ABSTRACT
The endoplasmic reticulum (ER) regulates protein folding and maintains proteostasis in cells. We observed that the ER transcriptome is impaired during chronic reductive stress (RS) in cardiomyocytes. Here, we hypothesized that a prolonged moderate treadmill exercise mitigates the RS-induced ER dysfunction and cardiac remodeling in cardiac-specific constitutively active Nrf2 mice (CaNrf2-TG). RNA sequencing showed notable alterations in the ER transcriptome of TG hearts at 4, 12, and 24 weeks (16, 28, and 35 genes, respectively). Notably, the downregulation of ER genes was significant at 12 weeks, and further pronounced at 24 weeks, at which the cardiac pathology is evident. We also observed increased levels of ubiquitinated proteins in CaNrf2-TG hearts across all ages, along with VCP, a marker of ERAD function, at 24 weeks. These findings indicate that constitutive Nrf2 activation and RS impair protein-folding activity and augments ERAD function over time. Exercise intervention for 20 weeks (beginning at 6 weeks of age), reduced cardiomyocyte hypertrophy (from 448 µm2 to 280 µm2) in TG mice, through adaptive remodeling, and preserved the cardiac function. However, while exercise did not influence antioxidants or ER stress protein levels, it significantly improved ERAD function and autophagy flux (LC-I to LC-II) in the TG-EXE hearts. Collectively, our findings underscore the prophylactic potential of exercise in mitigating RS-associated pathology, highlighting its essential role in maintaining cellular proteostasis through ER-independent mechanisms.
ABSTRACT
Heightened muscle sympathetic nerve activity (MSNA) contributes to impaired vasodilatory capacity and vascular dysfunction associated with aging and cardiovascular disease. The contribution of elevated MSNA to the vasodilatory response during passive leg movement (PLM) has not been adequately addressed. This study sought to test the hypothesis that elevated MSNA diminishes the vasodilatory response to PLM in healthy young males (n = 11, 25 ± 2 year). Post exercise circulatory occlusion (PECO) following 2 min of isometric handgrip (HG) exercise performed at 25% (ExPECO 25%) and 40% (ExPECO 40%) of maximum voluntary contraction was used to incrementally engage the metaboreceptors and augment MSNA. Control trials were performed without PECO (ExCON 25% and ExCON 40%) to account for changes due to HG exercise. PLM was performed 2 min after the cessation of exercise and central and peripheral hemodynamics were assessed. MSNA was directly recorded by microneurography in the peroneal nerve (n = 8). Measures of MSNA (i.e., burst incidences) increased during ExPECO 25% (+ 15 ± 5 burst/100 bpm) and ExPECO 40% (+ 22 ± 4 burst/100 bpm) and returned to pre-HG levels during ExCON trials. Vasodilation, assessed by the change in leg vascular conductance during PLM, was reduced by 16% and 44% during ExPECO 25% and ExPECO 40%, respectively. These findings indicate that elevated MSNA attenuates the vasodilatory response to PLM and that the magnitude of reduction in vasodilation during PLM is graded in relation to the degree of sympathoexcitation.
ABSTRACT
Lifestyle modification including exercise training is often the first line of defense in the treatment of obesity and hypertension (HTN), however, little is known regarding how these potentially compounding disease states impact vasodilatory and hemodynamic responses at baseline and exercise. Therefore, this study sought to compare the impact of obesity on vascular function and hemodynamics at baseline and during handgrip (HG) exercise among individuals with HTN. Non-obese (13M/7F, 56 ± 16 yr, 25 ± 4 kg/m2) and obese (17M/4F, 50 ± 7 yr, 35 ± 4 kg/m2) middle-aged individuals with HTN forwent antihypertensive medication use for ≥2 wk before assessment of vascular function by brachial artery flow-mediated dilation (FMD) and exercise hemodynamics during progressive HG exercise at 15-30-45% maximal voluntary contraction (MVC). FMD was not different between Non-Obese (4.1 ± 1.7%) and Obese (5.2 ± 1.9%, P = 0.11). Systolic blood pressure (SBP) was elevated by â¼15% during the supine baseline and during HG exercise in the obese group. The blood flow response to HG exercise at 30% and 45% MVC was â¼20% greater (P < 0.05) in the obese group but not different after normalizing for the higher, albeit, nonsignificant differences in workloads (MVC: obese: 24 ± 5 kg, non-obese: 21 ± 5 kg, P = 0.11). Vascular conductance and the brachial artery shear-induced vasodilatory response during HG were not different between groups (P > 0.05). Taken together, despite elevated SBP during HG exercise, obesity does not lead to additional impairments in vascular function and peripheral exercising hemodynamics in patients with HTN. Obesity may not be a contraindication when prescribing exercise for the treatment of HTN among middle-aged adults, however, the elevated SBP should be appropriately monitored.NEW & NOTEWORTHY This study examined vascular function and handgrip exercise hemodynamics in obese and nonobese individuals with hypertension. Obesity, when combined with hypertension, was neither associated with additional vascular function impairments at baseline nor peripheral hemodynamics and vasodilation during exercise compared with nonobese hypertension. Interestingly, systolic blood pressure and pulse pressure were greater in the obese group during supine baseline and exercise. These findings should not be ignored and may be particularly important for rehabilitation strategies.
