Age-related endothelial dysfunction in human skeletal muscle feed arteries: the role of free radicals derived from mitochondria in the vasculature.

AIM: This study sought to determine the role of free radicals derived from mitochondria in the vasculature in the recognized age-related endothelial dysfunction of human skeletal muscle feed arteries (SMFAs). METHODS: A total of 44 SMFAs were studied with and without acute exposure to the mitochondria-targeted antioxidant MitoQ and nitric oxide synthase (NOS) blockade. The relative abundance of proteins from the electron transport chain, phosphorylated (p-) to endothelial (e) NOS ratio, manganese superoxide dismutase (MnSOD) and the mitochondria-derived superoxide (O2-) levels were assessed in SMFA. Endothelium-dependent and endothelium-independent SMFA vasodilation was assessed in response to flow-induced shear stress, acetylcholine (ACh) and sodium nitroprusside (SNP). RESULTS: MitoQ restored endothelium-dependent vasodilation in the old to that of the young when stimulated by both flow (young: 68 ± 5; old: 25 ± 7; old + MitoQ 65 ± 9%) and ACh (young: 97 ± 4; old: 59 ± 10; old + MitoQ: 98 ± 5%), but did not alter the initially uncompromised, endothelium-independent vasodilation (SNP). Compared to the young, MitoQ in the old diminished the initially elevated mitochondria-derived O2- levels and appeared to attenuate the breakdown of MnSOD. Furthermore, MitoQ increased the ratio of p-eNOS to NOS and the restoration of endothelium-dependent vasodilation in the old by MitoQ was ablated by NOS blockade. CONCLUSION: This study demonstrated that MitoQ reverses age-related vascular dysfunction by what appears to be an NO-dependent mechanism in human SMFAs. These findings suggest that mitochondria-targeted antioxidants may have utility in terms of counteracting the attenuated blood flow and vascular dysfunction associated with advancing age.This work was supported by NIH Heart, Lung, Blood Institute grants (HL‐091830) and Veterans Affairs Rehabilitation Research and Development Merit (E6910‐R)

Impact of retrograde shear rate on brachial and superficial femoral artery flow-mediated dilation in older subjects

An inverse, dose-dependent relationship between retrograde shear rate and brachial artery endothelial function exists in young subjects. This relationship has not been investigated in older adults, who have been related to lower endothelial function, higher resting retrograde shear rate and higher risk of cardiovascular disease. Aim To investigate the impact of a step-wise increase in retrograde shear stress on flow-mediated dilation in older males in the upper and lower limbs. Methods Fifteen older (68±9 years) men reported to the laboratory 3 times. We examined brachial artery flow-mediated dilation before and after 30-minutes exposure to cuff inflation around the forearm at 0, 30 and 60 mmHg, to manipulate retrograde shear rate. Subsequently, the 30-minute intervention was repeated in the superficial femoral artery. Order of testing (vessel and intervention) was randomised. Results Increases in cuff pressure resulted in dose-dependent increases in retrograde shear in both the brachial and superficial femoral artery in older subjects. In both the brachial and the superficial femoral artery, no change in endothelial function in response to increased retrograde shear was observed in older males (‘time’ P=0.274, ‘cuff*time P=0.791’, ‘cuff*artery*time P=0.774’). Conclusion In contrast with young subjects, we found that acute elevation in retrograde shear rate does not impair endothelial function in older humans. This may suggest that subjects with a priori endothelial dysfunction are less responsive or requires a larger shear rate stimulus to alter endothelial function

Impact of inactivity and exercise on the vasculature in humans

The effects of inactivity and exercise training on established and novel cardiovascular risk factors are relatively modest and do not account for the impact of inactivity and exercise on vascular risk. We examine evidence that inactivity and exercise have direct effects on both vasculature function and structure in humans. Physical deconditioning is associated with enhanced vasoconstrictor tone and has profound and rapid effects on arterial remodelling in both large and smaller arteries. Evidence for an effect of deconditioning on vasodilator function is less consistent. Studies of the impact of exercise training suggest that both functional and structural remodelling adaptations occur and that the magnitude and time-course of these changes depends upon training duration and intensity and the vessel beds involved. Inactivity and exercise have direct “vascular deconditioning and conditioning” effects which likely modify cardiovascular risk

Cocoa-flavanols enhance moderate-intensity pulmonary [Formula: see text] kinetics but not exercise tolerance in sedentary middle-aged adults.

