α-Adrenergic regulation of skeletal muscle blood flow during exercise in patients with heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) has been characterized by lower blood flow to exercising limbs and lower peak oxygen utilization ( V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ), possibly associated with disease-related changes in sympathetic (α-adrenergic) signaling. Thus, in seven patients with HFpEF (70 ± 6 years, 3 female/4 male) and seven controls (CON) (66 ± 3 years, 3 female/4 male), we examined changes (%Δ) in leg blood flow (LBF, Doppler ultrasound) and leg V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ to intra-arterial infusion of phentolamine (PHEN, α-adrenergic antagonist) or phenylephrine (PE, α1-adrenergic agonist) at rest and during single-leg knee-extension exercise (0, 5 and 10 W). At rest, the PHEN-induced increase in LBF was not different between groups, but PE-induced reductions in LBF were lower in HFpEF (-16% ± 4% vs. -26% ± 5%, HFpEF vs. CON; P < 0.05). During exercise, the PHEN-induced increase in LBF was greater in HFpEF at 10 W (16% ± 8% vs. 8% ± 5%; P < 0.05). PHEN increased leg V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ in HFpEF (10% ± 3%, 11% ± 6%, 15% ± 7% at 0, 5 and 10 W; P < 0.05) but not in controls (-1% ± 9%, -4% ± 2%, -1% ± 5%; P = 0.24). The 'magnitude of sympatholysis' (PE-induced %Δ LBF at rest - PE-induced %Δ LBF during exercise) was lower in patients with HFpEF (-6% ± 4%, -6% ± 6%, -7% ± 5% vs. -13% ± 6%, -17% ± 5%, -20% ± 5% at 0, 5 and 10 W; P < 0.05) and was positively related to LBF, leg oxygen delivery, leg V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ , and the PHEN-induced increase in LBF (P < 0.05). Together, these data indicate that excessive α-adrenergic vasoconstriction restrains blood flow and limits V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ of the exercising leg in patients with HFpEF, and is related to impaired functional sympatholysis in this patient group. KEY POINTS: Sympathetic (α-adrenergic)-mediated vasoconstriction is exaggerated during exercise in patients with heart failure with preserved ejection fraction (HFpEF), which may contribute to limitations of blood flow, oxygen delivery and oxygen utilization in the exercising muscle. The ability to adequately attenuate α1-adrenergic vasoconstriction (i.e. functional sympatholysis) within the vasculature of the exercising muscle is impaired in patients with HFpEF. These observations extend our current understanding of HFpEF pathophysiology by implicating excessive α-adrenergic restraint and impaired functional sympatholysis as important contributors to disease-related impairments in exercising muscle blood flow and oxygen utilization in these patients.

The exercise pressor reflex - a pressure-raising mechanism with a limited role in regulating leg perfusion during locomotion in young healthy men.

We investigated the role of the exercise pressor reflex (EPR) in regulating the haemodynamic response to locomotor exercise. Eight healthy participants (23 ± 3 years, V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ : 49 ± 6 ml/kg/min) performed constant-load cycling exercise (∼36/43/52/98% V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ ; 4 min each) without (CTRL) and with (FENT) lumbar intrathecal fentanyl attenuating group III/IV locomotor muscle afferent feedback and, thus, the EPR. To avoid different respiratory muscle metaboreflex and arterial chemoreflex activation during FENT, subjects mimicked the ventilatory response recorded during CTRL. Arterial and leg perfusion pressure (femoral arterial and venous catheters), femoral blood flow (Doppler-ultrasound), microvascular quadriceps blood flow index (indocyanine green), cardiac output (inert gas breathing), and systemic and leg vascular conductance were quantified during exercise. There were no cardiovascular and ventilatory differences between conditions at rest. Pulmonary ventilation, arterial blood gases and oxyhaemoglobin saturation were not different during exercise. Furthermore, cardiac output (-2% to -12%), arterial pressure (-7% to -15%) and leg perfusion pressure (-8% to -22%) were lower, and systemic (up to 16%) and leg (up to 27%) vascular conductance were higher during FENT compared to CTRL. Leg blood flow, microvascular quadriceps blood flow index, and leg O2 -transport and utilization were not different between conditions (P > 0.5). These findings reflect a critical role of the EPR in the autonomic control of the heart, vasculature and, ultimately, arterial pressure during locomotor exercise. However, the lack of a net effect of the EPR on leg blood flow challenges the idea of this cardiovascular reflex as a key determinant of leg O2 -transport during locomotor exercise in healthy, young individuals. KEY POINTS: The role of the exercise pressor reflex (EPR) in regulating leg O2 -transport during human locomotion remains uncertain. We investigated the influence of the EPR on the cardiovascular response to cycling exercise. Lumbar intrathecal fentanyl was used to block group III/IV leg muscle afferents and debilitate the EPR at intensities ranging from 30% to 100% V ̇ O 2 max ${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ . To avoid different respiratory muscle metaboreflex and arterial chemoreflex activation during exercise with blocked leg muscle afferents, subjects mimicked the ventilatory response recorded during control exercise. Afferent blockade increased leg and systemic vascular conductance, but reduced cardiac output and arterial-pressure, with no net effect on leg blood flow. The EPR influenced the cardiovascular response to cycling exercise by contributing to the autonomic control of the heart and vasculature, but did not affect leg blood flow. These findings challenge the idea of the EPR as a key determinant of leg O2 -transport during locomotor exercise in healthy, young individuals.