Subject(s)
Hypertension , Hypotension , Adult , Middle Aged , Humans , Hand Strength , Hemodynamics , Exercise/physiology , Blood Pressure , Obesity , Vasodilation/physiology , Brachial Artery , Regional Blood FlowABSTRACT
Heart failure with preserved ejection fraction (HFpEF) is characterized by reduced ability to sustain physical activity that may be due partly to disease-related changes in autonomic function that contribute to dysregulated cardiovascular control during muscular contraction. Thus, we used a combination of static handgrip exercise (HG) and postexercise ischemia (PEI) to examine the pressor response to exercise and isolate the skeletal muscle metaboreflex, respectively. Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR) were assessed during 2-min of static HG at 30 and 40% of maximum voluntary contraction (MVC) and subsequent PEI in 16 patients with HFpEF and 17 healthy, similarly aged controls. Changes in MAP were lower in patients with HFpEF compared with controls during both 30%MVC (Δ11 ± 7 vs. Δ15 ± 8 mmHg) and 40%MVC (Δ19 ± 14 vs. Δ30 ± 8 mmHg), and a similar pattern of response was evident during PEI (30%MVC: Δ8 ± 5 vs. Δ12 ± 8 mmHg; 40%MVC: Δ13 ± 10 vs. Δ18 ± 9 mmHg) (group effect: P = 0.078 and P = 0.017 at 30% and 40% MVC, respectively). Changes in HR, CO, and TPR did not differ between groups during HG or PEI (P > 0.05). Taken together, these data suggest a reduced pressor response to static muscle contractions in patients with HFpEF compared with similarly aged controls that may be mediated partly by a blunted muscle metaboreflex. These findings support a disease-related dysregulation in neural cardiovascular control that may reduce an ability to sustain physical activity in HFpEF.NEW & NOTEWORTHY The current investigation has identified a diminution in the exercise-induced rise in arterial blood pressure (BP) that persisted during postexercise ischemia (PEI) in an intensity-dependent manner in patients with heart failure with preserved ejection fraction (HFpEF) compared with older, healthy controls. These findings suggest that the pressor response to exercise is reduced in patients with HFpEF, and this deficit may be mediated, in part, by a blunted muscle metaboreflex, highlighting the consequences of impaired neural cardiovascular control during exercise in this patient group.
Subject(s)
Heart Failure , Humans , Stroke Volume , Hand Strength/physiology , Ischemia , Muscle, Skeletal/physiology , Exercise/physiology , Reflex/physiology , Blood Pressure/physiologyABSTRACT
The age-related increase in α-adrenergic tone may contribute to decreased leg vascular conductance (LVC) both at rest and during exercise in the old. However, the effect on passive leg movement (PLM)-induced LVC, a measure of vascular function, which is markedly attenuated in this population, is unknown. Thus, in eight young (25 ± 5 yr) and seven old (65 ± 7 yr) subjects, this investigation examined the impact of systemic ß-adrenergic blockade (propanalol, PROP) alone, and PROP combined with either α1-adrenergic stimulation (phenylephrine, PE) or α-adrenergic inhibition (phentolamine, PHEN), on PLM-induced vasodilation. LVC, calculated from femoral artery blood flow and pressure, was determined and PLM-induced Δ peak (LVCΔpeak) and total vasodilation (LVCAUC, area under curve) were documented. PROP decreased LVCΔpeak (PROP: 4.8 ± 1.8, Saline: 7.7 ± 2.7 mL·mmHg-1, P < 0.001) and LVCAUC (PROP: 1.1 ± 0.7, Saline: 2.4 ± 1.6 mL·mmHg-1, P = 0.002) in the young, but not in the old (LVCΔpeak, P = 0.931; LVCAUC, P = 0.999). PE reduced baseline LVC (PE: 1.6 ± 0.4, PROP: 2.3 ± 0.4 mL·min-1·mmHg-1, P < 0.01), LVCΔpeak (PE: 3.2 ± 1.3, PROP: 4.8 ± 1.8 mL·min-1·mmHg-1, P = 0.004), and LVCAUC (PE: 0.5 ± 0.4, PROP: 1.1 ± 0.7 mL·mmHg-1, P = 0.011) in the young, but not in the old (baseline LVC, P = 0.199; LVCΔpeak, P = 0.904; LVCAUC, P = 0.823). PHEN increased LVC at rest and throughout PLM in both groups (drug effect: P < 0.05), however LVCΔpeak was only improved in the young (PHEN: 6.4 ± 3.1, PROP: 4.4 ± 1.5 mL·min-1·mmHg-1, P = 0.004), and not in the old (P = 0.904). Furthermore, the magnitude of α-adrenergic modulation (PHEN - PE) of LVCΔpeak was greater in the young compared with the old (Young: 3.35 ± 2.32, Old: 0.40 ± 1.59 mL·min-1·mmHg-1, P = 0.019). Therefore, elevated α-adrenergic tone does not appear to contribute to the attenuated vascular function with age identified by PLM.NEW & NOTEWORTHY Stimulation of α1-adrenergic receptors eliminated age-related differences in passive leg movement (PLM) by decreasing PLM-induced vasodilation in the young. Systemic ß-blockade attenuated the central hemodynamic component of the PLM response in young individuals. Inhibition of α-adrenergic receptors did not improve the PLM response in older individuals, though withdrawal of α-adrenergic modulation augmented baseline and maximal vasodilation in both groups. Accordingly, α-adrenergic signaling plays a role in modulating the PLM vasodilatory response in young but not in old adults, and elevated α-adrenergic tone does not appear to contribute to the attenuated vascular function with age identified by PLM.
