminally differentiated NK subsets and up-regulates the expression of activating molecules and cytotoxic granule proteins in NKs, thereby enhancing the capacity of anti-NPC cytotoxicity by NKs. These findings could help to determine effective hypoxic exercise regimens for improving individual aerobic capacity and simultaneously promoting the natural cytotoxicity of NKs.

Whether brachial artery FMD (flow-mediated dilation) is altered in pregnancy by 28–35 weeks compared with non-pregnant women remains controversial. The controversy may be due to limitations of previous studies that include failing to: (i) test non-pregnant controls in the mid-late luteal phase, (ii) account for effects of pregnancy on the dilatory shear stimulus, (iii) account for physical activity or (iv) control for inter-individual variation in the time to peak FMD. In the present study, brachial artery FMD was measured in 17 active and eight sedentary pregnant women (34.1±1.6 weeks of gestation), and in 19 active and 11 sedentary non-pregnant women (mid-late luteal phase). Decreased vascular tone secondary to increased shear stress contributes minimally to pregnancy-induced increases in baseline brachial artery diameter, as shear stress removal during distal cuff inflation in pregnant women did not reduce diameter to baseline levels observed in non-pregnant controls. Neither the shear stimulus nor the percentage FMD was affected by pregnancy or regular exercise. Continuous diameter measurements are required to control for delayed peak dilation during pregnancy (57±15 compared with 46±15 s; P =0.012), as post-release diameter measured at 60 or 55–65 s post-release underestimated FMD to a greater extent in non-pregnant than in pregnant women.

Humans are not programmed to be inactive. The combination of both accelerated sedentary lifestyle and constant food availability disturbs ancient metabolic processes leading to excessive storage of energy in tissue, dyslipidaemia and insulin resistance. As a consequence, the prevalence of Type 2 diabetes, obesity and the metabolic syndrome has increased significantly over the last 30 years. A low level of physical activity and decreased daily energy expenditure contribute to the increased risk of cardiovascular morbidity and mortality following atherosclerotic vascular damage. Physical inactivity leads to the accumulation of visceral fat and consequently the activation of the oxidative stress/inflammation cascade, which promotes the development of atherosclerosis. Considering physical activity as a ‘natural’ programmed state, it is assumed that it possesses atheroprotective properties. Exercise prevents plaque development and induces the regression of coronary stenosis. Furthermore, experimental studies have revealed that exercise prevents the conversion of plaques into a vulnerable phenotype, thus preventing the appearance of fatal lesions. Exercise promotes atheroprotection possibly by reducing or preventing oxidative stress and inflammation through at least two distinct pathways. Exercise, through laminar shear stress activation, down-regulates endothelial AT 1 R (angiotensin II type 1 receptor) expression, leading to decreases in NADPH oxidase activity and superoxide anion production, which in turn decreases ROS (reactive oxygen species) generation, and preserves endothelial NO bioavailability and its protective anti-atherogenic effects. Contracting skeletal muscle now emerges as a new organ that releases anti-inflammatory cytokines, such as IL-6 (interleukin-6). IL-6 inhibits TNF-α (tumour necrosis factor-α) production in adipose tissue and macrophages. The down-regulation of TNF-α induced by skeletal-muscle-derived IL-6 may also participate in mediating the atheroprotective effect of physical activity.

Advancing age is the major risk factor for the development of CVD (cardiovascular diseases). This is attributable, in part, to the development of vascular endothelial dysfunction, as indicated by reduced peripheral artery EDD (endothelium-dependent dilation) in response to chemical [typically ACh (acetylcholine)] or mechanical (intravascular shear) stimuli. Reduced bioavailability of the endothelium-synthesized dilating molecule NO (nitric oxide) as a result of oxidative stress is the key mechanism mediating reduced EDD with aging. Vascular oxidative stress increases with age as a consequence of greater production of reactive oxygen species (e.g. superoxide) without a compensatory increase in antioxidant defences. Sources of increased superoxide production include up-regulation of the oxidant enzyme NADPH oxidase, uncoupling of the normally NO-producing enzyme, eNOS (endothelial NO synthase) (due to reduced availability of the cofactor tetrahydrobiopterin) and increased mitochondrial synthesis during oxidative phosphorylation. Increased bioactivity of the potent endothelial-derived constricting factor ET-1 (endothelin-1), reduced endothelial production of/responsiveness to dilatory prostaglandins, the development of vascular inflammation, formation of AGEs (advanced glycation end-products), an increased rate of endothelial apoptosis and reduced expression of oestrogen receptor α (in postmenopausal females) also probably contribute to impaired EDD with aging. Several lifestyle and biological factors modulate vascular endothelial function with aging, including regular aerobic exercise, dietary factors (e.g. processed compared with non-processed foods), body weight/fatness, vitamin D status, menopause/oestrogen deficiency and a number of conventional and non-conventional risk factors for CVD. Given the number of older adults now and in the future, more information is needed on effective strategies for the prevention and treatment of vascular endothelial aging.

