Attenuated reactive hyperemia after prolonged sitting is associated with reduced local skeletal muscle metabolism: insight from artificial intelligence.

Blunted post-occlusive reactive hyperemia (PORH) after prolonged sitting (PS) has been used as evidence of microvascular dysfunction. However, it has not been determined if confounding variables are responsible for the reduction in PORH after PS. Therefore, the purpose of this study was to examine the PS-mediated changes in cardiovascular and metabolic factors that affect PORH using artificial intelligence (AI). We hypothesized that calf muscle metabolic rate (MMR) is attenuated after PS, which may reduce tissue hypoxia during an arterial occlusion (i.e., oxygen deficit) and PORH. Thirty-one subjects (male = 13, female = 18) sat for 2.5 h. A rapid-inflation cuff was placed around the thigh above the knee to generate an arterial occlusion. PORH was represented by the reoxygenation rate (RR) of the near-infrared spectroscopy (NIRS) tissue oxygenation index (TOI) after 5-min of arterial occlusion. An artificial intelligence model (AI) defined the stimulus-response relationship between the oxygen deficit (i.e., ΔTOI and TOI deficit), and RR with 65 previous PORH recordings. If the AI predicts the experimental RRs, then the change in RR is related to the change in the oxygen deficit. RR (Δ -0.27 ± 0.55 lnTOI%·s-1, P = 0.001), MMR (Δ -0.46 ± 0.61 lnTOI%·s-1, P < 0.001), ΔTOI (Δ -0.34 ± 0.62 lnTOI%, P < 0.001), and the TOI deficit (Δ -0.42 ± 0.68 lnTOI%·s, P < 0.001) were reduced after PS. In addition, strong linear associations were found between MMR and the TOI deficit (r2 = 0.900, P < 0.001) and ΔTOI (r2 = 0.871, P < 0.001). Furthermore, the AI accurately predicted the RRs pre- and post-PS (P = 0.471, P = 0.328, respectively). Therefore, blunted PORH after PS may be caused by attenuated MMR and not microvascular dysfunction.NEW & NOTEWORTHY Prolonged sitting reduces lower leg skeletal muscle metabolic rate in healthy individuals. Artificial intelligence revealed that impaired post-occlusive reactive hyperemia after prolonged sitting is related to a reduced stimulus for vasodilation and may not be evidence of microvascular dysfunction. Current post-occlusive reactive hyperemia protocols may be insufficient to assess micro- and macrovascular function after prolonged sitting.

Prolonged sitting and peripheral vascular function: potential mechanisms and methodological considerations.

Sitting time is associated with increased risks for subclinical atherosclerosis and cardiovascular disease development, and this is thought to be partially due to sitting-induced disturbances in macro- and microvascular function as well as molecular imbalances. Despite surmounting evidence supporting these claims, contributing mechanisms to these phenomena remain largely unknown. In this review, we discuss evidence for potential mechanisms of sitting-induced perturbations in peripheral hemodynamics and vascular function and how these potential mechanisms may be targeted using active and passive muscular contraction methods. Furthermore, we also highlight concerns regarding the experimental environment and population considerations for future studies. Optimizing prolonged sitting investigations may allow us to not only better understand the hypothesized sitting-induced transient proatherogenic environment but to also enhance methods and devise mechanistic targets to salvage sitting-induced attenuations in vascular function, which may ultimately play a role in averting atherosclerosis and cardiovascular disease development.

Moderate dose of dietary nitrate improves skeletal muscle microvascular function in patients with peripheral artery disease.

