This study sought to determine whether afferent feedback associated with peripheral muscle fatigue inhibits central motor drive (CMD) and thereby limits endurance exercise performance. On two separate days, eight men performed constant-load, single-leg knee extensor exercise to exhaustion (85% of peak power) with each leg (Leg₁ and Leg₂). On another day, the performance test was repeated with one leg (Leg₁) and consecutively (within 10 s) with the other/contralateral leg (Leg₂-post). Exercise-induced quadriceps fatigue was assessed by reductions in potentiated quadriceps twitch-force from pre- to postexercise (ΔQ_tw,pot) in response to supramaximal magnetic femoral nerve stimulation. The output from spinal motoneurons, estimated from quadriceps electromyography (iEMG), was used to reflect changes in CMD. Rating of perceived exertion (RPE) was recorded during exercise. Time to exhaustion (∼9.3 min) and exercise-induced ΔQ_tw,pot (∼51%) were similar in Leg₁ and Leg₂ ( P > 0.5). In the consecutive leg trial, endurance performance of the first leg was similar to that observed during the initial trial (∼9.3 min; P = 0.8); however, time to exhaustion of the consecutively exercising contralateral leg (Leg₂-post) was shorter than the initial Leg₂ trial (4.7 ± 0.6 vs. 9.2 ± 0.4 min; P < 0.01). Additionally, ΔQ_tw,pot following Leg₂-post was less than Leg₂ (33 ± 3 vs 52 ± 3%; P < 0.01). Although the slope of iEMG was similar during Leg₂ and Leg₂-post, end-exercise iEMG following Leg₂-post was 26% lower compared with Leg₂ ( P < 0.05). Despite a similar rate of rise, RPE was consistently ∼28% higher throughout Leg₂-post vs. Leg₂ ( P < 0.05). In conclusion, this study provides evidence that peripheral fatigue and associated afferent feedback limits the development of peripheral fatigue and compromises endurance exercise performance by inhibiting CMD.

Unlike cardiac and skeletal muscle, little is known about vascular smooth muscle mitochondrial respiration. Therefore, the present study examined mitochondrial respiratory rates in smooth muscle of healthy human feed arteries and compared with that of healthy cardiac and skeletal muscles. Cardiac, skeletal, and smooth muscles were harvested from a total of 22 subjects (53 ± 6 yr), and mitochondrial respiration was assessed in permeabilized fibers. Complex I + II, state 3 respiration, an index of oxidative phosphorylation capacity, fell progressively from cardiac to skeletal to smooth muscles (54 ± 1, 39 ± 4, and 15 ± 1 pmol·s⁻¹·mg⁻¹, P < 0.05, respectively). Citrate synthase (CS) activity, an index of mitochondrial density, also fell progressively from cardiac to skeletal to smooth muscles (222 ± 13, 115 ± 2, and 48 ± 2 μmol·g⁻¹·min⁻¹, P < 0.05, respectively). Thus, when respiration rates were normalized by CS (respiration per mitochondrial content), oxidative phosphorylation capacity was no longer different between the three muscle types. Interestingly, complex I state 2 normalized for CS activity, an index of nonphosphorylating respiration per mitochondrial content, increased progressively from cardiac to skeletal to smooth muscles, such that the respiratory control ratio, state 3/state 2 respiration, fell progressively from cardiac to skeletal to smooth muscles (5.3 ± 0.7, 3.2 ± 0.4, and 1.6 ± 0.3 pmol·s⁻¹·mg⁻¹, P < 0.05, respectively). Thus, although oxidative phosphorylation capacity per mitochondrial content in cardiac, skeletal, and smooth muscles suggest all mitochondria are created equal, the contrasting respiratory control ratio and nonphosphorylating respiration highlight the existence of intrinsic functional differences between these muscle mitochondria. This likely influences the efficiency of oxidative phosphorylation and could potentially alter ROS production.