The use of DOX (doxorubicin), an antibiotic used in oncological treatments, is limited by a dose-related cardiotoxicity against which acute exercise is protective. However, the mitochondrial-related mechanisms of this protection remain unknown. Therefore the present study aimed to determine the effects of an acute endurance exercise bout performed 24 h before DOX treatment on heart and liver mitochondrial function. A total of 20 adult male Wistar rats were divided into groups as follows: non-exercised with saline (NE+SAL), non-exercised DOX-treated (NE+DOX), exercised with saline (EX+SAL) and exercised DOX-treated (EX+DOX). The animals performed a 60 min exercise bout on a treadmill or remained sedentary 24 h before receiving either a DOX bolus (20 mg/kg of body weight) or saline. Heart and liver mitochondrial function [oxygen consumption, membrane potential (ΔΨ) and cyclosporin-A-sensitive calcium-induced MPTP (mitochondrial permeability transition pore) opening] were evaluated. The activities of the respiratory complex, Mn-SOD (superoxide dismutase), caspases 3 and 9, as well as the levels of ANT (adenine nucleotide translocase), VDAC (voltage-dependent anion channel), CypD (cyclophilin D), Bax and Bcl-2, were measured. Acute exercise prevented the decreased cardiac mitochondrial function (state 3, phosphorylative lag-phase; maximal ΔΨ generated both with complex I- and II-linked substrates and calcium-induced MPTP opening) induced by DOX treatment. Exercise also prevented the DOX-induced decreased activity of cardiac mitochondrial chain complexes I and V, and increased caspase 3 and 9 activities. DOX administration and exercise caused increased cardiac mitochondrial SOD activity. Exercise ameliorated liver mitochondrial complex activities. No alterations were observed in the measured MPTP and apoptosis-related proteins in heart and liver mitochondria. The results demonstrate that acute exercise protects against cardiac mitochondrial dysfunction, preserving mitochondrial phosphorylation capacity and attenuating DOX-induced decreased tolerance to MPTP opening.

Exercise is part of a healthy lifestyle and frequently is an important component in combating chronic diseases, such as obesity and diabetes. Understanding the molecular events initiated by regular exercise is best studied in laboratory animals, with mice and rats being favoured for a number of reasons. However, the wide variety of rodent strains available for biomedical research often makes it challenging to select an animal strain suitable for studying specific disease outcomes. In the present review we focus on exercise as a management strategy for obesity and diabetes and we discuss: (i) exercise paradigms in humans shown to ameliorate signs and symptoms of obesity and diabetes; (ii) different rodent strains in terms of their advantages, disadvantages and limitations when using specific forms of exercise; (iii) the strengths and weaknesses of commonly used laboratory methods for rodent exercise; and (iv) the unintended consequences of exercise that are often manifested by increased hormonal and oxidative stress responses.

COPD (chronic obstructive pulmonary disease) is the most common pulmonary disease and is the only common cause of death in which mortality is presently rising. It is caused by the inhalation of smoke, which leads to oxidative stress and inflammation both in the lungs and systemically. Reduced physical activity is a well-recognized consequence of the condition, but we argue here that inactivity is itself an early cause of lung function decline and symptoms. This hypothesis is supported by data from population studies that link activity levels to decline in spirometric indices, both in smokers and non-smokers. In addition, smokers with low physical activity levels are more likely to be diagnosed subsequently with COPD. Physical exercise reduces oxidative stress, has an anti-inflammatory effect and reduces the frequency of upper respiratory tract infections, providing a number of mechanisms by which it could attenuate the harmful effects of smoking. There is sufficient evidence to justify population trials of lifestyle interventions aimed at improving physical activity levels and reducing lung function decline in people diagnosed with early COPD through spirometry screening.

It is now widely accepted that hypertension and endothelial dysfunction are associated with an insulin-resistant state and thus with the development of T2DM (Type 2 diabetes mellitus). Insulin signalling is impaired in target cells and tissues, indicating that common molecular signals are involved. The free radical NO • regulates cell metabolism, insulin signalling and secretion, vascular tone, neurotransmission and immune system function. NO • synthesis is essential for vasodilation, the maintenance of blood pressure and glucose uptake and, thus, if levels of NO • are decreased, insulin resistance and hypertension will result. Decreased blood levels of insulin, increased AngII (angiotensin II), hyperhomocysteinaemia, increased ADMA (asymmetric ω- N G , N G -dimethylarginine) and low plasma L -arginine are all conditions likely to decrease NO • production and which are associated with diabetes and cardiovascular disease. We suggest in the present article that the widely reported beneficial effects of exercise in the improvement of metabolic and cardiovascular health are mediated by enhancing the flux of muscle- and kidney-derived amino acids to pancreatic and vascular endothelial cells aiding the intracellular production of NO • , therefore resulting in normalization of insulin secretion, vascular tone and insulin sensitivity. Exercise may also have an impact on AngII and ADMA signalling and the production of pro- and anti-inflammatory cytokines in muscle, so reducing the progression and development of vascular disease and diabetes. NO • synthesis will be increased during exercise in the vascular endothelial cells so promoting blood flow. We suggest that exercise may promote improvements in health due to positive metabolic and cytokine-mediated effects.

Exercise may contribute to the maintenance of vascular function via enhanced liberation and action of bone-marrow-derived progenitor cells. Activity related changes in oxidative stress may also influence the number and function of these cells. In the present study, we sought to determine (i) whether adaptations in reactive hyperaemic FBF (forearm blood flow) response associated with long-term endurance exercise and short-term detraining were related to resting putative progenitor cell number and function, and (ii) whether oxidative stress affected these factors. Participants included men with a history of more than 30 years of moderate-to-high-intensity exercise (HI group) and healthy low-active age- and BMI (body mass index)-matched control subjects (LO group). Vascular reactive hyperaemic FBF response, resting CD34 + and CD34 + /VEGFR2 + (vascular endothelial growth factor receptor 2 + ] cell number, CFU-EC (colony-forming unit-endothelial cell) count and CFU-EC senescence were evaluated. Oxidative stress measures included OxLDL (oxidized low-density lipoprotein) and TAC (total antioxidant capacity). These measures were assessed following 10 days of detraining in the HI group. The HI group had greater peak reactive hyperaemic FBF responses compared with the LO group, despite no difference in resting CD34 + cell number, CD34 + /VEGFR2 + cell number, CFU-EC colonies or CFU-EC senescence. With detraining in the HI group, CD34 + cells declined 44%, and the percentage change in CD34 + /VEGFR2 + cells was positively correlated with the change in FBF response to reactive hyperaemia. The percentage change in CD34 + /VEGFR2 + cells and the percentage change in EPC (endothelial progenitor cell) senescence with detraining were related to the percentage change in TAC. These results reveal that changes in reactive hyperaemic FBF are closely related to activity dependent dynamic changes in CD34 + /VEGFR2 + cell number, which may be influenced by alterations in oxidative stress.