On the role of skeletal muscle acidosis and inorganic phosphates as determinants of central and peripheral fatigue: A 31 P-MRS study.

Intramuscular hydrogen ion (H+ ) and inorganic phosphate (Pi) concentrations were dissociated during exercise to challenge their relationships with peripheral and central fatigue in vivo. Ten recreationally active, healthy men (27 ± 5 years; 180 ± 4 cm; 76 ± 10 kg) performed two consecutive intermittent isometric single-leg knee-extensor trials (60 maximal voluntary contractions; 3 s contraction, 2 s relaxation) interspersed with 5 min of rest. Phosphorus magnetic resonance spectroscopy (31 P-MRS) was used to continuously quantify intramuscular [H+ ] and [Pi] during both trials. Using electrical femoral nerve stimulation, quadriceps twitch force (Qtw ) and voluntary activation (VA) were quantified at rest and throughout both trials. Decreases in Qtw and VA from baseline were used to determine peripheral and central fatigue, respectively. Qtw was strongly related to both [H+ ] (ß coefficient: -0.9, P < 0.0001) and [Pi] (-1.1, P < 0.0001) across trials. There was an effect of trial on the relationship between Qtw and [H+ ] (-0.5, P < 0.0001), but not Qtw and [Pi] (0.0, P = 0.976). This suggests that, unlike the unaltered association with [Pi], a given level of peripheral fatigue was associated with a different [H+ ] in Trial 1 vs. Trial 2. VA was related to [H+ ] (-0.3, P < 0.0001), but not [Pi] (-0.2, P = 0.243), across trials and there was no effect of trial (-0.1, P = 0.483). Taken together, these results support intramuscular Pi as a primary cause of peripheral fatigue, and muscle acidosis, probably acting on group III/IV muscle afferents in the interstitial space, as a contributor to central fatigue during exercise. KEY POINTS: We investigated the relationship between intramuscular metabolites and neuromuscular function in humans performing two maximal, intermittent, knee-extension trials interspersed with 5 min of rest. Concomitant measurements of intramuscular hydrogen (H+ ) and inorganic phosphate (Pi) concentrations, as well as quadriceps twitch-force (Qtw ) and voluntary activation (VA), were made throughout each trial using phosphorus magnetic resonance spectroscopy (31 P-MRS) and electrical femoral nerve stimulations. Although [Pi] fully recovered prior to the onset of the second trial, [H+ ] did not. Qtw was strongly related to both [H+ ] and [Pi] across both trials. However, the relationship between Qtw and [H+ ] shifted leftward from the first to the second trial, whereas the relationship between Qtw and [Pi] remained unaltered. VA was related to [H+ ], but not [Pi], across both trials. These in vivo findings support the hypotheses of intramuscular Pi as a primary cause of peripheral fatigue, and muscle acidosis, probably acting on group III/IV muscle afferents, as a contributor to central fatigue.

On the haemodynamic consequence of the chemoreflex and muscle mechanoreflex interaction in women and men: two tales, one story.

The cardiovascular response resulting from the individual activation of the muscle mechanoreflex (MMR) or the chemoreflex (CR) is different between men and women. Whether the haemodynamic consequence resulting from the interaction of these sympathoexcitatory reflexes is also sex-dependent remains unknown. MMR and CR were activated by passive leg movement (LM) and exposure to hypoxia (O2 -CR) or hypercapnia (CO2 -CR), respectively. Twelve young men and 12 young women completed two experimental protocols: (1) resting in normoxia (PET O2 : ∼83 mmHg, PET CO2 : ∼34 mmHg), normocapnic hypoxia (PET O2 : ∼48 mmHg, PET CO2 : ∼34 mmHg) and hyperoxic hypercapnia (PET O2 : ∼524 mmHg, PET CO2 : ∼44 mmHg); (2) LM under the same gas conditions. During the MMR:O2 -CR coactivation, in men, the observed mean arterial pressure (MAP) and cardiac output (CO) were not different (additive effect), while the observed leg blood flow (LBF) and vascular conductance (LVC) were significantly lower (hypo-additive), compared with the sum of the responses elicited by each reflex alone. In women, the observed MAP was not different (additive) while the observed CO, LBF and LVC were significantly greater (hyper-additive), compared with the summated responses. During the MMR:CO2 -CR coactivation, in men, the observed MAP, CO and LBF were not different (additive), while the observed LVC was significantly lower (hypo-additive), compared with the summated responses. In women, the observed MAP was significantly higher (hyper-additive), while the observed CO, LBF and LVC were not different (additive), compared with the summated responses. The interaction of the MMR and CR has a pronounced influence on the autonomic cardiovascular control, with the haemodynamic consequences differing between men and women. KEY POINTS: The cardiovascular response resulting from the activation of the muscle mechanoreflex (MMR) or the chemoreflex (CR) was previously shown to be different between women and men; this study focused on the haemodynamic consequence of the interaction of these two sympathoexcitatory reflexes. MMR and CR were activated by passive leg movement and exposure to hypoxia (O2 -CR) or hypercapnia (CO2 -CR), respectively. Individual and interactive reflex effects on central and peripheral haemodynamics were quantified in healthy young women and men. In men, the MMR:O2 -CR and MMR:CO2 -CR interactions restricted peripheral haemodynamics, likely by potentiating sympathetic vasoconstriction. In women, the MMR:O2 -CR interaction facilitated central and peripheral haemodynamics, likely by potentiating sympathetic vasodilatation; however, the MMR:CO2 -CR interaction was simply additive for the central and peripheral haemodynamics. The interaction between the MMR and the CR exerts a profound influence on the autonomic control of cardiovascular function in humans, with the haemodynamic consequences differing between women and men.