Subject(s)
Leg , Vasodilation , Humans , Aged , Vasodilation/physiology , Leg/blood supply , Adrenergic Agents/pharmacology , Movement/physiology , Hemodynamics , Regional Blood Flow/physiologyABSTRACT
AIM: The importance of endothelial cell (EC) autophagy to vascular homeostasis in the context of health and disease is evolving. Earlier, we reported that intact EC autophagy is requisite to maintain shear-stress-induced nitric oxide (NO) generation via glycolysis-dependent purinergic signalling to endothelial NO synthase (eNOS). Here, we illustrate the translational and functional significance of these findings. METHODS AND RESULTS: First, we assessed translational relevance using older male humans and mice that exhibit blunted EC autophagy and impaired arterial function vs. adult controls. Active hyperaemia evoked by rhythmic handgrip exercise-elevated radial artery shear-rate similarly from baseline in adult and older subjects for 60 min. Compared with baseline, indexes of autophagy initiation, p-eNOSS1177 activation, and NO generation, occurred in radial artery ECs obtained from adult but not older volunteers. Regarding mice, indexes of autophagy and p-eNOSS1177 activation were robust in ECs from adult but not older animals that completed 60-min treadmill-running. Furthermore, 20 dyne ⢠cm2 laminar shear stress × 45-min increased autophagic flux, glycolysis, ATP production, and p-eNOSS1177 in primary arterial ECs obtained from adult but not older mice. Concerning functional relevance, we next questioned whether the inability to initiate EC autophagy, glycolysis, and p-eNOSS1177in vitro precipitates arterial dysfunction ex vivo. Compromised intraluminal flow-mediated vasodilation displayed by arteries from older vs. adult mice was recapitulated in vessels from adult mice by (i) NO synthase inhibition; (ii) acute autophagy impairment using 3-methyladenine (3-MA); (iii) EC Atg3 depletion (iecAtg3KO mice); (iv) purinergic 2Y1-receptor (P2Y1-R) blockade; and (v) germline depletion of P2Y1-Rs. Importantly, P2Y1-R activation using 2-methylthio-ADP (2-Me-ADP) improved vasodilatory capacity in arteries from (i) adult mice treated with 3-MA; (ii) adult iecAtg3KO mice; and (iii) older animals with repressed EC autophagy. CONCLUSIONS: Arterial dysfunction concurrent with pharmacological, genetic, and age-associated EC autophagy compromise is improved by activating P2Y1-Rs.
Subject(s)
Arteries , Hand Strength , Adult , Humans , Male , Animals , Mice , Receptors, Purinergic P2Y1 , Nitric Oxide Synthase Type III/genetics , Nitric Oxide Synthase , Autophagy , Nitric OxideABSTRACT
PURPOSE: Primary purpose wasâ¯to identify relationshipsâ¯between performance-based measures onto both computerized adaptive testing [Physical Function-Computer Adaptive Testing (PF-CAT)] and joint-specific legacy [Knee injury and Osteoarthritis Outcome Score-Activities of Daily Living (KOOS-ADL)] instruments pre- and 12-month post-TKA. METHODS: The PF-CAT and KOOS-ADL were identified as outcomes and performance on the 40-m fast-paced walking test, stair climb test and chair stand test were identified as predictors. Linear regression was used for all comparisons after adjusting for confounders. RESULTS: Sixty-eight people with TKA (56.7% male) were tested. Better scores on the 40-m fast-paced walking (KOOS-ADL, p = 0.02), stair climb (KOOS-ADL, p = 0.05) and chair stand (KOOS-ADL, p < 0.01) associated with better self-reported scores pre-TKA. Better scores on the 40-m fast-paced walking (PF-CAT, p = 0.05; KOOS-ADL, p = 0.01), stair climb (KOOS-ADL, p < 0.01), chair stand (PF-CAT, p < 0.01) and range of motion (KOOS-ADL, p = 0.02) were associated with better self-reported scores 12-month post-TKA. Decrease knee range of motion related to poorer 40-m fast-paced walking (p = 0.01) and stair climb (p = 0.03) scores pre-TKA. Quadriceps weakness related to poorer 40-m fast-paced walking (p = 0.04) score pre-TKA. CONCLUSION: Self-reported instruments are a moderate, but inconsistent surrogate to performance-based measures pre- and post-TKA. Our findings indicate that both self-reported and performance-based measures are necessary to fully characterize physical function and should be used jointly to aid in the recovery analysis of people undergoing TKA.Implications for RehabilitationMonitoring the trajectory of pre- to post-total knee arthroplasty (TKA) physical function is important as it directly relates to mortality, morbidity and poorer quality of life in older adults.Both self-reported and performance-based measures of physical function are used to determine progress in recovery for patients pre- and post- TKA.This study provides evidence that perceived physical function measures are a moderate, but an inconsistent, surrogate to objective physical function measures pre- and post-TKA.Joint specific deficits in knee range of motion and quadriceps strength were weakly associated with deficits in function measures pre-TKA, but no association was observed 12-month post-TKA.Our findings indicate that both self-reported and performance-based measures are necessary to fully characterize physical function and should be used jointly to aid in the complete recovery analysis of people undergoing TKA.
