Key pointsr 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.r 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.r 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.r 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 ( QT single ) 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 (ß8.8 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. QT single 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.

Objective To investigate the influence of group III/IV muscle afferents on the development of central fatigue and corticospinal excitability during exercise. Methods Fourteen males performed cycling-exercise both under control-conditions (CTRL) and with lumbar intrathecal fentanyl (FENT) impairing feedback from leg muscle afferents. Transcranial magnetic- and cervicomedullary stimulation was used to monitor cortical versus spinal excitability. Results While fentanyl-blockade during non-fatiguing cycling had no effect on motor-evoked potentials (MEPs), cervicomedullary-evoked motor potentials (CMEPs) were 13 ± 3% higher (P < 0.05), resulting in a decrease in MEP/CMEP (P < 0.05). Although the pre- to post-exercise reduction in resting twitch was greater in FENT vs. CTRL (−53 ± 3% vs. −39 ± 3%; P < 0.01), the reduction in voluntary muscle activation was smaller (−2 ± 2% vs. −10 ± 2%; P < 0.05). Compared to the start of fatiguing exercise, MEPs and CMEPs were unchanged at exhaustion in CTRL. In contrast, MEPs and MEP/CMEP increased 13 ± 3% and 25 ± 6% in FENT (P < 0.05). Conclusion During non-fatiguing exercise, group III/IV muscle afferents disfacilitate, or inhibit, spinal motoneurons and facilitate motor cortical cells. In contrast, during exhaustive exercise, group III/IV muscle afferents disfacilitate/inhibit the motor cortex and promote central fatigue. Significance Group III/IV muscle afferents influence corticospinal excitability and central fatigue during whole-body exercise in humans.

Key pointsr We aimed to elucidate the role of group III/IV locomotor muscle afferents in the development of central fatigue and the responsiveness of the corticospinal tract in relation to an unexercised arm muscle.r Intrathecal fentanyl, a μ-opioid receptor agonist, was employed to attenuate afferent feedback from the leg muscles during intense cycling exercise characterized by either no or severe peripheral locomotor muscle fatigue.r In the absence of locomotor muscle fatigue, group III/IV-mediated leg afferent feedback facilitates the responsiveness of the motor pathway to upper limb flexor muscles.r By contrast, in the presence of leg fatigue, group III/IV locomotor muscle afferents facilitate supraspinal fatigue in a remote muscle not involved in the exercise and disfacilitate the responsiveness of associated corticospinal projections. AbstractWe investigated the influence of group III/IV lower limb muscle afferents on the development of supraspinal fatigue and the responsiveness of corticospinal projections to an arm muscle. Eight males performed constant-load leg cycling exercise (80% peak power output) for 30 s (non-fatiguing) and to exhaustion (ß9 min; fatiguing) both under control conditions and with lumbar intrathecal fentanyl impairing feedback from μ-opioid receptor-sensitive lower limb muscle afferents. Voluntary activation (VA) of elbow flexors was assessed via transcranial magnetic stimulation (TMS) during maximum voluntary contraction (MVC) and corticospinal responsiveness was monitored via TMS-evoked potentials (MEPs) during a 25% MVC. Accompanied by a significant 5 ± 1% reduction in VA from pre-to post-exercise, elbow flexor MVC progressively decreased during the fatiguing trial (P < 0.05). By contrast, with attenuated feedback from locomotor muscle afferents, MVC and VA remained unchanged during fatiguing exercise (P > 0.3). MEPs decreased by 36 ± 6% (P < 0.05) from the start of exercise to exhaustion under control conditions, but this reduction was prevented with fentanyl blockade. Furthermore, fentanyl blockade prevented the significant increase in elbow flexor MEP observed from rest to non-fatiguing exercise under control conditions and resulted in a 14% lower corticospinal responsiveness during this short bout (P < 0.05). Taken together, in the absence of locomotor muscle fatigue, group III/IV-mediated leg muscle afferents facilitate responsiveness of the motor pathway to upper limb flexor muscles. By contrast, in the presence of cycling-induced leg fatigue, group III/IV locomotor muscle afferents facilitate supraspinal fatigue in remote muscle not involved in the exercise and disfacilitate, or inhibit, the responsiveness of corticospinal projections to upper limb muscles.

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 ischaemic 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 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 for the interpretation of previous work and the design of future studies.