Peripheral artery disease (PAD) is an atherosclerotic disease characterized by compromised lower-extremity blood flow that impairs walking ability. We showed that a moderate dose of dietary nitrate in the form of beetroot juice (BRJ, 0.11 mmol/kg) can improve macrovascular function and maximal walking distance in patients with PAD. However, its impacts on the microcirculation and autonomic nervous system have not been examined. Therefore, we investigated the impacts of this dose of dietary nitrate on skeletal muscle microvascular function and autonomic nervous system function and further related these measurements to 6-min walking distance, pain-free walking distance, and exercise recovery in patients with PAD. Patients with PAD (n = 10) ingested either BRJ or placebo in a randomized crossover design. Heart rate variability, skeletal muscle microvascular function, and 6-min walking distance were performed pre- and post-BRJ and placebo. There were significant group × time interactions (P < 0.05) for skeletal muscle microvascular function, 6-min walking distance, and exercise recovery, but no changes (P > 0.05) in heart rate variability or pain-free walking distance were noted. The BRJ group demonstrated improved skeletal muscle microvascular function (∆ 22.1 ± 7.5 %·min-1), longer 6-min walking distance (Δ 37.5 ± 9.1 m), and faster recovery post-exercise (Δ -15.3 ± 4.2 s). Furthermore, changes in skeletal muscle microvascular function were positively associated with changes in 6-min walking distance (r = 0.5) and pain-free walking distance (r = 0.6). These results suggest that a moderate dose of dietary nitrate may support microvascular function, which is related to improvements in walking distance and claudication in patients with PAD.

No Mitochondrial Related Transcriptional Changes in Human Skeletal Muscle after Local Heat Application.

The purpose of the study is to determine the impact of local heating on skeletal muscle transcriptional response related to mitochondrial biogenesis and mitophagy. Twelve healthy subjects (height, 176.0 ± 11.9 cm; weight, 83.6 ± 18.3 kg; and body composition, 19.0 ± 7.7% body fat) rested in a semi-reclined position for 4 h with a heated thermal wrap (HOT) around one thigh and a wrap without temperature regulation (CON) around the other (randomized). Skin temperature, blood flow, intramuscular temperature, and a skeletal muscle biopsy from the vastus lateralis were obtained after the 4 h intervention. Skin temperature via infrared thermometer and thermal camera was higher after HOT (37.3 ± 0.7 and 36.7 ± 1.0 °C, respectively) than CON (34.8 ± 0.7, 35.2 ± 0.8 °C, respectively, p < 0.001). Intramuscular temperature was higher in HOT (36.3 ± 0.4 °C) than CON (35.2 ± 0.8 °C, p < 0.001). Femoral artery blood flow was higher in HOT (304.5 ± 12.5 mL‧min-1) than CON (272.3 ± 14.3 mL‧min-1, p = 0.003). Mean femoral shear rate was higher in HOT (455.8 ± 25.1 s-1) than CON (405.2 ± 15.8 s-1, p = 0.019). However, there were no differences in any of the investigated genes related to mitochondrial biogenesis (PGC-1α, NRF1, GAPBA, ERRα, TFAM, VEGF) or mitophagy (PINK-1, PARK-2, BNIP-3, BNIP-3L) in response to heat (p > 0.05). These data indicate that heat application alone does not impact the transcriptional response related to mitochondrial homeostasis, suggesting that other factors, in combination with skeletal muscle temperature, are involved with previous observations of altered exercise induced gene expression with heat.

Influence of Local Muscle Cooling on Mitochondrial-Related Gene Expression at Rest.

The purpose of this study was to determine the impact of localized cooling of the skeletal muscle during rest on mitochondrial related gene expression. Thermal wraps were applied to the vastus lateralis of each limb of 12 participants. One limb received a cold application (randomized) (COLD), while the other did not (RT). Wraps were removed at the 4 h time point and measurements of skin temperature, blood flow, and intramuscular temperature were taken prior to a muscle biopsy. RT-qPCR was used to measure expression of genes associated with mitochondrial development. Skin and muscle temperatures were lower in COLD than RT (p < 0.05). Femoral artery diameter was lower in COLD after 4 h (0.62 ± 0.05 cm, to 0.60 ± 0.05 cm, p = 0.018). Blood flow was not different in COLD compared to RT (259 ± 69 mL·min-1 vs. 275 ± 54 mL·min-1, p = 0.20). PGC-1α B and GABPA expression was higher in COLD relative to RT (1.57-fold, p = 0.037 and 1.34-fold, p = 0.006, respectively). There was no difference (p > 0.05) in the expression of PGC-1α, NT-PGC-1α, PGC-1α A, TFAM, ESRRα, NRF1, GABPA, VEGF, PINK1, PARK 2, or BNIP3-L. The impact of this small magnitude of difference in gene expression of PGC-1α B and GABPA without alterations in other genes are unknown. There appears to be only limited impact of local muscle cooling on the transcriptional response related to mitochondrial development.

Assessing pulse transit time to the skeletal muscle microcirculation using near-infrared spectroscopy.