CHF (chronic heart failure) is associated with a prolonged recovery of skeletal muscle energy stores following submaximal exercise, limiting the ability to perform repetitive daily activities. However, the pathophysiological background of this impairment is not well established. The aim of the present study was to investigate whether muscle metabolic recovery following submaximal exercise in patients with CHF is limited by O 2 delivery or O 2 utilization. A total of 13 stable CHF patients (New York Heart Association classes II–III) and eight healthy subjects, matched for age and BMI (body mass index), were included. All subjects performed repetitive submaximal dynamic single leg extensions in the supine position. Post-exercise PCr (phosphocreatine) resynthesis was assessed by 31 P-MRS (magnetic resonance spectroscopy). NIRS (near-IR spectroscopy) was applied simultaneously, using the rate of decrease in HHb (deoxygenated haemoglobin) as an index of post-exercise muscle re-oxygenation. As expected, PCr recovery was slower in CHF patients than in control subjects (time constant, 47±10 compared with 35±12 s respectively; P =0.04). HHb recovery kinetics were also prolonged in CHF patients (mean response time, 74±41 compared with 44±17 s respectively; P =0.04). In the patient group, HHb recovery kinetics were slower than PCr recovery kinetics ( P =0.02), whereas no difference existed in the control group ( P =0.32). In conclusion, prolonged metabolic recovery in CHF patients is associated with an even slower muscle tissue re-oxygenation, indicating a lower O 2 delivery relative to metabolic demands. Therefore we postulate that the impaired ability to perform repetitive daily activities in these patients depends more on a reduced muscle blood flow than on limitations in O 2 utilization.

Skeletal muscle dysfunction in COPD (chronic obstructive pulmonary disease) patients, particularly of the quadriceps, is of clinical interest because it not only influences the symptoms that limit exercise, but may also contribute directly to poor exercise performance and health status, increased healthcare utilization, and mortality. Furthermore, unlike the largely irreversible impairment of the COPD lung, skeletal muscles represent a potential site to improve patients' level of function and quality of life. However, despite expanding knowledge of potential contributing factors and greater understanding of molecular mechanisms of muscle wasting, only one intervention has been shown to be effective in reversing COPD muscle dysfunction, namely exercise training. Pulmonary rehabilitation, an intervention based on individually tailored exercise training, has emerged as arguably the most effective non-pharmacological intervention in improving exercise capacity and health status in COPD patients. The present review describes the effects of chronic exercise training on skeletal muscles and, in particular, focuses on the known effects of pulmonary rehabilitation on the quadriceps muscle in COPD. We also describe the current methods to augment the effects of pulmonary rehabilitation and speculate how greater knowledge of the molecular pathways of skeletal muscle wasting may aid the development of novel pharmaceutical agents.

COPD (chronic obstructive pulmonary disease), although primarily a disease of the lungs, exhibits secondary systemic manifestations. The skeletal muscles are of particular interest because their function (or dysfunction) not only influences the symptoms that limit exercise, but may contribute directly to poor exercise performance. Furthermore, skeletal muscle weakness is of great clinical importance in COPD as it is recognized to contribute independently to poor health status, increased healthcare utilization and even mortality. The present review describes the current knowledge of the structural and functional abnormalities of skeletal muscles in COPD and the possible aetiological factors. Increasing knowledge of the molecular pathways of muscle wasting will lead to the development of new therapeutic agents and strategies to combat COPD muscle dysfunction.

Both antioxidant supplementation and exercise training have been identified as interventions which may reduce oxidative stress and thus improve cardiovascular health, but the interaction of these interventions on arterial BP (blood pressure) and vascular function has not been studied in older humans. Thus in six older (71±2 years) mildly hypertensive men, arterial BP was evaluated non-invasively at rest and during small muscle mass (knee-extensor) exercise with and without a pharmacological dose of oral antioxidants (vitamins C and E, and α-lipoic acid). The efficacy of the antioxidant intervention to decrease the plasma free radical concentration was verified via EPR (electron paramagnetic resonance) spectroscopy, while changes in endothelial function in response to exercise training and antioxidant administration were evaluated via FMD (flow-mediated vasodilation). Subjects were re-evaluated after a 6-week aerobic exercise training programme. Prior to training, acute antioxidant administration did not change resting arterial BP or FMD. Six weeks of knee-extensor exercise training reduced systolic BP (from 150±8 mmHg at pre-training to 138±3 mmHg at post-training) and diastolic BP (from 91±5 mmHg at pre-training to 79±3 mmHg at post-training), and improved FMD (1.5±1 to 4.9±1% for pre- and post-training respectively). However, antioxidant administration after exercise training negated these improvements, returning subjects to a hypertensive state and blunting training-induced improvements in FMD. In conclusion, the paradoxical effects of these interventions suggest a need for caution when exercise and acute antioxidant supplementation are combined in elderly mildly hypertensive individuals.