Arterial telomere dysfunction may contribute to chronic arterial inflammation by inducing cellular senescence and subsequent senescence-associated inflammation. Although telomere shortening has been associated with arterial aging in humans, age-related telomere uncapping has not been described in non-cultured human tissues and may have substantial prognostic value. In skeletal muscle feed arteries from 104 younger, middle-aged, and older adults, we assessed the potential role of age-related telomere uncapping in arterial inflammation. Telomere uncapping, measured by p-histone γ-H2A.X (ser139) localized to telomeres (chromatin immunoprecipitation; ChIP), and telomeric repeat binding factor 2 bound to telomeres (ChIP) was greater in arteries from older adults compared with those from younger adults. There was greater tumor suppressor protein p53 (P53)/cyclin-dependent kinase inhibitor 1A (P21)-induced senescence, measured by P53 bound to P21 gene promoter (ChIP), and greater expression of P21, interleukin 8, and monocyte chemotactic protein 1 mRNA (RT-PCR) in arteries from older adults compared with younger adults. Telomere uncapping was a highly influential covariate for the age-group difference in P53/P21-induced senescence. Despite progressive age-related telomere shortening in human arteries, mean telomere length was not associated with telomere uncapping or P53/P21-induced senescence. Collectively, these findings demonstrate that advancing age is associated with greater telomere uncapping in arteries, which is linked to P53/P21-induced senescence independent of telomere shortening.

Aging is associated with a pro-oxidant state and a decline in endothelial function. Whether acute, enteral antioxidant treatment can reverse this decrement in vascular function is not well known. Flow-mediated vasodilation and reactive hyperemia were evaluated after consumption of either placebo or an oral antioxidant cocktail (vitamin C, 1000 mg; vitamin E, 600 IU; α-lipoic acid, 600 mg) in 87 healthy volunteers (42 young: 25±1 years; 45 older: 71±1 years) using a double-blind, crossover design. Blood velocity and brachial artery diameter (ultrasound Doppler) were assessed before and after 5-minute forearm circulatory arrest. Serum markers of lipid peroxidation, total antioxidant capacity, endogenous antioxidant activity, and vitamin C were assayed, and plasma nitrate, nitrite, and 3-nitrotyrosine were determined. In the placebo trial, an age-related reduction in brachial artery vasodilation was evident (young: 7.4±0.6%; older: 5.2±0.4%). After antioxidant consumption, flow-mediated vasodilation improved in older subjects (placebo: 5.2±0.4%; antioxidant: 8.2±0.6%) but declined in the young (placebo: 7.4±0.6%; antioxidant: 5.8±0.6%). Reactive hyperemia was reduced with age, but antioxidant administration did not alter the response in either group. Together, these data demonstrate that antioxidant consumption acutely restores endothelial function in the elderly while disrupting normal endothelium-dependent vasodilation in the young and suggest that this age-related impairment is attributed, at least in part, to free radicals.

Key points : Passive limb movement elicits a robust increase in limb blood flow (LBF) and limb vascular conductance (LVC) without a concomitant increase in skeletal muscle metabolism. The peripheral vascular mechanisms associated with the increase in LBF and LVC are unknown. Using an intra‐arterial infusion of N^G‐monomethyl‐l‐arginine (l‐NMMA) to inhibit nitric oxide synthase (NOS) the hyperaemic and vasodilatory response to passive limb movement was attenuated by nearly 80%. This finding demonstrates that the increases in LBF and LVC during passive limb movement are primarily NO dependent. Passive limb movement appears to have significant promise as a new approach to assess NO‐mediated vascular function, an important predictor of cardiovascular disease risk.

In the peripheral circulation, nitric oxide (NO) is released in response to shear stress across vascular endothelial cells. We sought to assess the degree to which NO contributes to exercise-induced vasodilation in the brachial artery (BA) and to determine the potential of this approach to noninvasively evaluate NO bioavailability. In eight young (25 ± 1 yr) healthy volunteers, we used ultrasound Doppler to examine BA vasodilation in response to handgrip exercise (4, 8, 12, 16, 20, and 24 kg) with and without endothelial NO synthase blockade [intra-arterial N^G-monomethyl-l-arginine (l-NMMA), 0.48 mg·dl⁻¹·min⁻¹]. Higher exercise intensities evoked significant BA vasodilation (4–12%) that was positively correlated with the hyperemic stimulus ( r = 0.98 ± 0.003, slope = 0.005 ± 0.001). During NO blockade, BA vasodilation at the highest exercise intensity was reduced by ∼70% despite similar exercise-induced increases in shear rate (control, +224 ± 30 s⁻¹; l-NMMA, +259 ± 46 s⁻¹). The relationship and slope of BA vasodilation with increasing shear rate was likewise reduced ( r = 0.48 ± 0.1, slope = 0.0007 ± 0.0005). We conclude that endothelial NO synthase inhibition with l-NMMA abolishes the relationship between shear stress and BA vasodilation during handgrip exercise, providing clear evidence of NO-dependent vasodilation in this experimental model. These results support this paradigm as a novel and valid approach for a noninvasive assessment of NO-dependent vasodilation in humans.