Leg vascular function with advancing age in men: the impact of physical activity and endurance exercise training

Journal of Applied Physiology · 2025-07-10

In the current study, we provide evidence of a relation between high levels of physical activity associated with lifelong endurance exercise training and protection from age-related declines in vascular endothelial function in the lower limb in men. Moreover, our findings suggest that aerobic fitness, in particular, may confer the benefits of endurance exercise training in maintaining lower limb endothelial function with advancing age.

Chamber oxygen concentration impacts mitochondrial function and hydrogen peroxide appearance in permeabilized human skeletal muscle fibers

Biochimica et Biophysica Acta (BBA) - Bioenergetics · 2025-08-11 · 1 citations

Skeletal muscle mitochondrial respiration is commonly assessed ex vivo using permeabilized fibers in media with high oxygen (O 2 ) concentrations to ensure that O 2 availability does not limit respiration. However, high O 2 concentrations also increase the production of reactive O 2 species that can negatively affect respiration. In this study, we tested the hypotheses that permeabilized fiber mitochondria in a high, compared to low, O 2 concentration would (i) not be different at maximal state 3 respiration rate (V max ), (ii) have lower submaximal respiration rates at submaximal O 2 concentrations, and (iii) have greater total cumulative hydrogen peroxide (H 2 O 2 ) appearance. We continuously monitored mitochondrial state 3 respiration and H 2 O 2 appearance rates using high-resolution respirometry in permeabilized skeletal muscle fibers (12 untrained participants; 22 ± 4 yrs) with either control (~127 mmHg; CON) or high (~327 mmHg; HIGH) partial pressures of O 2 (PO 2 ). V max was not different between conditions (HIGH: 80.7 ± 16.7 vs. CON: 82.3 ± 18.7 pmol/s/mg, p = 0.695). The PO 2 at 80 % V max (P 80 ) was greater in HIGH (73.9 ± 25.5 vs. 28.0 ± 7.1 mmHg, p < 0.001) and respiration rates at 5–60 mmHg PO 2 were lower for HIGH than CON (all p < 0.001). Additionally, the total cumulative H 2 O 2 appearance was greater in HIGH than CON ( n = 11; 51.5 ± 23.2 vs. 18.3 ± 10.3 pmol/mg, p < 0.001), and this difference was directly correlated with the difference in P 80 ( r = 0.655, p = 0.029). The current findings support that a high O 2 concentration, by itself, does not appear to affect V max in the permeabilized skeletal muscle fiber preparation, but the corollary increase in H 2 O 2 exposure may diminish mitochondrial state 3 respiratory function. • High O 2 concentration does not appear to affect maximal state 3 respiration in the permeabilized skeletal muscle fibers. • High O 2 concentration does increase the total cumulative appearance of H 2 O 2 during the respiration protocol. • The increase in H 2 O 2 exposure from increased O 2 levels may diminish mitochondrial state 3 respiratory function over time.

Skeletal Muscle Fatigue in Rats Is More Consistently Related to Increased Inorganic Phosphate Concentration Than Acidosis

Acta Physiologica · 2025-07-21 · 4 citations

AIM: Distinguish the relative importance of intramuscular acidosis (hydrogen ion) and inorganic phosphate in skeletal muscle fatigue in vivo in rats. METHODS: We used direct sciatic nerve electrical stimulations to evoke twitches at different frequencies of contraction (0.25-, 0.50-, 0.75-, 1-, 2-, and 4-Hz) in the triceps surae to impose a range of intramuscular metabolic perturbations, quantified by phosphorus nuclear magnetic resonance spectroscopy. Linear mixed-effects models were used to analyze the relationships between peak twitch force and intramuscular hydrogen ion or inorganic phosphate concentration (as Z-scores) during the protocols that decreased peak twitch force (2- and 4-Hz). RESULTS: Although intramuscular hydrogen ion and inorganic phosphate concentrations increased with increasing frequencies of contraction, peak twitch force did not begin to decrease until a "threshold" inorganic phosphate concentration was reached. A given hydrogen ion accumulation was associated with a greater decrease in peak twitch force during 4-Hz compared to 2-Hz (β: -1.19 vs. -0.62, p < 0.001). In contrast, the decrease in peak twitch force for a given inorganic phosphate accumulation was not different between 4- and 2-Hz (β: -0.89 vs. -0.85, p = 0.889). CONCLUSIONS: The inconsistent relationship between the decrease in twitch force and intramuscular hydrogen ion accumulation is not congruent with the primary mechanisms by which acidosis is thought to mediate muscle fatigue. In contrast, the discernible twitch force-inorganic phosphate breakpoint and the consistent relationship between the decrease in twitch force and intramuscular inorganic phosphate accumulation are congruent with the concept of a critical concentration beyond which inorganic phosphate mediates muscle fatigue.