Gene and protein expression of dorsal root ganglion sensory receptors in normotensive and hypertensive male rats.

The exercise pressor reflex (EPR), a neurocirculatory control mechanism, is exaggerated in hypertensive humans and rats. Disease-related abnormalities within the afferent arm of the reflex loop, including mechano- and metabosensitive receptors located at the terminal end of group III/IV muscle afferents, may contribute to the dysfunctional EPR in hypertension. Using control (WKY) and spontaneous hypertensive (SHR) rats, we examined dorsal root ganglion (DRG) gene and protein expression of molecular receptors recognized as significant determinants of the EPR. Twelve lumbar DRGs (6 left, 6 right) were harvested from each of 10 WKY [arterial blood pressure (MAP): 96 ± 9 mmHg] and 10 SHR (MAP: 144 ± 9 mmHg). DRGs from the left side were used for protein expression (Western blotting; normalized to GAPDH), whereas right-side DRGs (i.e., parallel structure) were used to determine mRNA levels (RNA-sequencing, normalized to TPM). Analyses focused on metabosensitive (ASIC3, Bradykinin receptor B2, EP4, P2X3, TRPv1) and mechanosensitive (Piezo1/2) receptors. Although Piezo1 was similar in both groups (P = 0.75), protein expression for all other receptors was significantly higher in SHR compared with WKY. With the exception of a greater Bradykinin-receptor B2 in SHR (P < 0.05), mRNA expression of all other receptors was not different between groups (P > 0.18). The higher protein content of these sensory receptors in SHR indirectly supports the previously proposed hypothesis that the exaggerated EPR in hypertension is, in part, due to disease-related abnormalities within the afferent arm of the reflex loop. The upregulated receptor content, combined with normal mRNA levels, insinuates that posttranscriptional regulation of sensory receptor protein expression might be impaired in hypertension.

Acute high-intensity exercise and skeletal muscle mitochondrial respiratory function: role of metabolic perturbation.

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.

The exercise pressor reflex and chemoreflex interaction: cardiovascular implications for the exercising human.

KEY POINTS: Although the exercise pressor reflex (EPR) and the chemoreflex (CR) are recognized for their sympathoexcitatory effect, the cardiovascular implication of their interaction remains elusive. We quantified the individual and interactive cardiovascular consequences of these reflexes during exercise and revealed various modes of interaction. The EPR and hypoxia-induced CR interaction is hyper-additive for blood pressure and heart rate (responses during co-activation of the two reflexes are greater than the summation of the responses evoked by each reflex) and hypo-additive for peripheral haemodynamics (responses during co-activation of the reflexes are smaller than the summated responses). The EPR and hypercapnia-induced CR interaction results in a simple addition of the individual responses to each reflex (i.e. additive interaction). Collectively, EPR:CR co-activation results in significant cardiovascular interactions with restriction in peripheral haemodynamics, resulting from the EPR:CR interaction in hypoxia, likely having the most crucial impact on the functional capacity of an exercising human. ABSTRACT: We investigated the interactive effect of the exercise pressor reflex (EPR) and the chemoreflex (CR) on the cardiovascular response to exercise. Eleven healthy participants (5 females) completed a total of six bouts of single-leg knee-extension exercise (60% peak work rate, 4 min each) either with or without lumbar intrathecal fentanyl to attenuate group III/IV afferent feedback from lower limbs to modify the EPR, while breathing either ambient air, normocapnic hypoxia (Sa O2 ∼79%, Pa O2 ∼43 mmHg, Pa CO2 ∼33 mmHg, pH ∼7.39), or normoxic hypercapnia (Sa O2 ∼98%, Pa O2 ∼105 mmHg, Pa CO2 ∼50 mmHg, pH ∼7.26) to modify the CR. During co-activation of the EPR and the hypoxia-induced CR (O2 -CR), mean arterial pressure and heart rate were significantly greater, whereas leg blood flow and leg vascular conductance were significantly lower than the summation of the responses evoked by each reflex alone. During co-activation of the EPR and the hypercapnia-induced CR (CO2 -CR), the haemodynamic responses were not different from the summated responses to each reflex response alone (P ≥ 0.1). Therefore, while the interaction resulting from the EPR:O2 -CR co-activation is hyper-additive for blood pressure and heart rate, and hypo-additive for peripheral haemodynamics, the interaction resulting from the EPR:CO2 -CR co-activation is simply additive for all cardiovascular parameters. Thus, EPR:CR co-activation results in significant interactions between cardiovascular reflexes, with the impact differing when the CR activation is achieved by hypoxia or hypercapnia. Since the EPR:CR co-activation with hypoxia potentiates the pressor response and restricts blood flow to contracting muscles, this interaction entails the most functional impact on an exercising human.

