Reduced leg blood flow during dynamic exercise in older endurance-trained men

It is currentlyunclear whether aging alters the perfusion of active muscles duringlarge-muscle dynamic exercise in humans. To study this issue, directmeasurements of leg blood flow (femoral vein thermodilution) andsystemic arterial pressure during submaximal cycle ergometry (70, 140, and 210 W) were compared between six younger (Y; 22-30 yr) and sixolder (O; 55-68 yr) chronically endurance-trainedmen. Whole body O₂uptake, ventilation, and arterial and femoral venous samples forblood-gas, catecholamine, and lactate determinations were alsoobtained. Training duration (min/day), estimated leg muscle mass(dual-energy X-ray absorptiometry; Y, 21.5 ± 1.2 vs. O, 19.9 ± 0.9 kg), and blood hemoglobin concentration (Y, 14.9 ± 0.4 vs. O, 14.7 ± 0.2 g/dl) did not significantly differ (P > 0.05) between groups. Leg bloodflow, leg vascular conductance, and femoral venousO₂ saturation were ~20-30%lower in the older men at each work rate (allP < 0.05), despite similarlevels of whole body O₂ uptake. At210 W, leg norepinephrine spillover rates and femoral venous lactateconcentrations were more than twofold higher in the older men.Pulmonary ventilation was also higher in the older men at 140 (+24%)and 210 (+39%) W. These results indicate that leg blood flow andvascular conductance during cycle ergometer exercise are significantlylower in older endurance-trained men in comparison to their youngercounterparts. The mechanisms responsible for this phenomenon and theextent to which they operate in other groups of older subjects deservefurther attention.

     

Altered cardiovascular responsiveness to adrenoceptor agonists in endurance-trained men

The influence of physical training on responses to intravenous infusions of phenylephrine (Phe) and isoproterenol (Iso) were investigated in 10 well-trained runners (WT) and 10 age-matched untrained controls (UT). The latter were reinvestigated after a 4-mo training period. The venous plasma Iso and Phe concentrations attained during infusions were lower in WT than in UT. Responses were related to the corresponding plasma concentrations. Phe-induced decreases and Iso-induced increases in heart rate were less pronounced (P less than 0.01) in WT than in UT. At venous plasma concentrations of 100 nM Phe and 0.8 nM Iso, the responses were -9 +/- 1 and 30 +/- 2, and -17 +/- 2 and 44 +/- 4 beats/min, respectively. Increases in blood pressures during Phe infusions were greater in WT than in UT (100 nM Phe: systolic 36 +/- 3 vs. 25 +/- 3 mmHg, P less than 0.05). The Iso-induced decrease in diastolic blood pressure was also more pronounced in WT (0.8 nM Iso: -29 +/- 3 vs. -15 +/- 2 mmHg, P less than 0.01). Iso-induced changes in systolic time intervals showed no consistent differences between training states. Increases in plasma adenosine 3',5'-cyclic monophosphate during Iso infusions were smaller (P less than 0.05) in WT than in UT, whereas increases in plasma glycerol were larger (P less than 0.05). Lymphocyte beta 2-adrenoceptor function and binding characteristics did not differ between training states. In summary, the present results indicate that beta-adrenergic vasodilator and alpha-adrenergic vasopressor responses are enhanced in endurance-trained subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhanced endothelium-dependent vasodilation in older endurance-trained men.