ABSTRACT
An exaggerated mean arterial blood pressure (MAP) response to exercise in patients with peripheral artery disease (PAD), likely driven by inflammation and oxidative stress and, perhaps, required to achieve an adequate blood flow response, is well described. However, the blood flow response to exercise in patients with PAD actually remains equivocal. Therefore, eight patients with PAD and eight healthy controls completed 3 min of plantar flexion exercise at both an absolute work rate (WR) (2.7 W, to evaluate blood flow) and a relative intensity (40%WRmax, to evaluate MAP). The exercise-induced change in popliteal artery blood flow (BF, Ultrasound Doppler), MAP (Finapress), and vascular conductance (VC) were quantified. In addition, resting markers of inflammation and oxidative stress were measured in plasma and muscle biopsies. Exercise-induced ΔBF, assessed at 2.7 W, was lower in PAD compared with controls (PAD: 251 ± 150 vs. Controls: 545 ± 187 mL/min, P < 0.001), whereas ΔMAP, assessed at 40%WRmax, was greater for PAD (PAD: 23 ± 14 vs. Controls: 11 ± 6 mmHg, P = 0.028). The exercise-induced ΔVC was lower for PAD during both the absolute WR (PAD: 1.9 ± 1.6 vs. Controls: 4.7 ± 1.9 mL/min/mmHg) and relative intensity exercise (PAD: 1.9 ± 1.8 vs. Controls: 5.0 ± 2.2 mL/min/mmHg) trials (both, P < 0.01). Inflammatory and oxidative stress markers, including plasma interleukin-6 and muscle protein carbonyls, were elevated in PAD (both, P < 0.05), and significantly correlated with the hemodynamic changes during exercise (r = -0.57 to -0.78, P < 0.05). Thus, despite an exaggerated ΔMAP response, patients with PAD exhibit an impaired exercise-induced ΔBF and ΔVC, and both inflammation and oxidative stress likely play a role in this attenuated hemodynamic response.
Subject(s)
Exercise , Inflammation , Oxidative Stress , Peripheral Arterial Disease , Humans , Arterial Pressure , Inflammation/metabolism , Interleukin-6/metabolism , Muscle Proteins/metabolism , Muscle, Skeletal/metabolism , Peripheral Arterial Disease/physiopathology , Regional Blood Flow , HemodynamicsABSTRACT
Exaggerated blood pressure and diminished limb hemodynamics during exercise in patients with hypertension often are not resolved by antihypertensive medications. We hypothesized that, independent of antihypertensive medication status, dietary nitrate supplementation would increase limb blood flow, decrease mean arterial pressure (MAP), and increase limb vascular conductance during exercise in patients with hypertension. Patients with hypertension either abstained from (n = 14, Off-Meds) or continued (n = 12, On-Meds) antihypertensive medications. Within each group, patients consumed (crossover design) nitrate-rich or nitrate-depleted (placebo) beetroot juice for 3 days before performing handgrip (HG) and knee-extensor exercise (KE). Blood flow and MAP were measured using Doppler ultrasound and an automated monitor, respectively. Dietary nitrate increased plasma-[nitrite] Off-Meds and On-Meds. There were no significant effects of dietary nitrate on blood flow, MAP, or vascular conductance during HG in Off-Meds or On-Meds. For KE, dietary nitrate decreased MAP (means ± SD across all 3 exercise intensities, 118 ± 14 vs. 122 ± 14 mmHg, P = 0.024) and increased vascular conductance (26.2 ± 6.1 vs. 24.7 ± 7.0 mL/min/mmHg, P = 0.024), but did not affect blood flow for Off-Meds, with no effects On-Meds. Dietary nitrate-induced changes in blood flow (r = -0.67, P < 0.001), MAP (r = -0.43, P = 0.009), and vascular conductance (r = -0.64, P < 0.001) during KE, but only vascular conductance (r = -0.35, P = 0.039) during HG, were significantly related to the magnitude of placebo values, with no differentiation between groups. Thus, the effects of dietary nitrate on limb hemodynamics and MAP during exercise in patients with hypertension are dependent on the values at baseline, independent of antihypertensive medication status, and dependent on whether exercise was performed by the forearm or quadriceps.NEW & NOTEWORTHY Adverse hemodynamic responses to exercise in patients with hypertension, despite antihypertensive medication, indicate a sustained cardiovascular risk. The efficacy of dietary nitrate to improve limb vascular conductance during exercise was inversely dependent on the magnitude of exercising limb vascular conductance at baseline, rather than antihypertensive medication status. The effects of dietary nitrate on hemodynamics during exercise in patients with hypertension are dependent on the values at baseline and independent of antihypertensive medication status.