Despite the development of a wide range of therapies, heart failure remains a leading cause of death in Western society. New therapies are needed to help combat this debilitating condition. Exercise is becoming an increasingly important feature of rehabilitation programmes for patients with heart failure. Before the 1980s, patients with heart failure were advised not to exercise as it was thought that exercise would increase the risk of a cardiac event (such as myocardial infarction). However, in recent years both aerobic and resistance training have been shown to be safe and beneficial for patients with heart failure, improving exercise tolerance and quality of life, and preventing muscular deconditioning. The molecular mechanisms responsible for exercise-induced cardioprotection are yet to be elucidated, however studies in transgenic mice have identified PI3K(p110α) (phosphoinositide 3-kinase p110α) as a likely mediator. PI3K(p110α) is a lipid kinase which is activated in the heart during chronic exercise training, and is important for maintaining heart structure and function in various pathological settings. In the present review the protective effects of PI3K(p110α) in the failing heart and its potential as a therapeutic strategy for the treatment of heart failure is discussed.

Hypertriacylglycerolaemia is an important risk factor for cardiovascular disease. In men, we have shown that the effects of evening exercise on basal VLDL (very-low-density lipoprotein) metabolism are dose-dependent: a single prolonged bout of aerobic exercise [2 h at 60% of V ̇ O 2 peak (peak oxygen consumption)] reduces fasting plasma TAG [triacylglycerol (triglyceride)] concentrations, via enhanced clearance of VLDL-TAG from the circulation, whereas the same exercise performed for 1 h has no effect on VLDL-TAG metabolism and concentration. We hypothesized that women are more sensitive to the TAG-lowering effect of exercise because they reportedly use more intramuscular TAG as an energy source during exercise, and depletion of muscle TAG stores has been linked to reciprocal changes in skeletal muscle LPL (lipoprotein lipase) activity. To test our hypothesis, we measured basal VLDL-TAG and VLDL-apoB-100 (apolipoprotein B-100), and plasma NEFA [non-esterified fatty acid (‘free fatty acid’)] kinetics, by using stable isotope-labelled tracer techniques, on the morning after a single session of evening exercise of moderate duration and intensity (1 h at 60% of V ̇ O 2 peak ) in eight sedentary pre-menopausal women (age, 28±3 years; body mass index, 27±2 kg/m 2 ; body fat, 34±3%; values are means±S.E.M.). Compared with an equivalent period of evening rest, exercise had no effect on post-absorptive NEFA concentrations and the rate of appearance in plasma, VLDL-TAG and VLDL-apoB-100 concentrations, hepatic VLDL-TAG and VLDL-apoB-100 secretion and plasma clearance rates (all P >0.05). We conclude that, in women, as in men, a single session of exercise of moderate intensity and duration is not sufficient to bring about the alterations in VLDL metabolism that have been linked to post-exercise hypotriacylglycerolaemia.

The metabolic response when aerobic exercise is performed after the ingestion of glucose plus fructose is unclear. In the present study, we administered two beverages containing GluF (glucose+fructose) or Glu (glucose alone) in a randomized cross-over design to 20 healthy aerobically trained volunteers to compare the hormonal and lipid responses provoked during aerobic exercise and the recovery phase. After ingesting the beverages and a 15-min resting period, volunteers performed 30 min of moderate aerobic exercise. Urinary and blood samples were taken at baseline ( t −15 ), during the exercise ( t 0 , t 15 and t 30 ) and during the recovery phase ( t 45 , t 75 and t 105 ). Plasma insulin concentrations were higher halfway through the exercise period and during acute recuperation ( t 15 and t 75 ; P <0.05) following ingestion of GluF than after Glu alone, without any differences between the effects of either intervention on plasma glucose concentrations. Towards the end of the exercise period, urinary catecholamine concentrations were lower following GluF ( t 45 ; P <0.05). Plasma triacylglycerol (triglyceride) concentrations were higher after the ingestion of GluF compared with Glu ( t 15 , t 30 , t 45 and t 105 ; P <0.05). Furthermore, with GluF, we observed higher levels of lipoperoxides ( t 15 , t 30 , t 45 and t 105 ; P <0.05) and oxidized LDL (low-density lipoprotein; t 30 ; P <0.05) compared with after the ingestion of Glu alone. In conclusion, hormonal and lipid alterations are provoked during aerobic exercise and recovery by the addition of a dose of fructose to the pre-exercise ingestion of glucose.

The aim of the present study was to determine the effects of a 4-week exercise training intervention on blood glucose, insulin sensitivity, BMI (body mass index) and cardiorespiratory fitness in patients with Type 2 diabetes, and to identify and establish criteria for patients who are more likely to improve their blood glucose from short-term exercise training. A randomized, controlled trial of exercise training, comprising two supervised and one non-supervised sessions of individualized cardiorespiratory and resistance exercise per week, was performed in 132 healthy patients with Type 2 diabetes (exercise training group, n =68), with the aim of accumulating a minimum of 150 min of moderate-intensity exercise for 4 weeks. BMI, waist circumference, blood pressure, blood lipid profile, blood glucose, insulin, insulin sensitivity [calculated by HOMA IR (homoeostasis model assessment of insulin resistance) and QUICKI (quantitative insulin check index)], β-cell function (calculated by HOMA β-Cell ), HbA 1c (glycated haemoglobin) and V ̇ O 2max (maximal oxygen consumption) were measured at baseline and at 4 weeks. The exercise training group had significant improvements in V ̇ O 2max , BMI and triacylglycerols (triglycerides). There were no significant changes in blood glucose, HOMA IR , QUICKI or HOMA β-Cell . Decreases in blood glucose were significantly predicted by baseline blood glucose and HbA 1c , with these variables accounting for 15.9% of the change in blood glucose ( P <0.001). ROC (receiver operator characteristic) curve analysis revealed that patients with a blood glucose >8.85 mmol/l (sensitivity=73%, specificity=78%) and HbA 1c >7.15% (sensitivity=79%, specificity=60%) were more likely to achieve a clinically significant decrease in blood glucose. In conclusion, in apparently healthy patients with Type 2 diabetes, a 4-week exercise intervention improved cardiorespiratory fitness, BMI and triacylglycerols. Elevated blood glucose and HbA 1c predicted improvements in blood glucose.

