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.
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 (r2 = 0.79; P < 0.01) and H+ (r2 = 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.
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.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract Group III and IV muscle afferents originating in exercising limb muscle play a significant role in the development of fatigue during exercise in humans. Feedback from these sensory neurons ...to the central nervous system (CNS) reflexively increases ventilation and central (cardiac output) and peripheral (limb blood flow) hemodynamic responses during exercise and thereby assures adequate muscle blood flow and O2 delivery. This response depicts a key factor in minimizing the rate of development of peripheral fatigue and in optimizing aerobic exercise capacity. On the other hand, the central projection of group III/IV muscle afferents impairs performance and limits the exercising human via its diminishing effect on the output from spinal motoneurons which decreases voluntary muscle activation (i.e. facilitates central fatigue). Accumulating evidence from recent animal studies suggests the existence of two subtypes of group III/IV muscle afferents. While one subtype only responds to physiological and innocuous levels of endogenous intramuscular metabolites (lactate, ATP, protons) associated with ‘normal’, predominantly aerobic exercise, the other subtype only responds to higher and concurrently noxious levels of metabolites present in muscle during ischemic contractions or following, for example, hypertonic saline infusions. This review discusses the mechanisms through which group III/IV muscle afferent feedback mediates both central and peripheral fatigue in exercising humans. We also briefly summarize the accumulating evidence from recent animal and human studies documenting the existence of two subtypes of group III/IV muscle afferents and the relevance of this discovery to the interpretation of previous work and the design of future studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Highlights • We investigated the role of sensory muscle feedback on the development of central fatigue and their influence on corticospinal excitability during locomotor exercise. • During ...non-fatiguing exercise, group III/IV muscle afferents disfacilitate motoneurons, but enhance the excitability of motor cortical output cells. • During fatiguing exercise, group III/IV muscle afferents promote central fatigue, and disfacilitate motor cortical excitability without affecting motoneurons.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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% W
; 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 (ΔQ
) and voluntary quadriceps activation (ΔVA). Whereas nonfatiguing cycling caused no measureable fatigue, fatiguing cycling resulted in significant peripheral (ΔQ
: 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.
The normal agedependent increase in pulmonary artery pressure, coupled with an augmented pressure response during exercise and/or ascent to high altitude, may predispose preterm individuals to PH as ...adults....the need for identifying the long-term consequences of prematurity, including development of PH, remains important....one potential explanation for the differences between BPD and PRE is that impaired leftventricular relaxation leading to elevated leftatrial pressures in PRE, but not BPD, may have contributed to the greater pulmonary pressures we measured in PRE during exercise.Limitations of this study include our "relatively healthy" subject population, which may introduce bias toward including subjects with the ability and desire to exercise....the pulmonary vascular responses at rest and during exercise could be further impaired in those individuals with worse symptoms resulting from preterm birth.Author Contributions: A.T.L. conceptualized and designed the study and is the guarantor of the content of the manuscript, including the data and analysis; S.S.L., J.E.E., K.M.B., R.D.G., and I.M.G. contributed to the conception and design of the study; S.S.L., A.T.L., J.E.E., R.D.G., K.M.B., T.S.M., J.W.D., and I.M.G. assisted with data collection; R.D.G. performed all pulmonary artery pressure measurements; S.S.L., J.E.E., K.M.B., T.S.M., J.W.D., I.M.G., and A.T.L. contributed to the analysis and interpretation of data; J.E.E., T.S.M., and J.W.D. prepared figures; S.S.L. and A.T.L. drafted the initial manuscript; S.S.L., J.E.E., K.M.B., T.S.M., R.D.G., J.W.D., I.M.G., and A.T.L. reviewed, revised, and approved the final manuscript as submitted; and I.M.G. reviewed all medical records and confirmed the gestational age/characteristics of all subjects.