We hypothesized that abnormal endothelium-dependent vasodilation (EDD) found in older otherwise healthy subjects can be attenuated with long-term endurance training. Ten endurance-trained men, 68.5 +/- 2.3 yr old, and 10 healthy sedentary men, 64.7 +/- 1.4 yr old, were studied. Aerobic exercise capacity (VO(2 max)), fasting plasma cholesterol, insulin, and homocysteine concentrations were measured. Master athletes had higher VO(2 max) (42 +/- 2.3 vs. 27 +/- 1.4 ml. kg(-1). min(-1), P < 0.001), slightly higher total cholesterol (226 +/- 8 vs. 199 +/- 8 mg/dl, P = 0.05), similar insulin, and higher homocysteine (10.7 +/- 1.3 vs. 9.2 +/- 1.4 micromol/ml, p = 0.02) concentrations. Brachial arterial diameter, determined with vascular ultrasound, during the hyperemic response was greater in the master athletes than in controls (P = 0.005). Peak vasodilatory response was 109.1 +/- 2 vs. 103.6 +/- 2% (P < 0.05) in the athletes and controls, respectively. Endothelium-independent vasodilation in response to nitroglycerin was similar between the two groups. The increased arterial diameter during the hyperemic response correlated significantly with the VO(2 max) in the entire population (r = 0.66, P < 0.002). Our results suggest that long-term endurance exercise training in older men is associated with systemic enhanced EDD, which is even detectable in the conduit arteries of untrained muscle.     

Enhanced endothelial vasoreactivity in endurance-trained older men.

Using external vascular ultrasound, we measured brachial artery diameter (Diam) at rest, after release of 4 min of limb ischemia, i. e., endothelium-dependent dilation (EDD), and after sublingual nitroglycerin, i.e., non-endothelium-dependent dilation (NonEDD), in 35 healthy men aged 61-83 yr: 12 endurance athletes (A) and 23 controls (C). As anticipated, treadmill exercise maximal oxygen consumption (VO(2 max)) was significantly higher in A than in C (40. 2 +/- 6.6 vs. 27.9 +/- 3.8 ml. kg(-1). min(-1); respectively, P < 0. 0001). With regard to arterial physiology, A had greater EDD (8.9 +/- 4.2 vs. 5.7 +/- 3.5%; P = 0.02) and a tendency for higher NonEDD (13.9 +/- 6.7 vs. 9.7 +/- 4.2%; P = 0.07) compared with C. By multiple linear regression analysis in the combined sample of older men, only baseline Diam (beta = -2.0, where beta is the regression coefficient; P = 0.005) and VO(2 max) (beta = 0.23; P = 0.003) were independent predictors of EDD; similarly, only Diam (beta = -4.0; P = 0.003) and VO(2 max) (beta = 0.27; P = 0.01) predicted NonEDD. Thus endurance-trained older men demonstrate both augmented EDD and NonEDD, consistent with a generalized enhanced vasodilator responsiveness, compared with their sedentary age peers.     

Rest/activity rhythms and cardiovascular disease in older men

Prior studies have suggested an increased risk of cardiovascular disease (CVD)-related mortality in older adults with disturbed circadian rest/activity rhythms (RARs). The objective goal of this study was to examine the association between disrupted RARs and risk of CVD events in older men. A total of 2968 men aged 67 yrs and older wore wrist actigraphs for 115?±?18 consecutive hours. RAR parameters were computed from wrist actigraphy data and expressed as quartiles (Q). CVD events consisted of a composite outcome of coronary heart disease (CHD), stroke, and peripheral vascular disease (PVD) events. Secondary analyses examined associations between RARs and individual components of the composite outcome (CHD, stroke, and PVD). There were 490 CVD events over an average of 4.0?±?1.2 yrs. Overall, reduced amplitude (HR?=?1.31, 95% confidence interval [CI] 1.01-1.71 for Q2 vs. Q4) and greater minimum (HR?=?1.33, 95% CI 1.01-1.73 for Q4 vs. Q1) were associated with an increased risk of CVD events in multivariable-adjusted models. In secondary analyses, there was an independent association between reduced amplitude (HR?=?1.36, 95% CI 1.00-1.86) and greater minimum activity counts (HR?=?1.39, 95% CI 1.02-1.91) with increased risk of CHD events. Reduced F value (HR?=?2.88, 95% CI 1.41-5.87 for Q1 vs. Q4 and HR?=?2.71, 95% CI 1.34-5.48 for Q2 vs. Q4) and later occurring acrophase of the RAR (HR?=?1.65, 95% CI 1.04-2.63 for Q4 vs. Q2-3) were associated with an increased risk of PVD events. Results were similar in men without a history of CVD events. The findings revealed that among older men, measures of decreased circadian activity rhythm robustness (reduced amplitude and greater minimum activity) were associated with an increased risk of CVD events, primarily through increased risk of CHD or stroke events, whereas measures of reduced circadian activity rhythmicity were not associated with risk of CVD events overall, but were associated with an increased risk of PVD events. These results should be confirmed in other populations.     