It has been suggested that impaired respiratory muscle function occurs in patients with PH (pulmonary hypertension); however, comprehensive investigations of respiratory muscle function, including the application of non-volitional tests, needed to verify impairment of respiratory muscle strength in patients with PH have not yet been performed. In the present study, respiratory muscle function was assessed in 31 patients with PH (20 females and 11 males; mean pulmonary artery pressure, 51±20 mmHg; median World Health Organization class 3.0±0.5; 25 patients with pulmonary arterial hypertension and six patients with chronic thromboembolic PH) and in 31 control subjects (20 females and 11 males) well-matched for gender, age and BMI (body mass index). A 6-min walking test was performed to determine exercise capacity. Volitionally assessed maximal inspiratory (7.5±2.1 compared with 6.2±2.8 kPa; P =0.04) and expiratory (13.3±4.2 compared with 9.9±3.4 kPa; P <0.001) mouth pressures, sniff nasal (8.3±1.9 compared with 6.6±2.2 kPa; P =0.002) and transdiaphragmatic (11.3±2.5 compared with 8.7±2.5 kPa; P <0.001) pressures, non-volitionally assessed twitch mouth (1.46±0.43 compared with 0.97±0.41 kPa; P <0.001) and transdiaphragmatic (2.08±0.55 compared with 1.47±0.72 kPa; P =0.001) pressures during bilateral anterior magnetic phrenic nerve stimulation were markedly lower in patients with PH compared with control subjects. Maximal inspiratory mouth ( r =0.58, P <0.001) and sniff transdiaphragmatic ( r =0.43, P =0.02) pressures were correlated with the 6-min walking distance in patients with PH. In conclusion, the present study provides strong evidence that respiratory muscle strength is reduced in patients with PH compared with well-matched control subjects. Furthermore, the 6-min walking distance is significantly linked to parameters assessing inspiratory muscle strength.

A single bout of moderate-intensity exercise increases whole-body insulin sensitivity for 12–48 h post-exercise; however, the relationship between exercise energy expenditure and the improvement in insulin sensitivity is not known. We hypothesized that the exercise-induced increase in whole-body insulin sensitivity, assessed with HOMA IR (homoeostasis model assessment of insulin resistance), is directly related to the energy expended during exercise. We studied 30 recreationally active non-obese men (age, 27±5 years; body mass index, 24±2 kg/m 2 ) in the post-absorptive state on two separate occasions: once after exercising at 60% of V ̇ O 22peak (peak oxygen consumption) for 30–120 min on the preceding afternoon (expending a total of 1.28–5.76 MJ) and once after an equivalent period of rest. Blood samples were obtained the following morning. Exercise-induced changes in HOMA IR were curvilinearly related to exercise energy expenditure ( r =−0.666, P =0.001) with a threshold of approx. 3.77 MJ (900 kcal) for improvements in HOMA IR to be manifested. In particular, HOMA IR was reduced by 32±24% ( P =0.003) in subjects who expended more than 3.77 MJ during exercise, but did not change for those who expended fewer than 3.77 MJ (−2±21%; P =0.301). Furthermore, the magnitude of change in HOMA IR after exercise was directly associated with baseline (i.e. resting) HOMA IR ( r =−0.508, P =0.004); this relationship persisted in multivariate analysis. We conclude that improved whole-body insulin resistance after a single bout of exercise is curvilinearly related to exercise energy expenditure, and requires unfeasible amounts of exercise for most sedentary individuals.

Engaging in regular physical activity reduces the risk of developing CVD (cardiovascular disease), but it is not certain to what degree this may be due to the anti-inflammatory effects of exercise. Following acute exercise, there is a transient increase in circulating levels of anti-inflammatory cytokines, whereas chronic exercise reduces basal levels of pro-inflammatory cytokines. Exercise training also induces the expression of antioxidant and anti-inflammatory mediators in the vascular wall that may directly inhibit the development of atherosclerosis. Limited studies in humans and more comprehensive assessments in animal models have confirmed that exercise is atheroprotective and helped identify a number of the mechanisms to explain these effects. This review explores the relationship between systemic and vascular wall inflammation and the role that the anti-inflammatory effects of exercise have on the development and progression of CVD.

The effects of exercise on the distensibility of large and medium-sized arteries are poorly understood, but can be attributed to a combination of local vasodilator effects of exercise opposed by sympathetic vasoconstrictor tone. We sought to examine this relationship at the conduit artery level, with particular reference to the role of the sympatho-excitatory muscle metaboreflex. The effect of maintained muscle metaboreflex activation on a previously passive or exercised limb femoral artery was investigated. A total of ten healthy volunteers performed 2 min of isometric ankle plantar-flexion at 40% MVC (maximal voluntary force), in conjunction with 2 min of either non-ischaemic isometric HG (handgrip; control condition) or IHG (ischaemic HG) at 40% MVC. IHG was followed by 2 min of PECO (post-exercise circulatory occlusion) to maintain muscle metaboreflex activation. FTPWV [femoral–tibial PWV (pulse wave velocity)] was measured in the exercised or contralateral limb at baseline and immediately following calf exercise. BP (blood pressure) and HR (heart rate) were measured continuously throughout. In the HG condition, BP and HR returned promptly to baseline post-exercise, whereas exercised leg FTPWV was decreased (less stiff) by 0.6 m/s ( P <0.05) and the non-exercised leg PWV was not changed from baseline. PECO caused a sustained increase in BP, but not HR, in the IHG condition. Contralateral leg PWV increased (stiffened) during PECO by 0.9 m/s ( P <0.05), whereas exercised limb FTPWV was not changed from baseline. In conclusion, muscle metaboreflex activation causes a systemic stiffening of the arterial tree, which can overcome local exercise-induced decreases in arterial PWV.