Subject(s)
Dietary Supplements , Essential Hypertension , Exercise Therapy , Nitrates , Antihypertensive Agents , Blood Pressure , Cross-Over Studies , Essential Hypertension/diet therapy , Essential Hypertension/therapy , Hand Strength/physiology , Hemodynamics , Humans , MusclesABSTRACT
BACKGROUND: Vascular dysfunction, an independent risk factor for cardiovascular disease, often persists in patients with hypertension, despite improvements in blood pressure control induced by antihypertensive medications. METHODS: As some of these medications may directly affect vascular function, this study sought to comprehensively examine the impact of reducing blood pressure, by a nonpharmacological approach (5âdays of sodium restriction), on vascular function in 22 hypertensive individuals (14 men/8 women, 50â±â10 years). Following a 2-week withdrawal of antihypertensive medications, two 5-day dietary phases, liberal sodium (liberal sodium, 200âmmol/day) followed by restricted sodium (restricted sodium, 10âmmol/day), were completed. Resting blood pressure was assessed and vascular function, at both the conduit and microvascular levels, was evaluated by brachial artery flow-mediated dilation (FMD), reactive hyperemia, progressive handgrip exercise, and passive leg movement (PLM). RESULTS: Despite a sodium restriction-induced fall in blood pressure (liberal sodium: 141â±â14/85â±â9; restricted sodium 124â±â12/79â±â9âmmHg, Pâ<â0.01 for both SBP and DBP), FMD (liberal sodium: 4.6â±â1.8%; restricted sodium: 5.1â±â2.1%, Pâ=â0.27), and reactive hyperemia (liberal sodium: 548â±â201; restricted sodium: 615â±â206âml, Pâ=â0.08) were not altered. Similarly, brachial artery vasodilation during handgrip exercise was not different between conditions (liberal sodium: Δ0.36â±â0.19âmm; restricted sodium: Δ0.42â±â0.18âmm, Pâ=â0.16). Lastly, PLM-induced changes in peak blood flow (liberal sodium: 5.3â±â2.5; restricted sodium: 5.8â±â3.6âml/min per mmHg, Pâ=â0.30) and the total vasodilatory response [liberal sodium: 2 (0.9-2.5) vs. restricted sodium: 1.7 (1.1-2.6) ml/min per mmHg; Pâ=â0.5] were also not different between conditions. CONCLUSION: Thus vascular dysfunction, at both the conduit and microvascular levels, persists in patients with hypertension even when blood pressure is acutely reduced by a nonpharmacological approach.
Subject(s)
Hyperemia , Hypertension , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Blood Pressure , Brachial Artery/physiology , Endothelium, Vascular , Female , Hand Strength , Humans , Male , Regional Blood Flow , Sodium , VasodilationABSTRACT
BACKGROUND AND AIMS: Metformin is the most commonly prescribed medication to treat diabetes. Emerging evidence suggests that metformin could have off target effects that might help promote healthy muscle aging, but these effects have not been thoroughly studied in glucose tolerant older individuals. The purpose of this study was to investigate the short-term effects of metformin consumption on skeletal muscle mitochondrial bioenergetics in healthy older adults. METHODS: We obtained muscle biopsy samples from 16 healthy older adults previously naïve to metformin and treated with metformin (METF; 3F, 5M), or placebo (CON; 3F, 5M), for two weeks using a randomized and blinded study design. Samples were analyzed using high-resolution respirometry, immunofluorescence, and immunoblotting to assess muscle mitochondrial bioenergetics, satellite cell (SC) content, and associated protein markers. RESULTS: We found that metformin treatment did not alter maximal mitochondrial respiration rates in muscle compared to CON. In contrast, mitochondrial H2O2 emission and production were elevated in muscle samples from METF versus CON (METF emission: 2.59 ± 0.72 SE Fold, P = 0.04; METF production: 2.29 ± 0.53 SE Fold, P = 0.02). Furthermore, the change in H2O2 emission was positively correlated with the change in type 1 myofiber SC content and this was biased in METF participants (Pooled: R2 = 0.5816, P = 0.0006; METF: R2 = 0.674, P = 0.0125). CONCLUSIONS: These findings suggest that acute exposure to metformin does not impact mitochondrial respiration in aged, glucose-tolerant muscle, but rather, influences mitochondrial-free radical and SC dynamics. CLINICAL TRIAL REGISTRATION: NCT03107884, clinicaltrials.gov.
Subject(s)
Metformin , Aged , Glucose/metabolism , Humans , Hydrogen Peroxide/metabolism , Metformin/pharmacology , Metformin/therapeutic use , Mitochondria/metabolism , Mitochondria, Muscle/metabolism , Muscle, Skeletal/metabolismABSTRACT
Cardiovasomobility is a novel concept that encompasses the integration of cardiovascular and skeletal muscle function in health and disease with critical modification by physical activity, or lack thereof. Compelling evidence indicates that physical activity improves health while a sedentary, or inactive, lifestyle accelerates cardiovascular and skeletal muscle dysfunction and hastens disease progression. Identifying causative factors for vascular and skeletal muscle dysfunction, especially in humans, has proven difficult due to the limitations associated with cross-sectional investigations. Therefore, experimental models of physical inactivity and disuse, which mimic hospitalization, injury, and illness, provide important insight into the mechanisms and consequences of vascular and skeletal muscle dysfunction. This review provides an overview of the experimental models of disuse and inactivity and focuses on the integrated responses of the vasculature and skeletal muscle in response to disuse/inactivity. The time course and magnitude of dysfunction evoked by various models of disuse/inactivity are discussed in detail, and evidence in support of the critical roles of mitochondrial function and oxidative stress are presented. Lastly, strategies aimed at preserving vascular and skeletal muscle dysfunction during disuse/inactivity are reviewed. Within the context of cardiovasomobility, experimental manipulation of physical activity provides valuable insight into the mechanisms responsible for vascular and skeletal muscle dysfunction that limit mobility, degrade quality of life, and hasten the onset of disease.