Relationship between muscle blood flow and oxygen uptake during exercise in endurance-trained and untrained men.

A recent study showed good correlation between regional blood flow (BF) and oxygen uptake (Vo(2)) 30 min after exhaustive exercise. The question that remains open is whether there is similar good correlation between BF and Vo(2) also during exercise. We reanalyzed our previous data from a study in which BF and Vo(2) was measured in different quadriceps femoris muscles in seven healthy endurance-trained and seven healthy untrained men at rest and during low-intensity intermittent static knee-extension exercise (Kalliokoski KK, Oikonen V, Takala TO, Sipila H, Knuuti J, and Nuutila P. Am J Physiol Endocrinol Metab 280: E1015-E1021, 2001). When the mean values of each muscle were considered, there was good correlation between BF and Vo(2) during exercise in both groups (r(2) = 0.82 in untrained and 0.97 in trained). However, when calculated individually, the correlations were poorer, and the mean correlation coefficient (r(2)) was significantly higher in the trained men (0.71 +/- 0.07 vs. 0.40 +/- 0.11, P = 0.03). These results suggest that there is large individual variation in matching BF to Vo(2) in human skeletal muscles during exercise, ranging from very poor to excellent. Furthermore, this matching seems to be better in the endurance-trained than in untrained men.     

Circulating plasma VEGF response to exercise in sedentary and endurance-trained men.

The skeletal muscle capillary supply is an important determinant of maximum exercise capacity, and it is well known that endurance exercise training increases the muscle capillary supply. The muscle capillary supply and exercise-induced angiogenesis are regulated in part by vascular endothelial growth factor (VEGF). VEGF is produced by skeletal muscle cells and can be secreted into the circulation. We investigated whether there are differences in circulating plasma VEGF between sedentary individuals (Sed) and well-trained endurance athletes (ET) at rest or in response to acute exercise. Eight ET men (maximal oxygen consumption: 63.8 +/- 2.3 ml x kg(-1) x min(-1); maximum power output: 409.4 +/- 13.3 W) and eight Sed men (maximal oxygen consumption: 36.3 +/- 2.1 ml x kg(-1) x min(-1); maximum power output: 234.4 +/- 13.3 W) exercised for 1 h at 50% of maximum power output. Antecubital vein plasma was collected at rest and at 0, 2, and 4 h postexercise. Plasma VEGF was measured by ELISA analysis. Acute exercise significantly increased VEGF at 0 and 2 h postexercise in ET subjects but did not increase VEGF at any time point in Sed individuals. There was no difference in VEGF between ET and Sed subjects at any time point. When individual peak postexercise VEGF was analyzed, exercise did increase VEGF independent of training status. In conclusion, exercise can increase plasma VEGF in both ET athletes and Sed men; however, there is considerable variation in the individual time of the peak VEGF response.     

Heart rate and blood pressure responses to isometric exercise in young and older men

The aim of this study was to examine the isometric endurance response and the heart rate and blood pressure responses to isometric exercise in two muscle groups in ten young (age 23–29 years) and seven older (age 54–59 years) physically active men with similar estimated forearm and thigh muscle masses. Isometric contractions were held until fatigue using the finger flexor muscles (handgrip) and with the quadriceps muscle (one-legged knee extension) at 20%, 40%, and 60% of the maximal voluntary contraction (MVC). Heart rate and arterial pressure were related to the the individual's contraction times. The isometric endurance response was longer with handgrip than with one-legged knee extension, but no significant difference was observed between the age groups. The isometric endurance response averaged 542 (SEM 57), 153 (SEM 14), and 59 (SEM 5) s for the handgrip, and 276 (SEM 35), 94 (SEM 10) and 48 (SEM 5) s for the knee extension at the three MVC levels, respectively. Heart rate and blood pressure became higher during one-legged knee extension than during handgrip, and with increasing level of contraction. The older subjects had a lower heart rate and a higher blood pressure response than their younger counterparts, and the differences were more apparent at a higher force level. The results would indicate that increasing age is associated with an altered heart rate and blood pressure response to isometric exercise although it does not affect isometric endurance. Accepted: 23 October 1997     