INTRODUCTION: Cocoa flavanols (CF) may exert health benefits through their potent vasodilatory effects, which are perpetuated by elevations in nitric oxide (NO) bioavailability. These vasodilatory effects may contribute to improved delivery of blood and oxygen (O2) to exercising muscle. PURPOSE: Therefore, the objective of this study was to examine how CF supplementation impacts pulmonary O2 uptake ([Formula: see text]) kinetics and exercise tolerance in sedentary middle-aged adults. METHODS: We employed a double-blind cross-over, placebo-controlled design whereby 17 participants (11 male, 6 female; mean ± SD, 45 ± 6 years) randomly received either 7 days of daily CF (400 mg) or placebo (PL) supplementation. On day 7, participants completed a series of 'step' moderate- and severe-intensity exercise tests for the determination of [Formula: see text] kinetics. RESULTS: During moderate-intensity exercise, the time constant of the phase II [Formula: see text] kinetics ([Formula: see text]) was decreased by 15% in CF as compared to PL (mean ± SD; PL 40 ± 12 s vs. CF 34 ± 9 s, P = 0.019), with no differences in the amplitude of [Formula: see text] (A[Formula: see text]; PL 0.77 ± 0.32 l min-1 vs. CF 0.79 ± 0.34 l min-1, P = 0.263). However, during severe-intensity exercise, [Formula: see text], the amplitude of the slow component ([Formula: see text]) and exercise tolerance (PL 435 ± 58 s vs. CF 424 ± 47 s, P = 0.480) were unchanged between conditions. CONCLUSION: Our data show that acute CF supplementation enhanced [Formula: see text] kinetics during moderate-, but not severe-intensity exercise in middle-aged participants. These novel effects of CFs, in this demographic, may contribute to improved tolerance of moderate-activity physical activities, which appear commonly present in daily life. TRIAL REGISTRATION: Registered under ClinicalTrials.gov Identifier no. NCT04370353, 30/04/20 retrospectively registered

Potential cellular and biochemical mechanisms of exercise and physical activity on the ageing process

Exercise in young adults has been consistently shown to improve various aspects of physiological and psychological health but we are now realising the potential benefits of exercise with advancing age. Specifically, exercise improves cardiovascular, musculoskeletal, and metabolic health through reductions in oxidative stress, chronic low-grade inflammation and modulating cellular processes within a variety of tissues. In this this chapter we will discuss the effects of acute and chronic exercise on these processes and conditions in an ageing population, and how physical activity affects our vasculature, skeletal muscle function, our immune system, and cardiometabolic risk in older adults

Effects of ageing and exercise training on endothelium-dependent vasodilatation and structure of rat skeletal muscle arterioles

Ageing reduces endothelium-dependent vasodilatation in humans and animals, and in humans, exercise training reverses the ageing-associated reduction in endothelium-dependent vasodilatation. The purpose of this study was to determine the mechanism(s) by which 10–12 weeks of treadmill exercise enhances endothelium-dependent vasodilatation in muscles of differing fibre composition from young and old rats. Three- and 22-month-old male Fischer 344 rats were assigned to young sedentary, young exercise-trained, old sedentary, or old exercise-trained groups. Arterioles were isolated from the soleus and gastrocnemius muscles; luminal diameter changes were determined in response to the endothelium-dependent vasodilator acetylcholine (ACh, 10(−9)–10(−4) mol l(−1)) alone and in the presence of the nitric oxide synthase (NOS) inhibitor l-NAME (10(−5) mol l(−1)) or the combination of l-NAME and the cyclooxygenase inhibitor indomethacin (10(−5) mol l(−1)). Training ameliorated the ageing-induced reduction in endothelium-dependent vasodilatation in soleus muscle arterioles. Treatment with l-NAME alone and in combination with indomethacin abolished differences in ACh vasodilatation occurring with ageing and training. Expression of endothelial NOS (eNOS) mRNA in soleus arterioles was unaltered by ageing, whereas eNOS protein was increased with age; training elevated both eNOS mRNA and protein. In gastrocnemius muscle arterioles, ageing did not alter maximal vasodilatation, but ageing and training increased maximal arteriolar diameter. These results demonstrate that ageing-induced reductions and training-induced enhancement of endothelial vasodilatation both occur through the nitric oxide signalling mechanism in highly oxidative skeletal muscle, but ageing and training do not appear to act on the same portion of the signalling cascade