Vasodilatory and vascular mitochondrial respiratory function with advancing age: evidence of a free radically mediated link in the human vasculature.

Recognizing the age-related decline in skeletal muscle feed artery (SMFA) vasodilatory function, this study examined the link between vasodilatory and mitochondrial respiratory function in the human vasculature. Twenty-four SMFAs were harvested from young (35 ± 6 yr, n = 9) and old (71 ± 9 yr, n = 15) subjects. Vasodilation in SMFAs was assessed, by pressure myography, in response to flow-induced shear stress, acetylcholine (ACh), and sodium nitroprusside (SNP) while mitochondrial respiration was measured, by respirometry, in permeabilized SMFAs. Endothelium-dependent vasodilation was significantly attenuated in the old, induced by both flow (young: 92 ± 3, old: 45 ± 4%) and ACh (young: 92 ± 3, old: 54 ± 5%), with no significant difference in endothelium-independent vasodilation. Complex I and I + II state 3 respiration was significantly lower in the old (CI young: 10.1 ± 0.8, old: 7.0 ± 0.4 pmol·s-1·mg-1; CI + II young: 12.3 ± 0.6, old: 7.6 ± 0.4 pmol·s-1·mg-1). The respiratory control ratio (RCR) was also significantly attenuated in the old (young: 2.2 ± 0.1, old: 1.1 ± 0.1). Furthermore, state 3 (CI + II) and 4 respiration, as well as RCR, were significantly correlated (r = 0.49-0.86) with endothelium-dependent, but not endothelium-independent, function. Finally, the direct intervention with mitochondrial-targeted antioxidant (MitoQ) significantly improved endothelium-dependent vasodilation in the old but not in the young. Thus, the age-related decline in vasodilatory function is linked to attenuated vascular mitochondrial respiratory function, likely by augmented free radicals.NEW & NOTEWORTHY In human skeletal muscle feed arteries, the well-recognized age-related fall in endothelium-dependent vasodilatory function is strongly linked to a concomitant fall in vascular mitochondrial respiratory function. The direct intervention with the mitochondrial-targeted antioxidant restored vasodilatory function in the old but not in the young, supporting the concept that exacerbated mitochondrial-derived free radical production is linked to age-related vasodilatory dysfunction. Age-related vasodilatory dysfunction in humans is linked to attenuated vascular mitochondrial respiratory function, likely a consequence of augmented free radical production.

On the Influence of Group III/IV Muscle Afferent Feedback on Endurance Exercise Performance.

This review discusses evidence suggesting that group III/IV muscle afferents affect locomotor performance by influencing neuromuscular fatigue. These neurons regulate the hemodynamic and ventilatory response to exercise and, thus, assure appropriate locomotor muscle O2 delivery, which optimizes peripheral fatigue development and facilitates endurance performance. In terms of central fatigue, group III/IV muscle afferents inhibit motoneuronal output and thereby limit exercise performance.

Fatigue-related group III/IV muscle afferent feedback facilitates intracortical inhibition during locomotor exercise.

KEY POINTS: This study investigated the influence of group III/IV muscle afferents on corticospinal excitability during cycling exercise and focused on GABAB neuron-mediated inhibition as a potential underlying mechanism. The study provides novel evidence to demonstrate that group III/IV muscle afferent feedback facilitates inhibitory intracortical neurons during whole body exercise. Firing of these interneurons probably contributes to the development of central fatigue during physical activity. ABSTRACT: We investigated the influence of group III/IV muscle afferents in determining corticospinal excitability during cycling exercise and focused on GABAB neuron-mediated inhibition as a potential underlying mechanism. Both under control conditions (CTRL) and with lumbar intrathecal fentanyl (FENT) impairing feedback from group III/IV leg muscle afferents, subjects (n = 11) cycled at a comparable vastus-lateralis EMG signal (∼0.26 mV) before (PRE; 100 W) and immediately after (POST; 90 ± 2 W) fatiguing constant-load cycling exercise (80% Wpeak; 221 ± 10 W; ∼8 min). During, PRE and POST cycling, single and paired-pulse (100 ms interstimulus interval) transcranial magnetic stimulations (TMS) were applied to elicit unconditioned and conditioned motor-evoked potentials (MEPs), respectively. To distinguish between cortical and spinal contributions to the MEPs, cervicomedullary stimulations (CMS) were used to elicit unconditioned (CMS only) and conditioned (TMS+CMS, 100 ms interval) cervicomedullary motor-evoked potentials (CMEPs). While unconditioned MEPs were unchanged from PRE to POST in CTRL, unconditioned CMEPs increased significantly, resulting in a decrease in unconditioned MEP/CMEP (P < 0.05). This paralleled a reduction in conditioned MEP (P < 0.05) and no change in conditioned CMEP. During FENT, unconditioned and conditioned MEPs and CMEPs were similar and comparable during PRE and POST (P > 0.2). These findings reveal that feedback from group III/IV muscle afferents innervating locomotor muscle decreases the excitability of the motor cortex during fatiguing cycling exercise. This impairment is, at least in part, determined by the facilitating effect of these sensory neurons on inhibitory GABAB intracortical interneurons.

