Point: Afferent Feedback from Fatigued Locomotor Muscles is an Important Determinant of Endurance Exercise Performance

We thank Dr. Marcora for suggesting this discussion in which we advance the view that neural feedback from fatiguing limb muscles is a key determinant of endurance exercise performance. Previous findings suggest that muscle afferents affect endurance performance via two routes. First, neural feedback might facilitate peak exercise performance by preventing premature fatigue through optimizing muscle O₂ delivery via its influence on circulation and pulmonary ventilation. And second, neural feedback might limit exercise performance via restricting central motor output (CMO) to the locomotor muscles at both reflex and cognitive levels.

Some basics: During sustained exercise, metaboreceptive/nociceptive afferents (group III/IV) originating in working limb muscles are stimulated by intramuscular metabolic byproducts (2, 23) and increase, in parallel to accumulating metabolites, their ensemble input to the CNS. This central projection reflexively augments circulation (i.e., exercise pressor reflex) and ventilation (21), and progressively reduces CMO/voluntary muscle activation (“central fatigue” increases) (16). We explicitly emphasize that muscle afferents are only one of various determinants of the cardiorespiratory response and CMO during exercise.

Cardiovascular and Ventilatory Response

Exercise challenges the circulation by a potential enormous reduction in total peripheral resistance and increases the organism's O₂ consumption and CO₂ production. Yet blood pressure and alveolar PO₂ increase and arterial PO₂ remains, in most healthy individuals, close to resting values. Krogh and Lindhard (22) first approached this phenomenon and conducted exercise evoked by electrical muscle stimulation to find similar values for heart rate, blood pressure, and ventilation compared to the same exercise performed voluntarily. It was concluded that the regulation of these cardiorespiratory variables is predominantly influenced by exercising limb muscles. This notion was later affirmed by Alam and Smirk (3) who found that blood pressure, and less clearly also heart rate, maintains following exercise for as long as the previously working muscle is kept ischemic, i.e., trapping intramuscular metaboreceptor stimuli.

In contrast, when electrically induced exercise is carried out in spinal-blocked healthy humans (30) and in paraplegic patients (11), or in spinal cord-transected (or -blocked) animals (18, 20), the circulatory and ventilatory response to exercise is significantly deteriorated, which results in reduced convective O₂ transport. Similarly, the cardiovascular response is, compared with control conditions, substantially reduced when voluntary exercise is performed in the absence of afferent feedback from the working limbs (pharmacological spinal block) (14, 30).

Muscle afferents also significantly determine the resetting of the arterial baroreflex with exercise (29), a necessary adjustment to ensure optimized and sustained perfusion pressure to exercising muscles (3) and brain (19). Consequently, when muscle afferents are pharmacologically blocked during exercise, subjects are vulnerable to orthostatic intolerance, which is even more evident in tetraplegic patients (11). Numerous other studies have clearly demonstrated the crucial involvement of muscle afferents in the circulatory and respiratory regulation during exercise (1, 10, 21). Taken together, sensory input from working muscles depicts a prerequisite for achieving individual “optimal” endurance performance since controlled perfusion and peripheral O₂ delivery set a limit for how much work a muscle can perform. Indeed, running time to exhaustion in group IV-deficient rats is substantially shorter compared with rats exercising with an intact sensory feedback system (12). Furthermore, humans competitively bicycling with reduced afferent feedback (spinal anesthesia) rapidly develop severe metabolic/respiratory acidosis, which abnormally deteriorates their muscles ability to respond to neural drive (8).

Central Motor Output

During muscle contractions against a fixed load, afferent feedback increases in parallel with intramuscular metabolites and peripheral fatigue, CMO progressively decreases, and the subject eventually reaches task failure, i.e., exercise cannot be continued voluntarily at this intensity. However, if the muscle is then stimulated electrically, exercise continues effortlessly and peripheral fatigue further increases beyond the level observed at task failure (24, 25). These observations indicate that a muscle's performance is more curtailed than its actual ability to generate force/power and that exercise ceases due to CMO withdrawal rather than the inability of the muscle to contract.

It is well documented that CNS projection of group III/IV muscle afferents significantly determines the reduction in CMO and hence muscle performance (16). For example, when the firing frequency, and thus the CNS projection, of these afferents is kept elevated via occluding blood flow to the fatigued muscle at end exercise, CMO and force output remain low and only begin to recover after circulation is restored, i.e., metaboreceptor stimuli decrease (17).

These findings from isolated muscle studies suggest that the CNS monitors the peripheral state of working limb muscles via sensory feedback and uses this information to adjust the muscles' neural activation perhaps with the purpose of shielding a muscular reserve capacity. Alternatively, muscle afferents might progressively impair the willingness and/or ability to sustain a high CMO, and thus a high exercise intensity/performance, to avoid the development of peripheral fatigue beyond a “sensory tolerance limit” past which exercise might become “painful” (16). As stated by Gandevia (16), the reduction in CMO, as affected by inhibitory afferent feedback, is “at the expense of truly maximal performance.” This regulatory mechanism has been suggested to also limit whole body endurance performance (16).

Accumulating evidence indicates that the development of peripheral locomotor muscle fatigue during whole body endurance exercise is also confined to an individual “critical threshold” (or a critical rate of development), and associated sensory tolerance limit, which is voluntarily never exceeded (4–6, 9, 13, 15, 26–28). This means that, in case of constant-workload trials, exercise is either deliberately terminated, or CMO becomes insufficient to maintain the task, once peripheral fatigue has reached this, presumably task-dependent, critical threshold. For example, following electrostimulation of the quadriceps of healthy humans to induce significant peripheral fatigue, constant-workload bicycling time to task failure was substantially shorter as compared to the identical bicycle exercise but performed without preinduced quadriceps fatigue. However, at task failure in both trials, quadriceps fatigue and perception of leg fatigue were identical (15). These experiments confirm an earlier prefatigue study using time trial, instead of constant-load, bicycling. During the time trial performed with significant preinduced quadriceps fatigue, CMO was significantly lower and time-to-completion longer compared with the same time trial performed without preexisting fatigue. However, end-exercise quadriceps fatigue and perception of leg fatigue were identical in both time trials, insinuating that CMO was adjusted according to the peripheral state of the locomotor muscles (4).

The most compelling evidence for muscle afferents limiting CMO and peripheral fatigue during endurance exercise comes from two recent human studies. When the central projection of lower limb muscle afferents was pharmacologically blocked (L₃/L₄) during 5-km cycling time trial, CMO was significantly increased compared with the placebo race (7, 8) and the subjects substantially exceeded their critical threshold of peripheral fatigue (8). Compared with the placebo race, exercise performance was 4% faster during the first half of the time trial but, due to missing feedback leading to metabolic/respiratory acidosis (see above), 4% worse during the second half, despite continuous high CMO (8). Blocking muscle afferents apparently released a centrally mediated “brake” on CMO and the CNS “tolerated” locomotor muscle fatigue to develop ∼44% beyond the degree observed following the placebo trial. This extreme level of peripheral fatigue was associated with ambulatory problems (8).

In conclusion, during strenuous endurance exercise, somatosensory feedback from locomotor muscles appears to limit performance by imposing inhibitory influences on CMO with the purpose of restricting the development of peripheral locomotor muscle fatigue to an individual “fatigue threshold.”

Given the role of a “double-edged sword,” a clear evaluation of positive vs. negative effects of muscle afferents on endurance performance is an unenviable task. However, one thing is for sure: locomotor muscle afferents significantly determine endurance exercise performance one way or another.