Extracellular K⁺ accumulation: a physiological framework for fatigue during intense exercise

What are the causes of fatigue? Elevated lactate or lowered pH or failure of calcium release, I hear you say. Well yes, but under what conditions? The work of Nielsen et al. (2004) in this issue of The Journal of Physiology provides experimental evidence which sheds light on the mechanism of fatigue development during intense exercise.

A characterized ionic cross-membrane movement which accompanies exercise is the release of K⁺, facilitated by voltage-dependent K⁺ and ATP-dependent K⁺ (K_ATP) channels, from intracellular muscle stores to the interstitium. Consequently, fatigue ensues when the concentration of K⁺ in the interstitium is high enough (>8 mmol l⁻¹), to impair membrane excitability (Fitts, 1994). The complexity of the process is increased by the presence of Na⁺-K⁺-ATPase pumps on the muscle membrane, which facilitate the re-uptake of K⁺ into the intracellular space by extruding Na⁺. Extracellular K⁺ is also transferred to the blood vessels adjacent to the interstitium which serve as another intracellular K⁺ sink (McKenna et al. 1997). However, the coordination of these processes during exercise and their adaptation to high-intensity exercise is unclear. What is known is that, following high-intensity exercise training, fatigue is delayed. It is proposed that the delay in fatigue corresponds to a decreased accumulation of K⁺ in the interstitium. This delay may be caused by: (1) a decreased movement of K⁺ from the intracellular muscle stores via K_ATP channels; and/or (2) increased uptake of K⁺ into the muscle by increased Na⁺-K⁺-ATPase activity; and/or (3) increased removal of K⁺ into the blood stream. Some of these processes are known to respond to high-intensity training, e.g. elevated Na⁺-K⁺-ATPase. The interaction of these processes in conjunction with K⁺ kinetics (the time course of changes in K⁺ concentration) is unknown.

The aims of the work of Nielsen and colleagues were firstly to study K⁺ kinetics following high-intensity training, and secondly to investigate the density of Na⁺-K⁺-ATPase subunits and K_ATP channels. The K⁺ kinetics were studied using a combination of arterial/venous catheters, temperature thermistors and, most importantly, microdialysis probes. These probes, which were inserted 30 mm into the vastus lateralis, consist of two concentric tubes. The outer tube is semipermeable and is closed at the distal end. The inner tube is then perfused with an isotonic Ringer acetate solution, which flows back through the outer tube. During the passage through the outer tube, the solution equilibrates with the ions in the interstitium and is collected for analysis. Using a series of five probes the concentration of K⁺ in the interstitium could be calculated (Juel et al. 2000a).

At the conclusion of 7 weeks of high-intensity training the time to fatigue was 28% greater in the trained leg (TL) compared to the control leg (CL), consistent with an increase in performance. But was this facilitated by a delayed increase in interstitial K⁺ as hypothesized? Increased interstitial K⁺ was observed in the CL, compared to the TL, across all submaximal exercise intensities (30, 60 and 70 W) and the increase was also shown to be faster for exercise at 30 W. Most importantly there was no significant difference in the interstitial K⁺ concentration (∼10 mmol l⁻¹) at the time of fatigue in both conditions, yet the total time to reach this concentration was greater in the TL. The femoral venous and arterial K⁺ concentrations mimicked the results from the interstitium, with the CL K⁺ concentration being higher; thus there was also no change in the arterial–venous difference as demonstrated previously (McKenna et al. 1997). The K⁺ release into the blood also remained unaltered post training. Significantly following training there was a 29.0% increase in the α₁ subunits and a 15.1% in the α₂ subunits of the structural protein Na⁺-K⁺-ATPase. The β₁ subunits on the other hand remained unchanged, as did the number of K_ATP channels. The larger increase in α₁ subunits was hypothesized to result from a translocation of the subunits from intracellular stores to the sarcolemma (Juel et al. 2000b). These changes together suggested an overall relative increased movement of K⁺ back into the intracellular space of the muscle cell during exercise in the TL. Unfortunately, the question of the associated net shift of water out of the muscle with the inward movement of K⁺ was not addressed. This question could be answered in further experiments involving analysis of the Na⁺–K⁺–2Cl⁻ cotransporter. Evidence suggests that this cotransporter couples the inward transport of K⁺ and Cl⁻ to the Na⁺ concentration gradient, providing a K⁺ transport pathway that would complement the Na⁺-K⁺-ATPase mediated transport (Gosmanov et al. 2003).

The crux of this investigation was the time course of changes in K⁺ concentration, collected with the aid of microdialysis probes. It was also demonstrated that the K⁺ concentrations in the interstitium were greater than in the venous circulation, indicative of a possible diffusion restriction. The K⁺ gradient was decreased in the trained state, primarily through a decreased K⁺ concentration. This may be associated with a 20% increase in capillarization of the muscle bed, bringing the K⁺ release values in line with previous results (McKenna et al. 1997). Fatigue was also associated with increased extracellular K⁺ which interferes with the propagation of the action potential along the muscle membrane and into the t-tubule system. However, it may have been useful for the authors to comment on the idea of fatigue possibly being associated with lowered intracellar K⁺ concentration. They did state that pH was not to be discounted, but no difference was observed in the current investigation. On the other hand muscle lactate was collected and was shown to be greater in the TL compared to the CL at exhaustion, thus disproving lactate accumulation as a possible cause of fatigue here.

Some important concepts emanate from this work, particularly the complementary use of several experimental techniques which in combination provide convincing evidence for the mechanism of fatigue development during intense exercise. Neilsen and colleagues suggest that the key regulatory factor delaying K⁺ accumulation in the interstitium is the increased expression of Na⁺-K⁺-ATPase. The regulation of this pump is much studied (for review, see Clausen, 2003). The appeal of this paper is in the build-up towards a simple, yet elegant solution, one which most people will respond to by saying ‘why didn't I think of that.’ Nevertheless, there will still be many with alternative hypotheses. However, a platform has been provided that will inspire new experiments, which may include ratings of perceived exertion and more advanced studies investigating the Na⁺–K⁺–2Cl⁻ cotransporter.