Identifying the role of group III/IV muscle afferents in the carotid baroreflex control of mean arterial pressure and heart rate during exercise.

KEY POINTS: We investigated the contribution of group III/IV muscle afferents to carotid baroreflex resetting during electrically evoked (no central command) and voluntary (requiring central command) isometric knee extension exercise. Lumbar intrathecal fentanyl was used to attenuate the central projection of µ-opioid receptor-sensitive group III/IV leg muscle afferent feedback. Spontaneous carotid baroreflex control was assessed by loading and unloading the carotid baroreceptors with a variable pressure neck chamber. Group III/IV muscle afferents did not influence spontaneous carotid baroreflex responsiveness at rest or during exercise. Afferent feedback accounted for at least 50% of the exercise-induced increase in the carotid baroreflex blood pressure and heart rate operating points, adjustments that are critical for an appropriate cardiovascular response to exercise. These findings suggest that group III/IV muscle afferent feedback is, independent of central command, critical for the resetting of the carotid baroreflex blood pressure and heart rate operating points, but not for spontaneous baroreflex responsiveness. ABSTRACT: This study sought to comprehensively investigate the role of metabolically and mechanically sensitive group III/IV muscle afferents in carotid baroreflex responsiveness and resetting during both electrically evoked (EVO, no central command) and voluntary (VOL, requiring central command) isometric single-leg knee-extension (15% of maximal voluntary contraction; MVC) exercise. Participants (n = 8) were studied under control conditions (CTRL) and following lumbar intrathecal fentanyl injection (FENT) to inhibit µ-opioid receptor-sensitive lower limb muscle afferents. Spontaneous carotid baroreflex control of mean arterial pressure (MAP) and heart rate (HR) were assessed following rapid 5 s pulses of neck pressure (NP, +40 mmHg) or suction (NS, -60 mmHg). Resting MAP (87 ± 10 mmHg) and HR (70 ± 8 bpm) were similar between CTRL and FENT conditions (P > 0.4). In terms of spontaneous carotid baroreflex responsiveness, FENT did not alter the change in MAP or HR responses to NP (+13 ± 5 mmHg, P = 0.85; +9 ± 3 bpm; P = 0.99) or NS (-13 ± 5 mmHg, P = 0.99; -24 ± 11 bpm; P = 0.49) at rest or during either exercise protocol, which were of a remarkably similar magnitude to rest. In contrast, FENT administration reduced the exercise-induced resetting of the operating point for MAP and HR during both EVO (116 ± 10 mmHg to 100 ± 15 mmHg and 93 ± 14 bpm to 82 ± 10 bpm) and VOL (107 ± 13 mmHg to 100 ± 17 mmHg and 89 ± 10 bpm to 72 ± 10 bpm) exercise bouts. Together, these findings document that group III/IV muscle afferent feedback is critical for the resetting of the carotid baroreflex MAP and HR operating points, independent of exercise-induced changes in central command, but not for spontaneous carotid baroreflex responsiveness.

Vascular mitochondrial respiratory function: the impact of advancing age.