Isometric HG (handgrip) training lowers resting arterial BP (blood pressure), yet the mechanisms are elusive. In the present study, we investigated improved systemic endothelial function as a mechanism of arterial BP modification following isometric HG training in normotensive individuals. This study employed a within-subject repeated measures design primarily to assess improvements in BA FMD (brachial artery flow-mediated dilation; an index of endothelium-dependent vasodilation), with the non-exercising limb acting as an internal control. Eleven subjects performed four 2-min unilateral isometric HG contractions at 30% of maximal effort, three times per week for 8 weeks. Pre-, mid- and post-training resting ABP and BA FMD (exercised arm and non-exercised arm) were measured via automated brachial oscillometry and ultrasound respectively. BA FMD (normalized to the peak shear rate experienced in response to the reactive hyperaemic stimulus) remained unchanged [exercised arm, 0.029±0.003 to 0.026±0.003 to 0.029±0.004%/s −1 (pre- to mid- to post-training respectively); non-exercised arm, 0.023±0.003 to 0.023±0.003 to 0.024±0.003%/s −1 (pre- to mid- to post-training respectively); P =0.22]. In conclusion, improved systemic endothelial function is unlikely to be responsible for lowering arterial BP in this population.

The role of microvascular fluid shifts in the adaptation to hypobaric hypoxia and its contribution to the pathophysiology of AMS (acute mountain sickness) is unresolved. In a systematic prospective study, we investigated the effects of hypobaric hypoxia and physical exercise alone, and in combination, on microvascular fluid exchange and related factors. We used computer-assisted VCP (venous congestion plethysmography) on the calves of ten altitude-acclimatized volunteers. We investigated the effects of: (i) actively climbing to an altitude of 3196 m, (ii) airlifting these subjects to the same altitude, and (iii) exercise at low altitude. CFC (capillary filtration capacity), P vi (isovolumetric venous pressure) and Q a (calf blood flow) were assessed before and after each procedure and then repeated after an overnight rest. Measurements of CFC showed no evidence of increased microvascular permeability after any of the procedures. P vi was significantly decreased ( P <0.001) from 20.3±4.4 to 8.9±4.3 mmHg after active ascent, and was still significantly lower ( P =0.009) after overnight rest at high altitude (13.6±5.9 mmHg). No such changes were observed after the passive ascent (16.7±4.0 mmHg at baseline; 17.3±4.5 mmHg after passive ascent; and 19.9±5.3 mmHg after overnight rest) or after exercise at low altitude. After the active ascent, Q a was significantly increased. We also found a significant correlation between Q a , P vi and the number of circulating white blood cells. In conclusion, we found evidence to support the hypothesis that increased microvascular permeability associated with AMS does not occur in acclimatized subjects. We also observed that the microvascular equilibrium pressure ( P vi ) fell in inverse relation to the increase in Q a , especially in hypoxic exercise. We hypothesize that this inverse relationship reflects the haemodynamic changes at the microvascular interface, possibly attributable to the flow-induced increases in endothelial surface shear forces.

Maximal exercise in normoxia results in oxidative stress due to an increase in free radical production. However, the effect of a single bout of moderate aerobic exercise performed in either relative or absolute normobaric hypoxia on free radical production and lipid peroxidation remains unknown. To examine this, we randomly matched {according to their normobaric normoxic V ̇ O 2peak [peak V ̇ O 2 (oxygen uptake)]} and assigned 30 male subjects to a normoxia ( n =10), a hypoxia relative ( n =10) or a hypoxia absolute ( n =10) group. Each group was required to exercise on a cycle ergometer at 55% of V ̇ O 2peak for 2 h double-blinded to either a normoxic or hypoxic condition [ F i O 2 (inspired fraction of O 2 )=0.21 and 0.16 respectively]. ESR (electron spin resonance) spectroscopy in conjunction with ex vivo spin trapping was utilized for the direct detection of free radical species. The main findings show that moderate intensity exercise increased plasma-volume-corrected free radical and lipid hydroperoxide concentration (pooled rest compared with exercise data, P <0.05); however, there were no selective differences between groups (state×group interaction, P >0.05). The delta change in free radical concentration was moderately correlated with systemic V ̇ O 2 ( r 2 =0.48, P <0.05). The hyperfine coupling constants recorded from the ESR spectra [a N =13.8 Gauss, and a H β =1.9 Gauss; where 1 Gauss=10 −4 T (telsa)] are suggestive of oxygen-centred free radical species formed via the decomposition of lipid hydroperoxides. Peripheral leucocyte and neutrophil cells and total CK (creatine kinase) activity all increased following sustained exercise (pooled rest compared with exercise data, P <0.05), but no selective differences were observed between groups (state×group interaction, P >0.05). We conclude that a single bout of moderate aerobic exercise increases secondary free radical species. There is also evidence of exercise-induced muscle damage, possibly caused by the increase in free radical generation.