Endothelial function in highly endurance-trained men: effects of acute exercise

Exercise training reverses endothelial dysfunction, but the effect in young, healthy subjects is less clear. We determined the influence of maximal oxygen uptake (VO2max) and a single bout of high-intensity exercise on flow-mediated dilatation (FMD), brachial artery diameter, peak blood flow, nitric oxide (NO) bioavailability, and antioxidant status in highly endurance-trained men and their sedentary counterparts. Ten men athletes (mean +/- SEM age 23.5 +/- 0.9 years, height 182.6 +/- 2.4 cm, weight 72.5 +/- 2.4 kg, VO2max 75.9 +/- 0.8 mL.kg.min) and seven healthy controls (age 25.4 +/- 1.2 years, height 183.9 +/- 3.74 cm, weight 92.8 +/- 3.9 kg, VO2max 47.7 +/- 1.7 mL.kg.min) took part in the study. FMD, brachial artery diameter, and peak blood flow were measured using echo-Doppler before, 1 hour, 24 hours, and 48 hours after a single bout of interval running for 5 x 5 minutes at 90% of maximal heart rate. NO bioavailability and antioxidant status in blood were measured at all time points. Maximal arterial diameter and peak flow were 10-15% (P < 0.02) and 28-35% (P < 0.02) larger, respectively, in athletes vs. controls at all time points, and similar FMD were observed, apart from a transient decay of FMD in athletes 1 hour post exercise. NO bioavailability increased significantly after exercise in both groups and decreased to baseline levels after 24 hours in controls but remained increased 80% and 93% above baseline 24 and 48 hours post exercise in athletes. Antioxidant status was equal in the two groups at baseline and increased by approximately 10% 1 hour post exercise, an effect that lasted for 24 hours. Athletes had larger arterial diameter but similar FMD as untrained subjects, i.e., athletes had larger capacity for blood transport compared with their untrained counterparts. The observed FMD, bioavailability of NO, and antioxidant status in blood were highly dependent on the time elapsed after the exercise session.     

Substrate utilization and enzymes in skeletal muscle of extremely endurance-trained men

Substrate utilization during exercise at 65% of maximal O2 uptake (VO2 max) and biochemical characteristics of vastus lateralis were compared between five endurance-trained (T) and five untrained subjects (U). The oxidative enzyme activities were 100% greater in T than in U, and VO2 max was 50% higher. A greater proportion of ATP regeneration occurred through oxidative processes in T than in U (smaller leg lactate release and smaller muscle lactate accumulation). The respiratory exchange ratio together with the local leg respiratory quotient indicated a greater contribution of fat to oxidative metabolism in T than U (53 vs. 33%). No difference, however, in the ratio of plasma free fatty acid extraction to O2 extraction by the working legs was found between T and U. Thus it could be calculated that a greater fraction of fat oxidation would have been covered by intramuscular triglycerides in T than in U (34 vs. 15%, P less than 0.05). T in comparison to U were further characterized by a smaller glycogen breakdown and a smaller glucose uptake, which may have been one contributing factor that prevented the blood glucose level from falling in T. The greater leg muscle citrate concentration in T could have been one factor mediating a lower carbohydrate utilization as a response to an increase in the relative proportion of fat oxidation.     

Circulating blood island-derived cells contribute to vasculogenesis in the embryo proper

While recent findings have established that cells derived from the bone marrow can contribute to vasculogenesis in the adult, it is unclear whether an analogous population of cells in the embryo can also contribute to vasculogenesis. Using a retroviral labeling strategy, we demonstrate that circulating blood island-derived cells contribute to the genesis of both extra- and intraembryonic blood vessels in the early quail embryo. This finding establishes that vasculogenesis in the embryo is a composite of two processes: the direct in situ formation of blood vessels from mesodermally derived angioblasts and the incorporation and differentiation of circulating endothelial cell progenitors into forming embryonic blood vessels.     