Little is known about vascular mitochondrial respiratory function and the impact of age. Therefore, skeletal muscle feed arteries were harvested from young (33 ± 7 yr, n = 10), middle-aged (54 ± 5 yr, n = 10), and old (70 ± 7 yr, n = 10) subjects, and mitochondrial respiration as well as citrate synthase (CS) activity were assessed. Complex I (CI) and complex I + II (CI+II) state 3 respiration were greater in young (CI: 10.4 ± 0.8 pmol·s-1·mg-1 and CI+II: 12.4 ± 0.8 pmol·s-1·mg-1, P < 0.05) than middle-aged (CI: 7 ± 0.6 pmol·s-1·mg-1 and CI+II: 8.3 ± 0.5 pmol·s-1·mg-1) and old (CI: 7.2 ± 0.4 pmol·s-1·mg-1 and CI+II: 7.6 ± 0.5 pmol·s-1·mg-1) subjects and, as in the case of complex II (CII) state 3 respiration, were inversely correlated with age [ r = -0.56 (CI), r = -0.7 (CI+II), and r = 0.4 (CII), P < 0.05]. In contrast, state 4 respiration and mitochondria-specific superoxide levels were not different across groups. The respiratory control ratio was greater in young (2.2 ± 0.2, P < 0.05) than middle-aged and old (1.4 ± 0.1 and 1.1 ± 0.1, respectively) subjects and inversely correlated with age ( r = -0.71, P < 0.05). As CS activity was inversely correlated with age ( r = -0.54, P < 0.05), when normalized for mitochondrial content, the age-related differences and relationships with state 3 respiration were ablated. In contrast, mitochondrion-specific state 4 respiration was now lower in young (15 ± 1.4 pmol·s-1·mg-1·U CS-1, P < 0.05) than middle-aged and old (23.4 ± 3.6 and 27.9 ± 3.4 pmol·s-1·mg-1·U CS-1, respectively) subjects and correlated with age ( r = 0.46, P < 0.05). Similarly, superoxide/CS levels were lower in young (0.07 ± 0.01) than old (0.19 ± 0.41) subjects and correlated with age ( r = 0.44, P < 0.05). Therefore, with aging, vascular mitochondrial respiratory function declines, predominantly as a consequence of falling mitochondrial content. However, per mitochondrion, aging likely results in greater mitochondrion-derived oxidative stress, which may contribute to age-related vascular dysfunction. NEW & NOTEWORTHY This study determined, for the first time, that vascular mitochondrial oxidative respiratory capacity, oxidative coupling efficiency, and mitochondrial content fell progressively with advancing age. In terms of single mitochondrion-specific respiration, the age-related differences were completely ablated and the likelihood of free radical production increased progressively with advancing age. This study reveals that vascular mitochondrial respiratory capacity declines with advancing age, as a consequence of falling mitochondrial content, as does oxidative coupling efficiency.

Impact of age on the development of fatigue during large and small muscle mass exercise.

To examine the impact of aging on neuromuscular fatigue following cycling (CYC; large active muscle mass) and single-leg knee-extension (KE; small active muscle mass) exercise, 8 young (25 ± 4 years) and older (72 ± 6 years) participants performed CYC and KE to task failure at a given relative intensity (80% of peak power output). The young also matched CYC and KE workload and duration of the old (iso-work comparison). Peripheral and central fatigue were quantified via pre-/postexercise decreases in quadriceps twitch torque (∆Qtw, electrical femoral nerve stimulation) and voluntary activation (∆VA). Although young performed 77% and 33% more work during CYC and KE, respectively, time to task failure in both modalities was similar to the old (~9.5 min; P > 0.2). The resulting ΔQtw was also similar between groups (CYC ~40%, KE ~55%; P > 0.3); however, ∆VA was, in both modalities, approximately double in the young (CYC ~6%, KE ~9%; P < 0.05). While causing substantial peripheral and central fatigue in both exercise modalities in the old, ∆Qtw in the iso-work comparison was not significant (CYC; P = 0.2), or ~50% lower (KE; P < 0.05) in the young, with no central fatigue in either modality ( P > 0.4). Based on iso-work comparisons, healthy aging impairs fatigue resistance during aerobic exercise. Furthermore, comparisons of fatigue following exercise at a given relative intensity mask the age-related difference observed following exercise performed at the same workload. Finally, although active muscle mass has little influence on the age-related difference in the rate of fatigue at a given relative intensity, it substantially impacts the comparison during exercise at a given absolute intensity.

Group III/IV muscle afferents limit the intramuscular metabolic perturbation during whole body exercise in humans.

KEY POINTS: The purpose of this study was to determine the role of group III/IV muscle afferents in limiting the endurance exercise-induced metabolic perturbation assayed in muscle biopsy samples taken from locomotor muscle. Lumbar intrathecal fentanyl was used to attenuate the central projection of µ-opioid receptor-sensitive locomotor muscle afferents during a 5 km cycling time trial. The findings suggest that the central projection of group III/IV muscle afferent feedback constrains voluntary neural 'drive' to working locomotor muscle and limits the exercise-induced intramuscular metabolic perturbation. Therefore, the CNS might regulate the degree of metabolic perturbation within locomotor muscle and thereby limit peripheral fatigue. It appears that the group III/IV muscle afferents are an important neural link in this regulatory mechanism, which probably serves to protect locomotor muscle from the potentially severe functional impairment as a consequence of severe intramuscular metabolic disturbance. ABSTRACT: To investigate the role of metabo- and mechanosensitive group III/IV muscle afferents in limiting the intramuscular metabolic perturbation during whole body endurance exercise, eight subjects performed 5 km cycling time trials under control conditions (CTRL) and with lumbar intrathecal fentanyl impairing lower limb muscle afferent feedback (FENT). Vastus lateralis muscle biopsies were obtained before and immediately after exercise. Motoneuronal output was estimated through vastus lateralis surface electromyography (EMG). Exercise-induced changes in intramuscular metabolites were determined using liquid and gas chromatography-mass spectrometry. Quadriceps fatigue was quantified by pre- to post-exercise changes in potentiated quadriceps twitch torque (ΔQTsingle ) evoked by electrical femoral nerve stimulation. Although motoneuronal output was 21 ± 12% higher during FENT compared to CTRL (P < 0.05), time to complete the time trial was similar (∼8.8 min). Compared to CTRL, power output during FENT was 10 ± 4% higher in the first half of the time trial, but 11 ± 5% lower in the second half (both P < 0.01). The exercise-induced increase in intramuscular inorganic phosphate, H(+) , adenosine diphosphate, lactate and phosphocreatine depletion was 55 ± 30, 62 ± 18, 129 ± 63, 47 ± 14 (P < 0.001) and 27 ± 14% (P < 0.01) greater in FENT than CTRL. ΔQTsingle was greater following FENT than CTRL (-52 ± 2 vs -31 ± 1%, P < 0.001) and this difference was positively correlated with the difference in inorganic phosphate (r(2)  = 0.79; P < 0.01) and H(+) (r(2)  = 0.92; P < 0.01). In conclusion, during whole body exercise, group III/IV muscle afferents provide feedback to the CNS which, in turn, constrains motoneuronal output to the active skeletal muscle. This regulatory mechanism limits the exercise-induced intramuscular metabolic perturbation, preventing an abnormal homeostatic challenge and excessive peripheral fatigue.