Pulse transit time (PTT) is the time it takes for pressure waves to propagate through the arterial system. Arterial stiffness assessed via PTT has been extensively examined in the conduit arteries; however, limited information is available about PTT to the skeletal muscle microcirculation. Therefore, the purpose of this study was to assess PTT to the skeletal muscle microcirculation (PTTm) with near-infrared spectroscopy (NIRS) and to determine whether PTTm provides unique information about vascular function that PTT assessed in the conduit arteries (PTTc) cannot provide. This pilot study was conducted with 10 (male = 5; female = 5) individuals of similar age (21.5 ± 1.2 yr). The feasibility of using the intersecting tangents method to derive PTTm with NIRS was assessed during reactive hyperemia with the cross-correlation of PTTm produced by the intersecting tangents method and a different algorithm that used signal spectral properties. To determine whether PTTm was distinct from PTTc, the cross-correlation of PTTm and PTTc during reactive hyperemia was assessed. Cross-correlation indicated agreement between PTTm derived from both algorithms (r2 = 0.77, P < 0.01) and a lack of agreement between PTTm and PTTc during reactive hyperemia (r2 = 0.07, P < 0.01). Therefore, we conclude that it is feasible to assess PTTm using NIRS, and PTTm provides unique information about vascular function, including skeletal muscle microvascular elasticity, which cannot be achieved with traditional PTTc. PTTm with NIRS may provide a comprehensive and noninvasive assessment of vascular function and health.NEW & NOTEWORTHY Pulse transit time to the skeletal muscle microcirculation can be assessed using near-infrared spectroscopy and the intersecting tangents method. Pulse transit analysis to the microcirculation provides a comprehensive assessment of the vascular response to postocclusive reactive hyperemia that pulse transit analysis in the conduit arteries cannot provide. Pulse transit time to the skeletal muscle microcirculation using near-infrared spectroscopy provides unique information about microvascular elasticity in the skeletal muscle. These findings indicate that the combination of near-infrared spectroscopy and pulse transit analysis may be a useful method for assessing the skeletal muscle microcirculation.

Impaired microcirculatory function, mitochondrial respiration, and oxygen utilization in skeletal muscle of claudicating patients with peripheral artery disease.

Peripheral artery disease (PAD) is an atherosclerotic disease that impairs blood flow and muscle function in the lower limbs. A skeletal muscle myopathy characterized by mitochondrial dysfunction and oxidative damage is present in PAD; however, the underlying mechanisms are not well established. We investigated the impact of chronic ischemia on skeletal muscle microcirculatory function and its association with leg skeletal muscle mitochondrial function and oxygen delivery and utilization capacity in PAD. Gastrocnemius samples and arterioles were harvested from patients with PAD (n = 10) and age-matched controls (Con, n = 11). Endothelium-dependent and independent vasodilation was assessed in response to flow (30 µL·min-1), acetylcholine, and sodium nitroprusside (SNP). Skeletal muscle mitochondrial respiration was quantified by high-resolution respirometry, microvascular oxygen delivery, and utilization capacity (tissue oxygenation index, TOI) were assessed by near-infrared spectroscopy. Vasodilation was attenuated in PAD (P < 0.05) in response to acetylcholine (Con: 71.1 ± 11.1%, PAD: 45.7 ± 18.1%) and flow (Con: 46.6 ± 20.1%, PAD: 29.3 ± 10.5%) but not SNP (P = 0.30). Complex I + II state 3 respiration (P < 0.01) and TOI recovery rate were impaired in PAD (P < 0.05). Both flow and acetylcholine-mediated vasodilation were positively associated with complex I + II state 3 respiration (r = 0.5 and r = 0.5, respectively, P < 0.05). Flow-mediated vasodilation and complex I + II state 3 respiration were positively associated with TOI recovery rate (r = 0.8 and r = 0.7, respectively, P < 0.05). These findings suggest that chronic ischemia attenuates skeletal muscle arteriole endothelial function, which may be a key mediator for mitochondrial and microcirculatory dysfunction in the PAD leg skeletal muscle. Targeting microvascular dysfunction may be an effective strategy to prevent and/or reverse disease progression in PAD.NEW & NOTEWORTHY Ex vivo skeletal muscle arteriole endothelial function is impaired in claudicating patients with PAD, and this is associated with attenuated skeletal muscle mitochondrial respiration. In vivo skeletal muscle oxygen delivery and utilization capacity is compromised in PAD, and this may be due to microcirculatory and mitochondrial dysfunction. These results suggest that targeting skeletal muscle arteriole function may lead to improvements in skeletal muscle mitochondrial respiration and oxygen delivery and utilization capacity in claudicating patients with PAD.