Key pointsr The concept of symmorphosis predicts that the capacity of each step of the oxygen cascade is attuned to the task demanded of it during aerobic exercise at maximal rates of oxygen consumption (V O 2 max ) such that no single process is limiting or in excess atV O 2 max .r The present study challenges the applicability of this concept to humans by revealing clear, albeit very different, limitations and excesses in oxygen supply and consumption among untrained and endurance-trained humans.r Among untrained individuals,V O 2 max is limited by the capacity of the mitochondria to consume oxygen, despite an excess of oxygen supply, whereas, among trained individuals,V O 2 max is limited by the supply of oxygen to the mitochondria, despite an excess of mitochondrial respiratory capacity. AbstractThe 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 (O 2 ) supply and demand during maximal skeletal muscle O 2 consumption (V O 2 max ) in humans is unclear. Therefore, in vitro skeletal muscle mitochondrialV O 2 max ( MitoVO 2 max , mitochondrial respiration of fibres biopsied from vastus lateralis) was compared with in vivo skeletal muscleV O 2 max during single leg knee extensor exercise ( KEVO 2 max , direct Fick by femoral arterial and venous blood samples and Doppler ultrasound blood flow measurements) and whole-bodyV O 2 max during cycling ( BodyVO 2 max , indirect calorimetry) in 10 endurance exercise-trained and 10 untrained young males. In untrained subjects, during KE exercise, maximal O 2 supply ( KEQ O 2max ) exceeded (462 ± 37 ml kg −1 min −1 , P < 0.05) and KEVO 2 max matched (340 ± 22 ml kg −1 min −1 , P > 0.05) MitoVO 2 max (364 ± 16 ml kg −1 min −1 ). Conversely, in trained subjects, both KEQ O 2max (557 ± 35 ml kg −1 min −1 ) and KEVO 2 max (458 ± 24 ml kg −1 min −1 ) fell far short of MitoVO 2 max (743 ± 35 ml kg −1 min −1 , P < 0.05). Although MitoVO 2 max was related to KEVO 2 max (r = 0.69, P < 0.05) and BodyVO 2 max (r = 0.91, P < 0.05) in untrained subjects, these variables were entirely unrelated in trained subjects. Therefore, in untrained subjects,V O 2 max is limited by mitochondrial O 2 demand, with evidence of adequate O 2 supply, whereas, in trained subjects, an exercise training-induced mitochondrial reserve results in skeletal muscleV untrained and trained humans and challenge the concept of symmorphosis as it applies to O 2 supply and demand in humans. Abbreviations BIOPS, biopsy preservation fluid; Body, whole-body; KE, knee extensor; Mito, mitochondrial;Q O 2max , maximum specific oxygen uptake rate;V O2max , maximal oxygen uptake; WR max , maximum work rate.

We investigated the influence of group III/IV muscle afferents in determining corticospinal excitability during cycling exercise and focused on GABA 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 GABA intracortical interneurons.

We investigated the role of exercise intensity and associated central motor drive in determining corticomotoneuronal excitability. Ten participants performed a series of nonfatiguing (3 s) isometric single-leg knee extensions (ISO; 10-100% of maximal voluntary contractions, MVC) and cycling bouts (30-160% peak aerobic capacity, W peak). At various exercise intensities, electrical potentials were evoked in the vastus lateralis (VL) and rectus femoris (RF) via transcranial magnetic stimulation (motor-evoked potentials, MEP), and electrical stimulation of both the cervicomedullary junction (cervicomedullary evoked potentials, CMEP) and the femoral nerve (maximal M-waves, M max). Whereas M max remained unchanged in both muscles (P > 0.40), voluntary electromyographic activity (EMG) increased in an exercise intensity-dependent manner for ISO and cycling exercise in VL and RF (both P < 0.001). During ISO exercise, MEPs and CMEPs progressively increased in VL and RF until a plateau was reached at ∼ 75% MVC; further increases in contraction intensity did not cause additional changes (P > 0.35). During cycling exercise, VL-MEPs and CMEPs progressively increased by ∼ 65% until a plateau was reached at W peak. In contrast, RF MEPs and CMEPs progressively increased by ∼ 110% throughout the tested cycling intensities without the occurrence of a plateau. Furthermore, alterations in EMG below the plateau influenced corticomotoneuronal excitability similarly between exercise modalities. In both exercise modalities, the MEP-to-CMEP ratio did not change with exercise intensity (P > 0.22). In conclusion, increases in exercise intensity and EMG facilitates the corticomotoneuronal pathway similarly in isometric knee extension and locomotor exercise until a plateau occurs at a submaximal exercise intensity. This facilitation appears to be primarily mediated by increases in excitability of the motoneuron pool.

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.