Symmorphosis and skeletal muscle V̇O2 max : in vivo and in vitro measures reveal differing constraints in the exercise-trained and untrained human.

The concept of symmorphosis postulates a matching of structural capacity to functional demand within a defined physiological system, regardless of endurance exercise training status. Whether this concept applies to oxygen (O2 ) supply and demand during maximal skeletal muscle O2 consumption (V̇O2 max ) in humans is unclear. Therefore, in vitro skeletal muscle mitochondrial V̇O2 max (Mito V̇O2 max , mitochondrial respiration of fibres biopsied from vastus lateralis) was compared with in vivo skeletal muscle V̇O2 max during single leg knee extensor exercise (KE V̇O2 max , direct Fick by femoral arterial and venous blood samples and Doppler ultrasound blood flow measurements) and whole-body V̇O2 max during cycling (Body V̇O2 max , indirect calorimetry) in 10 endurance exercise-trained and 10 untrained young males. In untrained subjects, during KE exercise, maximal O2 supply (KE Q̇O2max ) exceeded (462 ± 37 ml kg(-1) min(-1) , P < 0.05) and KE V̇O2 max matched (340 ± 22 ml kg(-1) min(-1) , P > 0.05) Mito V̇O2 max (364 ± 16 ml kg(-1) min(-1) ). Conversely, in trained subjects, both KE Q̇O2max (557 ± 35 ml kg(-1) min(-1) ) and KE V̇O2 max (458 ± 24 ml kg(-1) min(-1) ) fell far short of Mito V̇O2 max (743 ± 35 ml kg(-1) min(-1) , P < 0.05). Although Mito V̇O2 max was related to KE V̇O2 max (r = 0.69, P < 0.05) and Body V̇O2 max (r = 0.91, P < 0.05) in untrained subjects, these variables were entirely unrelated in trained subjects. Therefore, in untrained subjects, V̇O2 max is limited by mitochondrial O2 demand, with evidence of adequate O2 supply, whereas, in trained subjects, an exercise training-induced mitochondrial reserve results in skeletal muscle V̇O2 max being markedly limited by O2 supply. Taken together, these in vivo and in vitro measures reveal clearly differing limitations and excesses at V̇O2 max in untrained and trained humans and challenge the concept of symmorphosis as it applies to O2 supply and demand in humans.

Fatigue diminishes motoneuronal excitability during cycling exercise.

Exercise-induced fatigue influences the excitability of the motor pathway during single-joint isometric contractions. This study sought to investigate the influence of fatigue on corticospinal excitability during cycling exercise. Eight men performed fatiguing constant-load (80% Wpeak; 241 ± 13 W) cycling to exhaustion during which the percent increase in quadriceps electromyography (ΔEMG; vastus lateralis and rectus femoris) was quantified. During a separate trial, subjects performed two brief (∼45 s) nonfatiguing cycling bouts (244 ± 15 and 331 ± 23W) individually chosen to match the ΔEMG across bouts to that observed during fatiguing cycling. Corticospinal excitability during exercise was quantified by transcranial magnetic, electric transmastoid, and femoral nerve stimulation to elicit motor-evoked potentials (MEP), cervicomedullary evoked potentials (CMEP), and M waves in the quadriceps. Peripheral and central fatigue were expressed as pre- to postexercise reductions in quadriceps twitch force (ΔQtw) and voluntary quadriceps activation (ΔVA). Whereas nonfatiguing cycling caused no measureable fatigue, fatiguing cycling resulted in significant peripheral (ΔQtw: 42 ± 6%) and central (ΔVA: 4 ± 1%) fatigue. During nonfatiguing cycling, the area of MEPs and CMEPs, normalized to M waves, similarly increased in the quadriceps (∼40%; P < 0.05). In contrast, there was no change in normalized MEPs or CMEPs during fatiguing cycling. As a consequence, the ratio of MEP to CMEP was unchanged during both trials (P > 0.5). Therefore, although increases in muscle activation promote corticospinal excitability via motoneuronal facilitation during nonfatiguing cycling, this effect is abolished during fatigue. We conclude that the unaltered excitability of the corticospinal pathway from start of intense cycling exercise to exhaustion is, in part, determined by inhibitory influences on spinal motoneurons obscuring the facilitating effects of muscle activation.