Effects of passive and active leg movements to interrupt sitting in mild hypercapnia on cardiovascular function in healthy adults.

Prolonged sitting in a mild hypercapnic environment impairs peripheral vascular function. The effects of sitting interruptions using passive or active skeletal muscle contractions are still unclear. Therefore, we sought to examine the vascular effects of brief periods (2 min every half hour) of passive and active lower limb movement to interrupt prolonged sitting with mild hypercapnia in adults. Fourteen healthy adults (24 ± 2 yr) participated in three experimental visits sitting for 2.5 h in a mild hypercapnic environment (CO2 = 1,500 ppm): control (CON, no limb movement), passive lower limb movement (PASS), and active lower limb movement (ACT) during sitting. At all visits, brachial and popliteal artery flow-mediated dilation (FMD), microvascular function, plasmatic levels of nitrate/nitrite and endothelin-1, and heart rate variability were assessed before and after sitting. Brachial and popliteal artery FMDs were reduced in CON and PASS (P < 0.05) but were preserved (P > 0.05) in ACT. Microvascular function was blunted in CON (P < 0.05) but was preserved in PASS and ACT (P > 0.05). In addition, total plasma nitrate/nitrite was preserved in ACT (P > 0.05) but was reduced in CON and PASS (P < 0.05), and endothelin-1 levels were decreased in ACT (P < 0.05). Both passive and active movement induced a greater ratio between the low-frequency and high-frequency bands for heart rate variability (P < 0.05). For the first time, to our knowledge, we found that brief periods of passive leg movement can preserve microvascular function, but that an intervention that elicits larger increases in shear rate, such as low-intensity exercise, is required to fully protect both macrovascular and microvascular function and circulating vasoactive substance balance.NEW & NOTEWORTHY Passive leg movement could not preserve macrovascular endothelial function, whereas active leg movement could protect endothelial function. Attenuated microvascular function can be salvaged by passive movement and active movement. Preservation of macrovascular hemodynamics and plasma total nitrate/nitrite and endothelin-1 during prolonged sitting requires active movement. These findings dissociate the impacts induced by mechanical stress (passive movement) from the change in metabolism (active movement) on the vasculature during prolonged sitting in a mild hypercapnic environment.

Combined effects of aerobic exercise and 40-Hz light flicker exposure on early cognitive impairments in Alzheimer's disease of 3×Tg mice.

Alzheimer's disease (AD) is a progressive degenerative brain disease and the primary cause of dementia. At an early stage, AD is generally characterized by short-term memory impairment, owing to dysfunctions of the cortex and hippocampus. We previously reported that a combination of exercise and 40-Hz light flickering can protect against AD-related neuroinflammation, gamma oscillations, reduction in Aß, and cognitive decline. Therefore, we sought to extend our previous findings to the 5-mo-old 3×Tg-AD mouse model to examine whether the same favorable effects occur in earlier stages of cognitive dysfunction. We investigated the effects of 12 wk of exercise combined with 40-Hz light flickering on cognitive function by analyzing neuroinflammation, mitochondrial function, and neuroplasticity in the hippocampus in a 3×Tg-AD mouse model. Five-month-old 3×Tg-AD mice performed 12 wk of exercise with 40-Hz light flickering administered independently and in combination. Spatial learning and memory, long-term memory, hippocampal Aß, tau, neuroinflammation, proinflammatory cytokine expression, mitochondrial function, and neuroplasticity were analyzed. Aß and tau proteins levels were significantly reduced in the early stage of AD, resulting in protection against cognitive decline by reducing neuroinflammation and proinflammatory cytokines. Furthermore, mitochondrial function improved, apoptosis was reduced, and synapse-related protein expression increased. Overall, exercise with 40-Hz light flickering was significantly more effective than exercise or 40-Hz light flickering alone, and the improvement was comparable to the levels in the nontransgenic aged-match control group. Our results indicate a synergistic effect of exercise and 40-Hz light flickering on pathological improvements in the hippocampus during early AD-associated cognitive impairment.NEW & NOTEWORTHY Exercising in a 40-Hz light flicker environment was more effective than exercise or 40-Hz light flicker alone. This synergistic effect may prevent cognitive dysfunction by inhibiting Aß, tau pathway, and neuroinflammation and enhancing neuroplasticity and mitochondrial functions in the hippocampus during early Alzheimer's disease.