Adults with a history of very preterm birth (<32 wk gestational age; PRET) have reduced lung function and significantly lower lung diffusion capacity for carbon monoxide (DLCO) relative to ...individuals born at term (CONT). Low DLCO may predispose PRET to diffusion limitation during exercise, particularly while breathing hypoxic gas because of a reduced O2 driving gradient and pulmonary capillary transit time. We hypothesized that PRET would have significantly worse pulmonary gas exchange efficiency i.e., increased alveolar-to-arterial Po2 difference (AaDO2) during exercise breathing room air or hypoxic gas (FiO2 = 0.12) compared with CONT. To test this hypothesis, we compared the AaDO2 in PRET (n = 13) with a clinically mild reduction in DLCO (72 ± 7% of predicted) and CONT (n = 14) with normal DLCO (105 ± 10% of predicted) pre- and during exercise breathing room air and hypoxic gas. Measurements of temperature-corrected arterial blood gases, and direct measure of O2 saturation (SaO2), were made prior to and during exercise at 25, 50, and 75% of peak oxygen consumption (V̇o2peak) while breathing room air and hypoxic gas. In addition to DLCO, pulmonary function and exercise capacity were significantly less in PRET. Despite PRET having low DLCO, no differences were observed in the AaDO2 or SaO2 pre- or during exercise breathing room air or hypoxic gas compared with CONT. Although our findings were unexpected, we conclude that reduced pulmonary function and low DLCO resulting from very preterm birth does not cause a measureable reduction in pulmonary gas exchange efficiency.
New Findings
What is the central question of this study?
Do individuals with a patent foramen ovale (PFO+) have a lower lung transfer factor for carbon monoxide than those without (PFO−)?
What is the ...main finding and its importance?
We found a lower rate constant for carbon monoxide uptake in PFO+ compared with PFO− women, which was physiologically relevant (≥0.5 z‐score difference), but not for PFO+ versus PFO− men. This suggests that factors independent of the PFO are responsible for our findings, possibly inherent structural differences in the lung.
The transfer factor of the lung for carbon monoxide (TLCO) measure assumes that all cardiac output flows through the pulmonary circuit. However, right‐to‐left blood flow through a shunt can result in a lower transfer factor than predicted. A patent foramen ovale (PFO) is a potential source of right‐to‐left shunt that is present in ∼35% of the population, but the effect of PFO on TLCO is unknown. We sought to determine the effect of PFO on the TLCO. We conducted a retrospective analysis of TLCO data from 239 (101 women) participants. Anthropometrics and lung function, including spirometry, plethysmography and TLCO, were compiled from our previously published work. Women, but not men, with a PFO had a significantly lower TLCO and rate constant for carbon monoxide uptake (KCO) (percentage of predicted and z‐score) than women without a PFO. Women and men with a PFO had normal alveolar volumes that did not differ from those without a PFO. Correcting the data for haemoglobin in a subset of subjects did not change the results (n = 58; 25 women). The lower KCO in women with versus without a PFO was physiologically relevant (≥0.5 z‐score difference). There was no effect of PFO in men. This suggests that factors independent of the PFO are responsible for our findings, possibly inherent structural differences in the lung.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Adults born very to extremely preterm, with or without bronchopulmonary dysplasia (BPD), have obstructive lung disease, but it is unknown whether this results in respiratory limitations, such as ...mechanical constraints to Vt expansion during exercise leading to intolerable dyspnea and reduced exercise tolerance, as it does in patients with chronic obstructive pulmonary disease.
To test the hypothesis that adult survivors of preterm birth (≤32 wk gestational age) with (n = 20) and without BPD (n = 15) with reduced exercise capacity demonstrate clinically important respiratory limitations at near-maximal exercise compared with full-term control subjects (n = 20).
Detailed ventilatory and sensory measurements were made before and during exercise on all patients in the three study groups.
