Markus Amann (1,2) and Jerome A Dempsey (2)

1: University of Utah, Department of Internal Medicine, Salt Lake City, UT, USA
2: University of Wisconsin, John Rankin Laboratory of Pulmonary Medicine, Madison, WI, USA

https://doi.org/10.36866/pn.75.13

When oxygen transport from the lungs to the legs is reduced (e.g. at altitude), the muscles utilized to ride a bicycle (locomotor muscles) fatigue faster and a person’s cycling time to exhaustion – against a fixed resistance – is significantly shorter compared with sea level. On the other hand, when oxygen transport to the locomotor muscles is increased (e.g. via blood doping or breathing 100% oxygen), the rate of fatigue of the working muscles is a lot slower and the person’s time to exhaustion is substantially longer compared with sea level. Interestingly, at exhaustion (subject is not able to continue exercise against the same fixed resistance), whether it is reached during cycling at sea level, or on the top of a 3000 m mountain, or while breathing 100% oxygen, the level of peripheral locomotor muscle fatigue – and the associated intramuscular milieu determining this level – is identical (Hogan et al. 1999; Amann et al. 2006, 2007)! Also interesting, when the fatigued muscle of a human, who just reached the point where he is unable to voluntarily continue the exercise against a fixed resistance (i.e. exhaustion), is artificially innervated – or ‘driven’ – via transcutaneous electric motor nerve stimulation, the muscle is able to continue the exercise (Löscher et al. 1996). These observations suggest that humans stop exercising once a certain level of locomotor muscle fatigue is reached and that, by stopping the exercise at this particular level of peripheral fatigue, a certain degree of muscular functional reserve is preserved.

The situation is somewhat similar with time trial exercise. During a time trial performed on a bicycle ergometer, subjects cover a set distance as fast as possible and are able to adjust power output (i.e. speed) by switching gears – just like on a real bike. We recently observed that during a 5 km cycling time trial performed at simulated altitude (locomotor muscles fatigue faster), central neural drive and consequently power output/speed is down-regulated, whereas during the same time trial performed while breathing 100% oxygen (locomotor muscles fatigue slower), central neural drive and power output/speed is up-regulated compared with sea level. Astonishingly, despite the different performances achieved in these three time trials (fastest with 100% oxygen and slowest at altitude), the magnitude of locomotor muscle fatigue at end-exercise was identical (Amann et al. 2006). Considering this, it appears that the down-regulation of central neural drive and power output at altitude ensured that the rate of development of locomotor muscle fatigue was slowed and end-exercise peripheral fatigue prevented from exceeding a certain limit. On the other hand, the up-regulation of central neural drive and power output while breathing 100% oxygen accelerated the rate of development of peripheral locomotor muscle fatigue; however, end-exercise locomotor muscle fatigue was still limited to that ‘threshold’. It seems like the brain, consciously and/or subconsciously, senses peripheral fatigue and alterations in the associated intramuscular metabolic milieu (and/or it’s rate of change) – presumably via the cortical projection of metabosensitive small-diameter muscle afferents (group III/IV) – and regulates central neural drive to restrict the development of locomotor muscle fatigue to a certain threshold that varies between individuals. Based on these observations, we formulated a hypothesis claiming that locomotor muscle afferent feedback exerts an inhibitory influence on the determination of central motor drive during high-intensity, whole-body endurance exercise and restricts the development of peripheral locomotor muscle fatigue to an individual critical threshold (Fig. 1) (Amann et al. 2006).

To experimentally evaluate whether ascending sensory pathways affect the magnitude of central motor drive, we recently blocked locomotor muscle afferents during a 5 km cycling time trial via lumbar epidural anaesthesia (lidocaine). In the absence of neural feedback from the legs, central motor drive was substantially higher compared with the control race performed with an intact regulatory feedback mechanism as illustrated in Fig. 1. However, since local anaesthetics also reduce efferent nerve traffic between the injection site and the end-organ, less ‘push’ arrived at the locomotor muscles and time trial performance was expectedly reduced (i.e. longer time to finish the race) (Amann et al. 2008).

To circumvent this problem and to adequately determine the effect of locomotor muscle afferents on exercise performance and the development of peripheral fatigue, we repeated the study and used placebo vs fentanyl, an opioid analgesic, to selectively block the activity in ascending sensory pathways without affecting motor nerve activity (Amann et al. 2009). We clearly emphasize that we only blocked opioid-mediated afferents; other ascending pathways were unaffected by this intervention. Similar to the first study, blocking somatosensory feedback from the legs released a centrally mediated ‘brake’ on central motor drive but this time, exercise performance was substantially improved over the first half of the race. Evidently, the missing neural feedback tricked the athletes to overestimate their work capacity and they ‘chose’ a power output which exceeded their aerobic capacity and quickly resulted in severe muscle acidosis, leading to a curtailed power output during the second half of the race – despite continuing high central motor drive. Although the overall time trial performance was similar between the trials, the induced acidosis in the fentanyl race accelerated the rate of development of locomotor muscle fatigue – but this was, due to the missing neural feedback, ‘unseen’ by the brain.

Therefore, the brain ‘allowed’ or ‘tolerated’ the exercise-induced development of locomotor muscle fatigue significantly beyond levels as observed following the placebo race, i.e. with intact neural feedback system. All athletes substantially exceeded their critical threshold which resulted in severely impaired locomotor muscle functions and acute ambulatory problems (Amann et al. 2009).

In conclusion, our results suggest that neural feedback from the working and fatiguing muscles exerts inhibitory influences on the determination of the magnitude of central motor drive during high-intensity endurance exercise. Furthermore, it appears that neural influence of exercising muscles on the brain causes a restriction of the exercise-induced development of peripheral muscle fatigue to an individual’s critical threshold – presumably to prevent severely impaired muscle functions and to preserve a functional muscle reserve following exhaustion induced via whole-body endurance exercise. Finally, we propose that somatosensory feedback is necessary to match/adjust central motor drive to the metabolic milieu of the working muscles to avoid acidosis and guarantee optimal exercise performance.

References

Amann M & Dempsey JA (2009). Ensemble input of group III/IV muscle afferents to CNS: a limiting factor of central motor drive during endurance exercise from normoxia to moderate hypoxia. Adv Exp Med Biol (in press).

Amann M, Eldridge MW, Lovering AT, Stickland MK, Pegelow DF & Dempsey JA (2006). Arterial oxygenation influences central motor output and exercise performance via effects on peripheral locomotor muscle fatigue. J Physiol 575, 937–952.

Amann M, Proctor LT, Sebranek JJ, Eldridge MW, Pegelow DF & Dempsey JA (2008). Somatosensory feedback from the limbs exerts inhibitory influences on central neural drive during whole body endurance exercise. J Appl Physiol 105, 1714–1724.

Amann M, Proctor LT, Sebranek JJ, Pegelow DF & Dempsey JA (2009). Opioid-mediated muscle afferents inhibit central motor drive and limit peripheral muscle fatigue development in humans. J Physiol 587, 271–283.

Amann M, Romer LM, Subudhi AW, Pegelow DF & Dempsey JA (2007). Severity of arterial hypoxaemia affects the relative contributions of peripheral muscle fatigue to exercise performance in healthy humans. J Physiol 581, 389–403.

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