Acute high-intensity exercise and skeletal muscle mitochondrial respiratory function: role of metabolic perturbation.

Recently it was documented that fatiguing, high-intensity exercise resulted in a significant attenuation in maximal skeletal muscle mitochondrial respiratory capacity, potentially due to the intramuscular metabolic perturbation elicited by such intense exercise. With the utilization of intrathecal fentanyl to attenuate afferent feedback from group III/IV muscle afferents, permitting increased muscle activation and greater intramuscular metabolic disturbance, this study aimed to better elucidate the role of metabolic perturbation on mitochondrial respiratory function. Eight young, healthy males performed high-intensity cycle exercise in control (CTRL) and fentanyl-treated (FENT) conditions. Liquid chromatography-mass spectrometry and high-resolution respirometry were used to assess metabolites and mitochondrial respiratory function, respectively, pre- and postexercise in muscle biopsies from the vastus lateralis. Compared with CTRL, FENT yielded a significantly greater exercise-induced metabolic perturbation (PCr: -67% vs. -82%, Pi: 353% vs. 534%, pH: -0.22 vs. -0.31, lactate: 820% vs. 1,160%). Somewhat surprisingly, despite this greater metabolic perturbation in FENT compared with CTRL, with the only exception of respiratory control ratio (RCR) (-3% and -36%) for which the impact of FENT was significantly greater, the degree of attenuated mitochondrial respiratory capacity postexercise was not different between CTRL and FENT, respectively, as assessed by maximal respiratory flux through complex I (-15% and -33%), complex II (-36% and -23%), complex I + II (-31% and -20%), and state 3CI+CII control ratio (-24% and -39%). Although a basement effect cannot be ruled out, this failure of an augmented metabolic perturbation to extensively further attenuate mitochondrial function questions the direct role of high-intensity exercise-induced metabolite accumulation in this postexercise response.

Body mass-normalized moderate dose of dietary nitrate intake improves endothelial function and walking capacity in patients with peripheral artery disease.

Peripheral artery disease (PAD) is characterized by the accumulation of atherosclerotic plaques in the lower extremity conduit arteries, which impairs blood flow and walking capacity. Dietary nitrate has been used to reduce blood pressure (BP) and improve walking capacity in PAD. However, a standardized dose for PAD has not been determined. Therefore, we sought to determine the effects of a body mass-normalized moderate dose of nitrate (0.11 mmol nitrate/kg) as beetroot juice on serum nitrate/nitrite, vascular function, walking capacity, and tissue oxygen utilization capacity in patients with PAD. A total of 11 patients with PAD received either nitrate supplement or placebo in a randomized crossover design. Total serum nitrate/nitrite, resting BP, brachial and popliteal artery endothelial function (flow-mediated dilation, FMD), arterial stiffness (pulse-wave velocity, PWV), augmentation index (AIx), maximal walking distance and time, claudication onset time, and skeletal muscle oxygen utilization were measured pre- and postnitrate and placebo intake. There were significant group × time interactions (P < 0.05) for serum nitrate/nitrite, FMD, BP, walking distance and time, and skeletal muscle oxygen utilization. The nitrate group showed significantly increased serum nitrate/nitrite (Δ1.32 µM), increased brachial and popliteal FMD (Δ1.3% and Δ1.7%, respectively), reduced peripheral and central systolic BP (Δ-4.7 mmHg and Δ-8.2 mmHg, respectively), increased maximal walking distance (Δ92.7 m) and time (Δ56.3 s), and reduced deoxygenated hemoglobin during walking. There were no changes in PWV, AIx, or claudication (P > 0.05). These results indicate that a body-mass normalized moderate dose of nitrate may be effective and safe for reducing BP, improving endothelial function, and improving walking capacity in patients with PAD.