Acute sympathetic activation blunts the hyperemic and vasodilatory response to passive leg movement in young healthy males

Physiological Reports · 2025-02-27 · 6 citations

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) is not fully understood. This study tested the hypothesis that elevated MSNA diminishes the vasodilatory response to PLM in healthy young males (n = 11, 25 ± 2 yr). Post exercise circulatory occlusion (PECO) following 2 min of isometric handgrip (HG) exercise performed at 25% (ExPECO 25%) and 40% (ExPECO 40%) 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 exercise and hemodynamics were assessed. MSNA was 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. Leg vascular conductance (vasodilation) during PLM was reduced by 16% and 44% during ExPECO 25% and ExPECO 40%, respectively. These findings indicate elevated MSNA attenuates the vasodilatory response to PLM and the magnitude of reduction in vasodilation during PLM is graded with the degree of sympathoexcitation.

Acute sympathetic activation blunts the hyperemic and vasodilatory response to passive leg movement

Research Square · 2024-05-10

Lasting Effects of Surgically Used Topical Vasodilators on DIEP Artery Vascular Function

Journal of Reconstructive Microsurgery · 2024-07-22 · 1 citations

Abstract Background Surgeons routinely apply papaverine, lidocaine, or verapamil to produce acute vasodilation and prevent vasospasms during microvascular surgeries. There is evidence that topical vasodilators may induce postoperative endothelial and smooth muscle dysfunction, which would present after the acute vasodilatory effects of the topical drugs wear off. Therefore, the purpose of the current study was to evaluate the lasting effects of papaverine, lidocaine, and verapamil on human deep inferior epigastric perforator artery vasodilatory function after the acute effects of the topical drugs had worn off. Methods Deep inferior epigastric arterial samples were obtained from 12 patients during surgery. Each artery was dissected into four rings which where incubated for 1 minute in either physiological saline solution (control), papaverine (30 mg/mL), lidocaine (20 mg/mL), or verapamil (2.5 mg/mL), followed by a 2-hour washout. Endothelial-dependent and -independent vasorelaxation were then assessed by the isometric tension responses to acetylcholine or sodium nitroprusside, respectively. Results Peak acetylcholine-evoked vasorelaxation (mean ± standard deviation) was not different between control (62 ± 23%) and lidocaine (57 ± 18%, p = 0.881), but was reduced (all p &lt; 0.002) in papaverine (22 ± 27%) and verapamil (22 ± 20%). Peak sodium nitroprusside-evoked vasorelaxation was not different (all p &gt; 0.692) among control (132 ± 35%), lidocaine (121 ± 22%), and verapamil (127 ± 22%), but was less in papaverine (104 ± 41%; p = 0.045) than control. Conclusion Surgically used doses of papaverine and verapamil, but not lidocaine, have lasting negative effects on arterial vasodilatory function despite the acute effects of the drugs having worn off. These findings, in conjunction with the spasmolytic properties of each drug, may help guide the selection of an optimal topical vasodilator for use during microvascular surgeries.

Physiological determinants of mechanical efficiency during advanced ageing and disuse

The Journal of Physiology · 2024-01-01 · 5 citations

This study aimed to determine which physiological factors impact net efficiency (ηnet) in oldest-old individuals at different stages of skeletal muscle disuse. To this aim, we examined ηnet, central haemodynamics, peripheral circulation, and peripheral factors (skeletal muscle fibre type, capillarization and concentration of mitochondrial DNA [mtDNA]). Twelve young (YG; 25 ± 2 years), 12 oldest-old mobile (OM; 87 ± 3 years), and 12 oldest-old immobile (OI; 88 ± 4 years) subjects performed dynamic knee extensor (KE) and elbow flexors (EF) exercise. Pulmonary oxygen uptake, photoplethysmography, Doppler ultrasound and muscle biopsies of the vastus lateralis and biceps brachii were used to assess central and peripheral adaptations to advanced ageing and disuse. Compared to the YG (12.1 ± 2.4%), the ηnet of lower-limb muscle was higher in the OM (17.6 ± 3.5%, P < 0.001), and lower in the OI (8.9 ± 1.9%, P < 0.001). These changes in ηnet during KE were coupled with significant peripheral adaptations, revealing strong correlations between ηnet and the proportion of type I muscle fibres (r = 0.82), as well as [mtDNA] (r = 0.77). No differences in ηnet were evident in the upper-limb muscles between YG, OM and OI. In view of the differences in limb-specific activity across the lifespan, these findings suggest that ηnet is reduced by skeletal muscle inactivity and not by chronological age, per se. Likewise, this study revealed that the age-related changes in ηnet are not a consequence of central or peripheral haemodynamic adaptations, but are likely a product of peripheral changes related to skeletal muscle fibre type and mitochondrial density. KEY POINTS: Although the effects of ageing and muscle disuse deeply impact the cardiovascular and skeletal muscle function, the combination of these factors on the mechanical efficiency are still a matter of debate. By measuring both upper- and lower-limb muscle function, which experience differing levels of disuse, we examined the influence of central and peripheral haemodynamics, and skeletal muscle factors linked to mechanical efficiency. Across the ages and degree of disuse, upper-limb muscles exhibited a preserved work economy. In the legs the oldest-old without mobility limitations exhibited an augmented mechanical efficiency, which was reduced in those with an impairment in ambulation. These changes in mechanical efficiency were associated with the proportion of type I muscle fibres. Recognition that the mechanical efficiency is not simply age-dependent, but the consequence of inactivity and subsequent skeletal muscle changes, highlights the importance of maintaining physical activity across the lifespan.