Aging alters muscle reflex control of autonomic cardiovascular responses to rhythmic contractions in humans.

We investigated the influence of aging on the group III/IV muscle afferents in the exercise pressor reflex-mediated cardiovascular response to rhythmic exercise. Nine old (OLD; 68 ± 2 yr) and nine young (YNG; 24 ± 2 yr) males performed single-leg knee extensor exercise (15 W, 30 W, 80% max) under control conditions and with lumbar intrathecal fentanyl impairing feedback from group III/IV leg muscle afferents. Mean arterial pressure (MAP), cardiac output, leg blood flow (QL), systemic (SVC) and leg vascular conductance (LVC) were continuously determined. With no hemodynamic effect at rest, fentanyl blockade during exercise attenuated both cardiac output and QL ∼17% in YNG, while the decrease in cardiac output in OLD (∼5%) was significantly smaller with no impact on QL (P = 0.8). Therefore, in the face of similar significant ∼7% reduction in MAP during exercise with fentanyl blockade in both groups, LVC significantly increased ∼11% in OLD, but decreased ∼8% in YNG. The opposing direction of change was reflected in SVC with a significant ∼5% increase in OLD and a ∼12% decrease in YNG. Thus while cardiac output seems to account for the majority of group III/IV-mediated MAP responses in YNG, the impact of neural feedback on the heart may decrease with age and alterations in SVC become more prominent in mediating the similar exercise pressor reflex in OLD. Interestingly, in terms of peripheral hemodynamics, while group III/IV-mediated feedback plays a clear role in increasing LVC during exercise in the YNG, these afferents seem to actually reduce LVC in OLD. These peripheral findings may help explain the limited exercise-induced peripheral vasodilation often associated with aging.

Endurance exercise performance in acute hypoxia is influenced by expiratory flow limitation.

PURPOSE: We sought to determine if expiratory flow limitation influences intensive aerobic exercise performance in mild hypoxia. METHODS: Fourteen trained male cyclists were separated into flow-limited (FL, n = 7) and non-FL (n = 7) groups based on the extent of expiratory flow limitation exhibited during maximal exercise in normoxia. Participants performed two self-paced 5-km cycling time trials, one in normoxic (F IO2 = 0.21) and one in mild hypoxic (F IO2 = 0.17) conditions in a randomized, balanced order with the subjects blinded to composition of the inspirate. Percent change from normoxia to hypoxia in average power output (%ΔP TT) and time to completion (%ΔT TT) were used to assess performance. RESULTS: Hypoxia resulted in a significant decline in estimated arterial O2 saturation and decrements in performance in both groups, although FL had a significantly smaller %ΔP TT (-4.0 ± 0.5 vs. -9.0 ± 1.8 %) and %ΔT TT (1.3 ± 0.3 vs. 3.7 ± 0.9 %) compared to non-FL. At the 5th km of the time trial, minute ventilation did not change from normoxia to hypoxia in FL (3.4 ± 3.1 %) or non-FL (2.3 ± 3.7 %), but only the non-FL reported a significantly increased dyspnea rating in hypoxia compared to normoxia (~9 %). Non-FL athletes did not utilize their ventilatory reserve to defend arterial oxygen saturation in hypoxia, which may have been due to an increased measure of dyspnea in the hypoxic trial. CONCLUSION: FL athletes experience less hypoxia-related aerobic exercise performance impairment as compared to non-FL athletes, despite having less ventilatory reserve.

Low intensity resistance exercise training with blood flow restriction: insight into cardiovascular function, and skeletal muscle hypertrophy in humans.

Attenuated functional exercise capacity in elderly and diseased populations is a common problem, and stems primarily from physical inactivity. Decreased function and exercise capacity can be restored by maintaining muscular strength and mass, which are key factors in an independent and healthy life. Resistance exercise has been used to prevent muscle loss and improve muscular strength and mass. However, the intensities necessary for traditional resistance training to increase muscular strength and mass may be contraindicated for some at risk populations, such as diseased populations and the elderly. Therefore, an alternative exercise modality is required. Recently, blood flow restriction (BFR) with low intensity resistance exercise (LIRE) has been used for such special populations to improve their function and exercise capacity. Although BFR+LIRE has been intensively studied for a decade, a comprehensive review detailing the effects of BFR+LIRE on both skeletal muscle and vascular function is not available. Therefore, the purpose of this review is to discuss previous studies documenting the effects of BFR+LIRE on hormonal and transcriptional factors in muscle hypertrophy and vascular function, including changes in hemodynamics, and endothelial function.