Microvascular Dysfunction in Peripheral Artery Disease: Is Heat Therapy a Viable Treatment?

Peripheral artery disease (PAD) is characterized by the development of atherosclerotic plaques in the lower-body conduit arteries. PAD is commonly accompanied by microvascular disease, which may result in poor wound healing, plantar ulcer development, and subsequent limb amputation. Understanding the mechanisms underlying the development of plantar ulcers is a critical step in the development of adequate treatment options for patients with PAD. Skin is classified into two major components: glabrous and non-glabrous. These skin types have unique microcirculation characteristics, making it important to differentiate between the two when investigating mechanisms for plantar ulcer development in PAD. There is evidence for a microcirculation compensatory mechanism in PAD. This is evident by the maintenance of basal microcirculation perfusion and capillary filling pressure despite a reduced pressure differential beyond an occlusion in non-critical limb ischemia PAD. The major mechanism for this compensatory system seems to be progressive vasodilation of the arterial network below an occlusion. Recently, heat therapies have emerged as novel treatment options for attenuating the progression of PAD. Heat therapies are capable of stimulating the cardiovascular system, which may lead to beneficial adaptations that may ultimately reduce fatigue during walking in PAD. Early work in this area has shown that full-body heating is capable of generating an acute cardiovascular response, similar to exercise, which has been suggested as the most efficient treatment modality and may generate adaptations with chronic exposure. Heat therapies may emerge as a conservative treatment option capable of attenuating the progression of PAD and ultimately impeding the development of plantar ulcers.

Combined anthocyanins and bromelain supplement improves endothelial function and skeletal muscle oxygenation status in adults: a double-blind placebo-controlled randomised crossover clinical trial.

Anthocyanins and bromelain have gained significant attention due to their antioxidative and anti-inflammatory properties. Both have been shown to improve endothelial function, blood pressure (BP) and oxygen utility capacity in humans; however, the combination of these two and the impacts on endothelial function, BP, total antioxidant capacity (TAC) and oxygen utility capacity have not been previously investigated. The purpose of this study was to investigate the impacts of a combined anthocyanins and bromelain supplement (BE) on endothelial function, BP, TAC, oxygen utility capacity and fatigability in healthy adults. Healthy adults (n 18, age 24 (sd 4) years) received BE or placebo in a randomised crossover design. Brachial artery flow-mediated dilation (FMD), BP, TAC, resting heart rate, oxygen utility capacity and fatigability were measured pre- and post-BE and placebo intake. The BE group showed significantly increased FMD, reduced systolic BP and improved oxygen utility capacity compared with the placebo group (P < 0·05). Tissue saturation and oxygenated Hb significantly increased following BE intake, while deoxygenated Hb significantly decreased (P < 0·05) during exercise. Additionally, TAC was significantly increased following BE intake (P < 0·05). There were no significant differences for resting heart rate, diastolic BP or fatigability index. These results suggest that BE intake is an effective nutritional therapy for improving endothelial function, BP, TAC and oxygen utility capacity, which may be beneficial to support vascular health in humans.

The impacts of exercise on pediatric obesity.

Over the last few decades, the rates of pediatric obesity have more than doubled regardless of sociodemographic categorization, and despite these rates plateauing in recent years there continues to be an increase in the severity of obesity in children and adolescents. This review will discuss the pediatric obesity mediated cardiovascular disease (CVD) risk factors such as attenuated levels of satiety and energy metabolism hormones, insulin resistance, vascular endothelial dysfunction, and arterial stiffness. Additionally, early intervention to combat pediatric obesity is critical as obesity has been suggested to track into adulthood, and these obese children and adolescents are at an increased risk of early mortality. Current suggested strategies to combat pediatric obesity are modifying diet, limiting sedentary behavior, and increasing physical activity. The effects of exercise intervention on metabolic hormones such as leptin and adiponectin, insulin sensitivity/resistance, and body fat in obese children and adolescents will be discussed along with the exercise modality, intensity, and duration. Specifically, this review will focus on the differential effects of aerobic exercise, resistance training, and combined exercise on the cardiovascular risks in pediatric obesity. This review outlines the evidence that exercise intervention is a beneficial therapeutic strategy to reduce the risk factors for CVD and the ideal exercise prescription to combat pediatric obesity should contain both muscle strengthening and aerobic components with an emphasis on fat mass reduction and long-term adherence.