Subject(s)
Muscular Atrophy , Quality of Life , Cross-Sectional Studies , Humans , Muscle, Skeletal/metabolism , Sedentary BehaviorABSTRACT
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.
Subject(s)
Energy Metabolism , Exercise , Mitochondria, Muscle/metabolism , Muscle Contraction , Quadriceps Muscle/metabolism , Adult , Analgesics, Opioid/administration & dosage , Bicycling , Cell Respiration , Fentanyl/administration & dosage , Healthy Volunteers , Humans , Injections, Spinal , Male , Neurons, Afferent/drug effects , Neurons, Afferent/physiology , Quadriceps Muscle/innervation , Random Allocation , Young AdultABSTRACT
The impact of COVID-19 has been largely described after symptom development. Although the SARS-CoV-2 virus elevates heart rate (HR) prior to symptom onset, whether this virus evokes other presymptomatic alterations is unknown. This case study details the presymptomatic impact of COVID-19 on vascular and skeletal muscle function in a young woman [24 yr, 173.5 cm, 89 kg, body mass index (BMI): 29.6 kg·m-2]. Vascular and skeletal muscle function were assessed as part of a separate study with the first and second visits separated by 2 wk. On the evening following the second visit, the participant developed a fever and a rapid antigen test confirmed a positive COVID-19 diagnosis. Compared with the first visit, the participant presented with a markedly elevated HR (â¼30 beats/min) and a lower mean blood pressure (â¼8 mmHg) at the second visit. Vascular function measured by brachial artery flow-mediated dilation, reactive hyperemia, and passive leg movement were all noticeably attenuated (25%-65%) as was leg blood flow during knee extension exercise. Muscle strength was diminished as was ADP-stimulated respiration (30%), assessed in vitro, whereas there was a 25% increase in the apparent Km. Lastly, an elevation in IL-10 was observed prior to symptom onset. Notably, 2.5 mo after diagnosis symptoms of fatigue and cough were still present. Together, these findings provide unique insight into the physiological responses immediately prior to onset of COVID-19 symptoms; they suggest that SARS-CoV-2 negatively impacts vascular and skeletal muscle function prior to the onset of common symptoms and may set the stage for the widespread sequelae observed following COVID-19 diagnosis.NEW & NOTEWORTHY This unique case study details the impact of SARS-CoV-2 infection on vascular and skeletal muscle function in a young predominantly presymptomatic woman. Prior to COVID-19 diagnosis, substantial reductions in vascular, skeletal muscle, and mitochondrial function were observed along with an elevation in IL-10. This integrative case study indicates that the presymptomatic impact of COVID-19 is widespread and may help elucidate the acute and long-term sequelae of this disease.
Subject(s)
COVID-19 , Brachial Artery , COVID-19 Testing , Female , Humans , Muscle, Skeletal , SARS-CoV-2ABSTRACT
The regulation of mean arterial pressure (MAP) during exercise has important physiological and clinical implications. Kinetics analysis on numerous physiological variables following the transition from unloaded-to-loaded exercise has revealed important information regarding their control. Surprisingly, the dynamic response of MAP during this transition remains to be quantified. Therefore, ten healthy participants (5/5 M/F, 24 ± 3 yr) completed repeated transitions from unloaded to moderate- and heavy-intensity dynamic single-leg knee-extensor exercise to investigate the on-kinetics of MAP. Following the transition to loaded exercise, MAP increased in a first-order dynamic manner, subsequent to a time delay (moderate: 23 ± 10; heavy: 19 ± 9 s, P > 0.05) at a speed (τ, moderate: 59 ± 30; heavy: 66 ± 19 s, P > 0.05), which did not differ between intensities, but the MAP amplitude was doubled during heavy-intensity exercise (moderate: 12 ± 5; heavy: 24 ± 8 mmHg, P < 0.001). The reproducibility [coefficient of variation (CV)] during heavy intensity for unloaded baseline, amplitude, and mean response time, when assessed as individual transitions, was 7 ± 1%, 18 ± 2%, and 25 ± 4%, respectively. Averaging two transitions improved the CVs to 4 ± 1%, 8 ± 2%, and 13 ± 3%, respectively. Preliminary findings supporting the clinical relevance of evaluating MAP kinetics in middle-aged hypertensive (n = 5) and, age-matched, normotensive (n = 5) participants revealed an exaggerated MAP response in both older groups (P < 0.05), but the MAP response was slowed only for the patients with hypertension (P < 0.05). It is concluded that kinetics modeling of MAP is practical for heavy-intensity knee-extensor exercise and may provide insight into cardiovascular health and the effect of aging.NEW & NOTEWORTHY Kinetics analysis of physiological variables following workload transitions provides important information, but this has not been performed on mean arterial pressure (MAP), despite the clear clinical importance of this variable. This investigation reveals that kinetic modeling of MAP following unloaded-to-loaded knee-extensor exercise is practical and repeatable. Additional preliminary findings in hypertensive and, age-matched, normotensive subjects suggest that MAP kinetics may provide insight into cardiovascular health and the effect of aging.