In the present study, we have developed and demonstrated a coronary artery imaging protocol in rats using transthoracic high-frequency CDE (colour Doppler echocardiography) to investigate the potential direct effects of exercise on CFVR (coronary flow velocity reserve). SHR (spontaneously hypertensive rats) performed voluntary exercise for 6 weeks. Rats were then submitted to ultrasonographic examination and CFVR measurements. The LAD (left anterior descending coronary artery) was visualized using transthoracic CDE in a modified parasternal long-axis view. Doppler measurement was made in mid-LAD during baseline and adenosine-induced hyperaemic condition. Gene and protein expression in cardiac tissue were studied using real-time PCR and immunohistochemistry. Adenosine infusion significantly ( P <0.001, as determined by ANOVA) decreased HR, without affecting blood pressure in anaesthetized SHR. A significantly greater adenosine dose-dependent response was seen in exercised rats compared with controls ( P =0.02, as determined by ANOVA). The baseline flow velocity in mid-LAD was 0.33±0.06 and 0.41±0.14 m/s in the exercised and control animals respectively ( P value was not significant). The maximum adenosine-induced response was reached at a dose of 140 μg·kg −1 of body weight·min −1 , and CFVR averaged at 2.6±0.53 and 1.5±0.24 in exercised and control animals respectively ( P <0.01). Gene expression of CuZnSOD was up-regulated by 21% in exercised animals compared with controls (1.1±0.16 compared with 0.89±0.09; P <0.01), whereas eNOS expression was unchanged. In conclusion, CFVR in rats can be non-invasively assessed using CDE with high feasibility. Physical exercise is associated with improved CFVR and antioxidative capacity in SHR.

Tissue-Doppler echocardiography (TDE) has been introduced to quantify stress echocardiography by means of assessing the left ventricular (LV) segmental myocardial velocities and excursion. The interaction between LV long- and short-axis function during physical exercise has not been elucidated completely. The aim of the present study was to investigate long- and short-axis LV function, as assessed by myocardial velocities and excursions at rest and during exercise and its possible relationship with heart rate in healthy elderly individuals by TDE. Twenty-seven individuals underwent an exercise test in the supine position on a bicycle ergometer. The initial workload was 30 Watts, followed by 20-Watt increments every third minute. Standard echocardiographic images with super-imposed colour TDE were digitized at the end of each step. The following variables were studied in the LV long- and short-axis: myocardial peak systolic velocity (PSV) and excursion, isovolumic contraction and relaxation times, peak velocity at early diastole (E´-wave) and peak velocity at late diastole (A´-wave) and the E´/A´ ratio. Increments in myocardial peak systolic velocity and excursion in the LV long-axis were more pronounced during low workloads. The increase in those variables in the short-axis occurred mainly at higher exercise loads. The improvement in LV long- and short-axis functions was closely related to the increase in the heart rate. Shortening of the isovolumic contraction and relaxation times occurred only at the initial stages of exercise. An increase in the long-axis E´/A´ ratio occurred during exercise, whereas this ratio was unchanged in the short-axis. In conclusion, during exercise, the LV long- and short-axis functions behave differently, and increases in LV long- and short-axis functions are related to changes in heart rate. Therefore, in the interpretation of echocardiographic findings during exercise stress echocardiography, these facts have to be taken into account.

Portapres® derives continuous estimates of cardiac output from the peripheral pulse and has the potential to be an extremely valuable physiological and clinical tool. We assessed Portapres® estimates of cardiac output in healthy subjects at rest, during maximal treadmill exercise ( n =8) and during decreases caused by orthostatic stress ( n =8). Comparison with a rebreathing method indicated that Portapres® tended to overestimate cardiac output. The random errors of the estimates (precision), expressed as ±2 S.D. of the differences between paired estimates during steady states, ranged between 1.2 and 2.6 litres/min. We conclude that these errors indicate that the method is probably only useful for assessing changes in individual subjects where large changes are anticipated, as during exercise. When smaller changes occur, as during orthostasis, the errors preclude the use of individual subject data and only permit group average data to be examined.

Sedentary aging is associated with endothelial dysfunction and nitric oxide (NO) impairment. The aim of the present study was to assess the effects of regular physical exercise on nitrite/nitrate (NOx) concentrations and microcirculatory function in older men compared with young individuals. We measured NOx plasma concentrations and baseline and stimulated skin blood flow (SBF) by laser Doppler flowmetry in 39 male athletes [range, 22–72 years; maximal oxygen consumption ( V O 2 max), 60.0±4.7 ml·min -1 ·kg of body weight -1 (mean±S.D.)] and 45 age- and sex-matched sedentary controls ( V O 2 max, 38.0±7.1 ml·min -1 ·kg of body weight -1 ). NOx concentrations were higher in athletes than in controls (50.4±16.3 compared with 39.0±15.4 µmol/l; P <0.005), whereas baseline SBF was comparable. Hand SBF after heating and ischaemia and foot SBF after heating were higher in athletes ( P <0.0001) than in controls. By comparing the lowest and the highest tertile of age, sedentary young subjects had higher NOx concentrations than sedentary older subjects (43.3±13.4 compared with 31.8±12.2 µmol/l respectively; P <0.05). Exercise abolished this difference (49.1±9.6 µmol/l for young subjects and 52.1±11.5 µmol/l for older subjects; not significant). Resting SBF was similar in all the subgroups, but stimulated SBFs were lower in both subgroups of untrained compared with trained subjects. NOx concentrations were positively correlated with V O 2 max ( r =0.46, P <0.001). Stimulated SBFs were correlated with NOx ( r >0.30, P <0.05). These findings show that chronic exercise may improve endothelial function in older (and young) men, probably by increasing NO availability.