Correlation of Pre-Hypertension with Carotid Artery Damage in Middle-Aged and Older Adults.

The intima-media thickness (IMT), luminal diameters (LDs), flow velocities (FVs), compliance, and ß-stiffness of the carotid artery (CA) are considered as independent risk factors for cardiovascular diseases (CVDs). Pre-hypertension (PHT) is also an independent CVD risk factor. This study investigated the association between CA damage (CAD) and PHT. A total of 544 adults participated; their blood pressures (BPs) and CA characteristics were measured using a mercury-free sphygmomanometer and ultrasound. Analysis of covariance (ANCOVA) was performed to assess the differences in the CA characteristics according to the BPs, multinomial logistic regression to evaluate the risk of CAD associated with PHT. In ANCOVA, the CA characteristics of PHT were significantly different from normotensive. The odds ratios (ORs) of IMTmax, LDmax, LDmin, peak-systolic FV (PFV), end-diastolic FV (EFV), PFV/LDmin, EFV/LDmax, compliance, and ß-stiffness of PHT were 4.20, 2.70, 3.52, 2.41, 3.06, 3.55, 3.29, 2.02, and 1.84 times higher than those of the normotensive, respectively, in Model 2. In Model 3 adjusted for age, the ORs of LDmax, LDmin, EFV, PFV/LDmin, and EFV/LDmax of PHT were 2.10, 2.55, 1.96, 2.20, and 2.04 times higher than those of the normotensive, respectively. Therefore, the present study revealed that CAD is closely correlated with pre-hypertensive status in adults.

Functional, proteomic and bioinformatic analyses of Nrf2- and Keap1- null skeletal muscle.

KEY POINTS: Nrf2 is a master regulator of endogenous cellular defences, governing the expression of more than 200 cytoprotective proteins, including a panel of antioxidant enzymes. Nrf2 plays an important role in redox haemostasis of skeletal muscle in response to the increased generation of reactive oxygen species during contraction. Employing skeletal muscle-specific transgenic mouse models with unbiased-omic approaches, we uncovered new target proteins, downstream pathways and molecular networks of Nrf2 in skeletal muscle following Nrf2 or Keap1 deletion. Based on the findings, we proposed a two-way model to understand Nrf2 function: a tonic effect through a Keap1-independent mechanism under basal conditions and an induced effect through a Keap1-dependent mechanism in response to oxidative and other stresses. ABSTRACT: Although Nrf2 has been recognized as a master regulator of cytoprotection, its functional significance remains to be completely defined. We hypothesized that proteomic/bioinformatic analyses from Nrf2-deficient or overexpressed skeletal muscle tissues will provide a broader spectrum of Nrf2 targets and downstream pathways than are currently known. To this end, we created two transgenic mouse models; the iMS-Nrf2flox/flox and iMS-Keap1flox/flox , employing which we demonstrated that selective deletion of skeletal muscle Nrf2 or Keap1 separately impaired or improved skeletal muscle function. Mass spectrometry revealed that Nrf2-KO changed expression of 114 proteins while Keap1-KO changed expression of 117 proteins with 10 proteins in common between the groups. Gene ontology analysis suggested that Nrf2 KO-changed proteins are involved in metabolism of oxidoreduction coenzymes, purine ribonucleoside triphosphate, ATP and propanoate, which are considered as the basal function of Nrf2, while Keap1 KO-changed proteins are involved in cellular detoxification, NADP metabolism, glutathione metabolism and the electron transport chain, which belong to the induced effect of Nrf2. Canonical pathway analysis suggested that Keap1-KO activated four pathways, whereas Nrf2-KO did not. Ingenuity pathway analysis further revealed that Nrf2-KO and Keap1-KO impacted different signal proteins and functions. Finally, we validated the proteomic and bioinformatics data by analysing glutathione metabolism and mitochondrial function. In conclusion, we found that Nrf2-targeted proteins are assigned to two groups: one mediates the tonic effects evoked by a low level of Nrf2 at basal condition; the other is responsible for the inducible effects evoked by a surge of Nrf2 that is dependent on a Keap1 mechanism.

Impacts of prolonged sitting with mild hypercapnia on vascular and autonomic function in healthy recreationally active adults.