Subject(s)
Arterial Pressure , Exercise , Aging , Health Status , Humans , Middle Aged , Muscle, Skeletal/metabolism , Oxygen Consumption , Reproducibility of ResultsABSTRACT
Passive leg movement (PLM) evokes a robust and predominantly nitric oxide (NO)-mediated increase in blood flow that declines with age and disease. Consequently, PLM is becoming increasingly accepted as a sensitive assessment of endothelium-mediated vascular function. However, a substantial PLM-induced hyperemic response is still evoked despite nitric oxide synthase (NOS) inhibition. Therefore, in nine young healthy men (25 ± 4 yr), this investigation aimed to determine whether the combination of two potent endothelium-dependent vasodilators, specifically prostaglandin (PG) and endothelium-derived hyperpolarizing factor (EDHF), account for the remaining hyperemic response to the two variants of PLM, PLM (60 movements) and single PLM (sPLM, 1 movement), when NOS is inhibited. The leg blood flow (LBF, Doppler ultrasound) response to PLM and sPLM following the intra-arterial infusion of NG-monomethyl-l-arginine (l-NMMA), to inhibit NOS, was compared to the combined inhibition of NOS, cyclooxygenase (COX), and cytochrome P-450 (CYP450) by l-NMMA, ketorolac tromethamine (KET), and fluconazole (FLUC), respectively. NOS inhibition attenuated the overall LBF [area under the curve (LBFAUC)] response to both PLM (control: 456 ± 194, l-NMMA: 168 ± 127 mL, P < 0.01) and sPLM (control: 185 ± 171, l-NMMA: 62 ± 31 mL, P = 0.03). The combined inhibition of NOS, COX, and CYP450 (i.e., l-NMMA+KET+FLUC) did not further attenuate the hyperemic responses to PLM (LBFAUC: 271 ± 97 mL, P > 0.05) or sPLM (LBFAUC: 72 ± 45 mL, P > 0.05). Therefore, PG and EDHF do not collectively contribute to the non-NOS-derived NO-mediated, endothelium-dependent hyperemic response to either PLM or sPLM in healthy young men. These findings add to the mounting evidence and understanding of the vasodilatory pathways assessed by the PLM and sPLM vascular function tests.NEW & NOTEWORTHY Passive leg movement (PLM) evokes a highly nitric oxide (NO)-mediated hyperemic response and may provide a novel evaluation of vascular function. The contributions of endothelium-dependent vasodilatory pathways, beyond NO and including prostaglandins and endothelium-derived hyperpolarizing factor, to the PLM-induced hyperemic response to PLM have not been evaluated. With intra-arterial drug infusion, the combined inhibition of nitric oxide synthase (NOS), cyclooxygenase, and cytochrome P-450 (CYP450) pathways did not further diminish the hyperemic response to PLM compared with NOS inhibition alone.
Subject(s)
Endothelium, Vascular/physiology , Hyperemia , Movement , Muscle Contraction , Muscle, Skeletal/blood supply , Nitric Oxide/metabolism , Vasodilation , Adult , Biological Factors/metabolism , Blood Flow Velocity , Cyclooxygenase Inhibitors/administration & dosage , Cytochrome P-450 Enzyme Inhibitors/administration & dosage , Endothelium, Vascular/metabolism , Healthy Volunteers , Humans , Infusions, Intra-Arterial , Leg , Male , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/metabolism , Prostaglandins/metabolism , Regional Blood Flow , Signal Transduction , Time Factors , Young AdultABSTRACT
The effect of a spinal cord injury (SCI) on vascular function has been clouded by both the physiological and mathematical bias of assessing vasodilation in arteries with differing diameters both above and below the lesion and when comparing with healthy, nondisabled controls (CTRL). Thus, we measured vascular function, with flow-mediated vasodilation (FMD), in 10 SCI and 10 CTRL with all arteries matched for diameter (≈0.5 cm): brachial artery (BA, arm, functional limb in both groups) and popliteal artery (PA, leg, disused limb in SCI, functional limb in CTRL). PA %FMD was significantly attenuated in SCI (5.6 ± 0.6%) compared with CTRL (8.4 ± 1.3%), with no difference in the BA (SCI: 8.6 ± 0.9%; CTRL: 8.7 ± 0.7%). However, unlike the arm, where muscle mass was preserved, the legs of the SCI were significantly smaller than CTRL (â¼70%). Thus, reactive hyperemia (RH), which is heavily dependent on the volume of muscle occluded, in the PA was attenuated in the SCI (144 ± 22 mL) compared with CTRL (258 ± 16 mL) but not different in the BA. Consequently, shear rate was significantly diminished in the PA of the SCI, such that %FMD/shear rate (vascular responsiveness) was actually greater in the SCI (1.5 ± 0.1% · s-1) than CTRL (1.2 ± 0.1% · s-1). Of note, this was significantly greater than both their own BA (0.9 ± 0.1% · s-1) and that of the CTRL (0.9 ± 0.1% · s-1). Therefore, examining vessels of similar size, this study reveals normal vascular function above the lesion and vascular dysfunction below the lesion. However, below the lesion there was, actually, evidence of increased vascular responsiveness in this population.NEW & NOTEWORTHY This study examined the effect of a spinal cord injury (SCI) and subsequent limb disuse on vascular function, assessed by %FMD, in diameter-matched vessels above and below the lesion in subjects with SCI and controls. The results reveal normal vascular function above the lesion and vascular dysfunction below the lesion (%FMD). However, below the lesion there was, actually, evidence of increased vascular responsiveness (%FMD/shear rate) in this population.