During exercise at 90% of peak Formula: see texto2 (Formula: see texto2peak), inspiratory reserve volume decreased to ∼0.5 L in all groups, but this occurred at significantly lower absolute workloads and Formula: see texte in ex-preterm subjects with and without BPD compared with full-term control subjects. Severe dyspnea was present and similar at comparable Formula: see texte between all groups, but leg discomfort at comparable workloads was greater in ex-preterm subjects with and without BPD compared with control subjects. At 50 to 90% of Formula: see texto2peak, exercise-induced expiratory flow limitation was significantly greater in ex-preterm subjects with BPD compared with ex-preterm subjects without BPD and control subjects. The degree of expiratory flow limitation in ex-preterm subjects with and without BPD was significantly related to neonatal O2 therapy duration.
Severe dyspnea and leg discomfort associated with critical constraints on Vt expansion may lead to reduced exercise tolerance in adults born very or extremely preterm, whether or not their birth was complicated by BPD and despite differences in expiratory flow limitation. In this regard, adults born very or extremely preterm have respiratory limitations to exercise similar to patients with chronic obstructive pulmonary disease.
Mean pulmonary arterial pressure (Ppa) during exercise is significantly higher in individuals aged ≥50 yr compared with their younger counterparts, but the reasons for this are unknown. Blood flow ...through intrapulmonary arteriovenous anastomoses (IPAVA) can be detected during exercise or while breathing hypoxic gas mixtures using saline contrast echocardiography in almost all healthy young individuals. It has been previously hypothesized that a lower degree of exercise-induced blood flow through IPAVA is associated with high Ppa during exercise. This association may suggest that individuals who are known to have high Ppa during exercise, such as those ≥50 yr of age, may have lower blood flow through IPAVA, but the presence and degree of exercise-induced blood flow through IPAVA has not been specifically studied in older populations. Using transthoracic saline contrast echocardiography, we investigated the potential effects of age on exercise-induced blood flow through IPAVA in a cross-section of subjects aged 19-72 yr. To verify our findings, we assessed the effects of age on hypoxia-induced blood flow through IPAVA. Age groups were ≤41 yr (younger, n = 16) and ≥50 yr (older, n = 14). Qualitatively measured exercise- and hypoxia-induced blood flow through IPAVA was significantly lower in older individuals compared with younger controls. Older individuals also had significantly higher pulmonary arterial systolic pressure and total pulmonary resistance (TPR) during exercise. Low blood flow through IPAVA was independently associated with high TPR. The reasons for the age-related decrease in blood flow through IPAVA are unknown.
Cardiopulmonary function is reduced in adults born very preterm, but it is unknown if this results in reduced pulmonary gas exchange efficiency during exercise and, consequently, leads to reduced ...aerobic capacity in subjects with and without bronchopulmonary dysplasia (BPD). We hypothesized that an excessively large alveolar to arterial oxygen difference (AaDO2) and resulting exercise-induced arterial hypoxemia (EIAH) would contribute to reduced aerobic fitness in adults born very preterm with and without BPD. Measurements of pulmonary function, lung volumes and diffusion capacity for carbon monoxide (DLco) were made at rest. Measurements of maximal oxygen consumption, peak workload, temperature- and tonometry-corrected arterial blood gases, and direct measure of hemoglobin saturation with oxygen (SaO2) were made preexercise and during cycle ergometer exercise in ex-preterm subjects ≤32-wk gestational age, with BPD (n = 12), without BPD (PRE; n = 12), and full term controls (CONT; n = 12) breathing room air. Both BPD and PRE had reduced pulmonary function and reduced DLco compared with CONT. The AaDO2 was not significantly different between groups, and there was no evidence of EIAH (SaO2 < 95% and/or AaDO2 ≥ 40 Torr) in any subject group preexercise or at any workload. Arterial O2 content was not significantly different between the groups preexercise or during exercise. However, peak power output was decreased in BPD and PRE subjects compared with CONT. We conclude that EIAH in adult subjects born very preterm with and without BPD does not likely contribute to the reduction in aerobic exercise capacity observed in these subjects.
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