Prolonged sitting, which is known to impair peripheral vascular function, often occurs in spaces (e.g., offices) with mild hypercapnic atmospheres. However, the effects of prolonged sitting in hypercapnic conditions on vascular function are unknown. Therefore, the purpose of this study was to investigate the effects of prolonged sitting in mild hypercapnic conditions on vascular and autonomic function in humans. Twelve healthy young adults participated in two experimental visits that consisted of sitting for 2.5 h in a control condition [normal atmospheric conditions sitting (PSIT)] or a mild hypercapnic condition (HCAP; CO2 = 1,500 ppm). During each visit, heart rate variability (HRV), blood pressure (BP), pulse wave velocity (PWV), augmentation index (AIx), brachial and popliteal artery flow-mediated dilation (FMD), and near-infrared spectroscopy (NIRS) were assessed before and after prolonged sitting. Sitting significantly decreased AIx in both groups (P < 0.05). Brachial and popliteal FMD were reduced with sitting (P < 0.05), and the reduction in popliteal FMD was amplified by HCAP (P < 0.05). Baseline microvascular oxygenation was decreased following sitting in both groups (P < 0.05). However, microvascular reoxygenation upon cuff release was slower only in HCAP (P < 0.05). HRV, HR, BP, and PWV did not significantly change with sitting in either group (P > 0.05). We conclude that prolonged sitting attenuated both brachial and popliteal endothelial function and was associated with perturbed microcirculation. Additionally, mild hypercapnic conditions further impaired peripheral endothelial and microvascular function. Together, these findings suggest that prolonged sitting is accompanied by a host of deleterious effects on the vasculature, which are exacerbated by mild hypercapnia.NEW & NOTEWORTHY The results of this study reveal that prolonged sitting attenuates endothelial function and microvascular function. Additionally, prolonged sitting with mild hypercapnia, which is similar to everyday environments, further exacerbates peripheral endothelial function and microvascular function.

Acute mitochondrial antioxidant intake improves endothelial function, antioxidant enzyme activity, and exercise tolerance in patients with peripheral artery disease.

Peripheral artery disease (PAD) is a manifestation of atherosclerosis in the leg arteries, which causes claudication. This may be in part due to vascular mitochondrial dysfunction and excessive reactive oxygen species (ROS) production. A mitochondrial-targeted antioxidant (MitoQ) has been shown to improve vascular mitochondrial function that, in turn, led to improved vascular function in older adults and animal models. However, the roles of vascular mitochondria in vascular function including endothelial function and arterial stiffness in patients with PAD are unknown; therefore, with the use of acute MitoQ intake, this study examined the roles of vascular mitochondria in endothelial function, arterial stiffness, exercise tolerance, and skeletal muscle function in patients with PAD. Eleven patients with PAD received either MitoQ or placebo in a randomized crossover design. At each visit, blood samples, brachial and popliteal artery flow-mediated dilation (FMD), peripheral and central pulse-wave velocity (PWV), blood pressure (BP), maximal walking capacity, time to claudication (COT), and oxygen utility capacity were measured pre- and-post-MitoQ and placebo. There were significant group by time interactions (P < 0.05) for brachial and popliteal FMD that both increased by Δ2.6 and Δ3.3%, respectively, and increases superoxide dismutase (Δ0.03 U/mL), maximal walking time (Δ73.8 s), maximal walking distance (Δ49.3 m), and COT (Δ44.2 s). There were no changes in resting heart rate, BP, malondialdehyde, total antioxidant capacity, PWV, or oxygen utility capacity (P > 0.05). MitoQ intake may be an effective strategy for targeting the vascular mitochondrial environment, which may be useful for restoring endothelial function, leg pain, and walking time in patients with PAD.NEW & NOTEWORTHY The results of this study reveal for the first time that acute oral intake of mitochondrial-targeted antioxidant (MitoQ, 80 mg) is effective for improving vascular endothelial function and superoxide dismutase in patients with peripheral artery disease (PAD). Acute MitoQ intake is also effective for improving maximal walking capacity and delaying the onset of claudication in patients with PAD. These findings suggest that the acute oral intake of MitoQ-mediated improvements in vascular mitochondria play a pivotal role for improving endothelial function, the redox environment, and skeletal muscle performance in PAD.