Subject(s)
Brachial Artery , Spinal Cord Injuries , Endothelium, Vascular , Humans , Leg , Popliteal Artery , Regional Blood Flow , VasodilationABSTRACT
Nitric oxide synthase (NOS) inhibition with N(G)-monomethyl-l-arginine (L-NMMA) is often used to assess the role of NO in human cardiovascular function. However, the window of effect for L-NMMA on human vascular function is unknown, which is critical for designing and interpreting human-based studies. This study utilized the passive leg movement (PLM) assessment of vascular function, which is predominantly NO-mediated, in 7 young male subjects under control conditions, immediately following intra-arterial L-NMMA infusion (0.24 mgâ dl-1â min-1), and at 45-60 and 90-105 min post L-NMMA infusion. The leg blood flow (LBF) and leg vascular conductance (LVC) responses to PLM, measured with Doppler ultrasound and expressed as the change from baseline to peak (ΔLBFpeak and ΔLVCpeak) and area under the curve (LBFAUC and LVCACU), were assessed. PLM-induced robust control ΔLBFpeak (1135 ± 324 mlâ min-1) and ΔLVCpeak (10.7 ± 3.6 mlâ min-1â mmHg-1) responses that were significantly attenuated (704 ± 196 mlâ min-1 and 6.7 ± 2 mlâ min-1â mmHg-1) immediately following L-NMMA infusion. Likewise, control condition PLM ΔLBFAUC (455 ± 202 ml) and ΔLVCAUC (4.0 ± 1.4 mlâ mmHg-1) were significantly attenuated (141 ± 130 ml and 1.3 ± 1.2 mlâ mmHg-1) immediately following L-NMMA infusion. However, by 45-60 min post L-NMMA infusion all PLM variables were not significantly different from control, and this was still the case at 90-105 min post L-NMMA infusion. These findings reveal that the potent reduction in NO bioavailability afforded by NOS inhibition with L-NMMA has a window of effect of less than 45-60 min in the human vasculature. These data are particularly important for the commonly employed approach of pharmacologically inhibiting NOS with L-NMMA in the human vasculature.
Subject(s)
Enzyme Inhibitors/pharmacokinetics , Nitric Oxide Synthase/antagonists & inhibitors , omega-N-Methylarginine/pharmacokinetics , Adult , Femoral Artery/physiology , Hemodynamics/drug effects , Humans , Leg/blood supply , Male , Nitric Oxide/metabolism , Regional Blood Flow/drug effects , Time Factors , Young AdultABSTRACT
Although the contribution of noncardiac complications to the pathophysiology of heart failure with preserved ejection fraction (HFpEF) have been increasingly recognized, disease-related changes in peripheral vascular control remain poorly understood. We utilized small muscle mass handgrip exercise to concomitantly evaluate exercising muscle blood flow and conduit vessel endothelium-dependent vasodilation in individuals with HFpEF (n = 25) compared with hypertensive controls (HTN) (n = 25). Heart rate (HR), stroke volume (SV), cardiac output (CO), mean arterial pressure (MAP), brachial artery blood velocity, and brachial artery diameter were assessed during progressive intermittent handgrip (HG) exercise [15-30-45% maximal voluntary contraction (MVC)]. Forearm blood flow (FBF) and vascular conductance (FVC) were determined to quantify the peripheral hemodynamic response to HG exercise, and changes in brachial artery diameter were evaluated to assess endothelium-dependent vasodilation. HR, SV, and CO were not different between groups across exercise intensities. However, although FBF was not different between groups at the lowest exercise intensity, FBF was significantly lower (20-40%) in individuals with HFpEF at the two higher exercise intensities (30% MVC: 229 ± 8 versus 274 ± 23 ml/min; 45% MVC: 283 ± 17 versus 399 ± 34 ml/min, HFpEF versus HTN). FVC was not different between groups at 15 and 30% MVC but was â¼20% lower in HFpEF at the highest exercise intensity. Brachial artery diameter increased across exercise intensities in both HFpEF and HTN, with no difference between groups. These findings demonstrate an attenuation in muscle blood flow during exercise in HFpEF in the absence of disease-related changes in central hemodynamics or endothelial function.NEW & NOTEWORTHY The current study identified, for the first time, an attenuation in exercising muscle blood flow during handgrip exercise in individuals with heart failure with preserved ejection fraction (HFpEF) compared with overweight individuals with hypertension, two of the most common comorbidities associated with HFpEF. These decrements in exercise hyperemia cannot be attributed to disease-related changes in central hemodynamics or endothelial function, providing additional evidence for disease-related vascular dysregulation, which may be a predominant contributor to exercise intolerance in individuals with HFpEF.