Imaging Transcranial Doppler Ultrasound To Measure Middle Cerebral Artery Blood Flow: The Application To Aging

Medicine & Science in Sports & Exercise · 2023-09-01

Imaging transcranial Doppler ultrasound (ITCD), utilizing color flow images and pulse wave velocity, has been documented to be a novel approach to measure cerebral blood flow (CBF) in the middle cerebral artery (MCA) of young healthy adults. However, the application of this approach to aging, which is associated with greater cerebral blood flow abnormalities, has yet to occur. PURPOSE: Therefore, the aim of this study was to determine the feasibility of ITCD in older adults and examine the impact of aging on ITCD measured CBF. METHODS: ITCD was performed at rest in 12 young (Y; 6 men/6 women; 22 ± 4 yr) and 11 old (O; 6 men/5 women; 67 ± 3 yr) healthy adults with pharmaceutically-induced vasodilation (nitroglycerin (NTG), 0.8 mg) and without (CON). RESULTS: ITCD assessments were equally feasible in the young and old, with the notable exception of imaging the MCA in old women which resulted in an 38% fail rate. In both young and old there was a significant fall in MCA blood velocity in response to NTG (Y: Δ -8.45 ± 4.58; O: Δ -9.71 ± 7.57 cm/s) compared to minimal fluctuations in CON (p < 0.001). Additionally, in both young and old there was a significant increase in MCA diameter in response to NTG (Y: Δ 0.10 ± 0.03; O: Δ 0.10 ± 0.04 cm) compared with the minimal basal variation in CON (p < 0.001). Of importance, also in both young and old, the product of the NTG-induced fall in MCA blood velocity and increase in diameter was a significant increase in MCA blood flow following NTG (Y: Δ 119 ± 99; O: Δ 95 ± 87 ml.min-1) compared with CON (p < 0.001). However, there were no age-related differences in CON or NTG-induced MCA diameter, blood velocity, or blood flow changes. CONCLUSIONS: These findings document the general feasibility of ITCD to measure CBF with aging and, again, highlights the importance of measuring both MCA blood velocity and diameter when assessing CBF.

Obesity does not alter vascular function and handgrip exercise hemodynamics in middle-aged patients with hypertension

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · 2023-10-16 · 2 citations

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.

Two Weeks of Nrf2 Activation Improves Maximal Mitochondrial Respiration in Older Adults with Lower Starting Values

Physiology · 2023-05-01

Background: The impact of aging on skeletal muscle mitochondrial function, as assessed by maximal mitochondrial respiration (OXPHOS), is a developing field of research with no clear consensus. Older individuals often display a greater range of OXPHOS, compared to younger individuals, possibly reflecting heterogeneity in the aging process. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a role in the transcription of genes involved in many pathways including the regulation of metabolism, inflammation, oxidative stress, and mitochondrial physiology. Since Nrf2 is downregulated with aging and significantly inactivated with sedentary behaviors, we hypothesized that activating this pathway with the nutraceutical PB125 would improve OXPHOS in older individuals with lower OXPHOS starting values. Methods: OXPHOS (CI&amp;II, State 3) was assessed in permeabilized muscle fibers via high-resolution respirometry (Oroboros, O2k) on samples biopsied from the vastus lateralis in 19 young (26 ± 5 years; 13 female) and 18 older (67 ± 7 years; 11 female) volunteers. Sixteen of the older individuals were then randomized to receive a two-week supplementation of either PB125 (n = 10) or Placebo (n = 6) and OXPHOS was reassessed post-supplementation. Results: Baseline OXPHOS was not different between the young (32 ± 8 pmol/s/mg; Range: 18-44) and old (35 ± 12 pmol/s/mg; Range: 14-60; P = 0.49). The supplement-induced change in OXPHOS was not different between the older groups (PB125: 3 ± 9 vs Placebo: -0 ± 10 pmol/s/mg; P = 0.56) and neither was different from baseline (both, P &gt; 0.05). However, a “threshold-like” relationship between the baseline OXPHOS and the PB125-induced change was identified within the PB125-treated group, whereby older individuals with a relatively lower baseline OXPHOS (&lt;25 pmol/s/mg) had a significant improvement (11 ± 7 pmol/s/mg, n = 4; P = 0.03) compared to baseline, while individuals with a normal baseline OXPHOS had no significant change (-2 ± 2 pmol/s/mg, n = 6; P &gt; 0.05). Conclusion: These findings support previous reports that mitochondrial function, as measured by OXPHOS, is not impaired in older individuals compared to their younger counterparts. However, older individuals with low mitochondrial function exhibited improved OXPHOS following Nrf2 activation via PB125 supplementation. These findings highlight the importance of heterogeneity in aging and provide novel evidence that activating Nrf2 may prove beneficial to improve maximal mitochondrial respiration. NIH: T32HL007576, T32HL139451, R01HL142603; VA: I01CX001999 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.