Considerable evidence points towards a prominent role for central nervous system (CNS) mechanisms in the pathogenesis of chronic fatigue syndrome (CFS), a disorder characterized chiefly by persistent, often debilitating, fatigue. We wished to characterize circulating profiles of putative amino acid modulators of CNS 5-hydroxytryptamine (5-HT; serotoninergic) and dopaminergic function in CFS patients at rest, as well as during symptom-limited exercise and subsequent recovery. Groups of 12 CFS patients and 11 age- and sex-matched sedentary controls, with similar physical activity histories, underwent ramp-incremental exercise to the limit of tolerance. Plasma amino acid concentrations, oxygen uptake and ratings of perceived exertion were measured at rest, and during exercise and recovery. Peak oxygen uptake was significantly lower in the CFS patients compared with controls. Rating of perceived exertion in the patients was higher at all time points measured, including at rest, relative to controls. Levels of free tryptophan (free Trp), the rate-limiting 5-HT precursor, were significantly higher in CFS patients at exhaustion and during recovery, whereas concentrations of branched-chain amino acids (BCAA) and large neutral amino acids (LNAA) were lower in CFS patients at exhaustion, and for LNAA also during recovery. Consequently, the [free Trp]/[BCAA] and [free Trp]/[LNAA] ratios were significantly higher in CFS patients, except at rest. On the other hand, levels of tyrosine, the rate-limiting dopaminergic precursor, were significantly lower at all time points in the CFS patients. The significant differences observed in a number of key putative CNS 5-HT and dopaminergic modulators, coupled with the exacerbated perception of effort, provide further evidence for a potentially significant role for CNS mechanisms in the pathogenesis of CFS.

There are conflicting reports on the reproducibility of the visual analogue scale (VAS) and the modified Borg scale for the estimation of breathlessness during exercise. In an attempt to clarify the situation, two groups of healthy subjects undertook a progressive exercise test either daily (Group A) or weekly (Group B) on 10 separate occasions. Breathlessness was estimated every 1 min using the VAS. After 10 occasions, both Group A ( P <0.05) and Group B ( P <0.01) showed a significant increase in the mean intercept of the breathlessness/ventilation (VAS/ V I ) relationship. The increase was not progressive; using change point regression, reproducible values were found to occur after approximately the fifth occasion in both subject groups. As the slope of the VAS/ V I relationship was highly reproducible and did not change with repeat testing, it would appear that at least two mechanisms are involved in the generation of the sensation of breathlessness. A decrease in the exercise heart rate over the same time period was significantly correlated with changes in the VAS/ V I intercept in both groups ( P <0.01 and P <0.005 respectively). The relationship is unlikely to be causal, but may be indicative of a common underlying mechanism. It is suggested that breathlessness scores are likely to decrease as a direct result of repetitive testing over, on average, the first five periods of assessment. On the basis of this study, it may be inferred that a physiological mechanism contributes to the modulation of breathlessness during repetitive exercise testing.

The purpose of this study was to determine if chronic fatigue syndrome (CFS) is associated with reduced blood flow and oxidative delivery to skeletal muscle. Patients with CFS according to CDC (Center for Disease Control) criteria ( n =19) were compared with normal sedentary subjects ( n =11). Muscle blood flow was measured with Doppler ultrasound after cuff ischaemia and exercise. Muscle oxygen delivery was measured as the rate of post-exercise and post-ischaemic oxygen-haem resaturation. Oxygen-haem resaturation was measured in the medial gastrocnemius muscle using continuous wavelength near-IR spectroscopy. Muscle metabolism was measured using 31 P magnetic resonance spectroscopy. CFS patients and controls were not different in the peak blood flow after cuff ischaemia, the rate of recovery of phosphocreatine after submaximal exercise, and the rate of recovery of oxygen saturation after cuff ischaemia. In conclusion, CFS patients showed no deficit in blood flow or oxidative metabolism. This suggests that CFS symptoms do not require abnormal peripheral function.

The effects of comparable lower-limb eccentric exercise that induces high (bench-stepping; STEP) and low (repeated eccentric muscle action; ECC) systemic stress on neutrophil and monocyte phagocytic and respiratory burst activity, and activation antigen (CD11b, CD66b, CD64) expression, were compared in recreationally active subjects (20–37 years old). Leucocyte responses were determined before and 4, 24, 48 and 72h after exercise using whole-blood flow cytometry. Serum creatine kinase (CK) activity and perceived muscle soreness [delayed-onset muscle soreness (DOMS)] were assessed at the same time points up to 96 h; as a control, measurements were taken during 5 days of rest. DOMS in quadriceps and contralateral triceps surae peaked 24–72h after STEP ( P <0.05) and 48–72h after ECC ( P <0.05), whereas serum CK activity (mean±S.E.M.) was only higher than baseline after ECC (15123±3488 at 96h compared with 115±29 units·l -1 pre-exercise; P <0.01). The total leucocyte count increased from (5.4±0.4)×10 9 ·l -1 and (5.7±0.5)×10 9 ·l -1 at baseline to (7.6±0.5)×10 9 ·l -1 and (7.0±0.5)×10 9 ·l -1 at 4h after STEP and ECC respectively; this was largely attributable to changes in the neutrophil count ( P <0.05). The proportion of neutrophils undergoing phagocytosis and respiratory burst was unchanged 4h after ECC and STEP, which, given the increase in neutrophil count after exercise, would suggest an overall improvement in systemic neutrophil microbicidal potential. The intensity of neutrophil ( P = 0.01) and monocyte ( P <0.05) phagocytosis and neutrophil respiratory burst responses ( P <0.05) was only increased 24h after STEP, whereas no changes in these measures were observed after ECC. Activation antigen expression was unchanged in all groups. These findings suggest that systemic stress evoked during an acute bout of eccentric exercise has a greater influence on subsequent leucocyte functional responses than the degree of muscle damage induced.