Signal transduction pathways that contribute to increased protein synthesis during T-cell activation

Protein synthesis rates were maximally stimulated in human lymphocytes by ionomycin and the phorbol ester PMA (I+P), which promotes proliferation, whereas PMA alone, which does not promote proliferation, stimulated protein synthesis to a lesser degree. Three translation-associated activities, eIF4E phosphorylation, eIF2B activity and 4E-BP1 phosphorylation also increased with stimulation by I+P and PMA, but only 4E-BP1 phosphorylation was differentially stimulated by these conditions. Correspondingly, signaling pathways activated in T cells were probed for their connection to these activities. Immunosuppressants FK506 and rapamycin partially blocked the protein synthesis rate increases by I+P stimulation. FK506 had less of an inhibitory effect with PMA stimulation suggesting that its mechanism mostly affected ionomycin-activated signals. I+P and PMA equally stimulated phosphorylation of ERK1/2, but I+P more strongly stimulated Akt, and p70(S6K) phosphorylation. An inhibitor that blocks ERK1/2 phosphorylation only slightly reduced protein synthesis rates stimulated by I+P or PMA, but greatly reduced eIF4E phosphorylation and eIF2B activity. In contrast, inhibitors of the PI-3 kinase and mTOR pathways strongly blocked early protein synthesis rate stimulated by I+P and PMA and also blocked 4E-BP1 phosphorylation and release of eIF4E suggesting that these pathways regulate protein synthesis activities, which are important for proliferation in T cells.     

Multiple arginine residues contribute to the increased efficacy of peptide substrates for the cAMP-dependent protein kinase

Efficient cAMP-dependent protein kinase substrates typically contain an arginine dyad one amino acid removed from the residue which undergoes phosphorylation (ie. Arg-Arg-X-Ser). However, several naturally occurring protein kinase inhibitors and substrates possess additional basic residues that are proximal to the arginine dyad, implying the presence of either an extended or an additional acidic subsite on the enzyme. In this study, we investigated the substrate efficacy of several multiple arginine-bearing peptides. The most efficient substrate studied, Arg-Arg-Leu-Arg-Arg-Ala-Ser-Leu-Gly, exhibits a nearly eleven-fold increase in kcat/Km relative to Leu-Arg-Arg-Ala-Ser-Leu-Gly. The enhanced kcat/Km is primarily a consequence of a reduced Km. These results suggest that a double arginine dyad, separated by a single amino acid, represents the optimal sequence for basic residues on cAMP-dependent protein kinase substrates.     

Cardiovascular response to exercise in younger and older men

Measurements of cardiac performance for humans at various ages is influenced by the variable examined, the population and techniques employed, and the factors that co-vary with age, including the presence of disease and physical conditioning. Interstudy differences in the extent to which occult coronary disease is present in older subjects and in the level of physical conditioning among subjects may underlie the variable perspectives contained in the literature of how aging affects cardiovascular function. In carefully screened, highly motivated but not athletically trained community-dwelling subjects, resting cardiovascular parameters are not age related except for systolic blood pressure, which increases with age. During vigorous exercise the mechanisms used to achieve a high level of cardiac output shift from a dependence on a catecholamine-mediated increase in heart rate and inotropy to a dependence on the Frank Starling mechanism. One reason for the age difference in cardiovascular response to exercise may be a diminished responsiveness to beta-adrenergic stimulation in these subjects. In other elderly subjects who cannot exercise to high work loads, a decline in stroke volume as well as heart rate at peak exercise has been observed. Whether the inability of these individuals to augment stroke volume is caused by a decrease in the ability of the heart to increase diastolic filling, by a decrease in systolic pump function caused by an increased afterload, by intrinsic myocardial contractile defects, or by a greater diminution of the cardiovascular response to beta-adrenergic stimuli is presently unknown.