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Review
. 2008 Sep 1;586(17):4039-54.
doi: 10.1113/jphysiol.2008.155424. Epub 2008 Jun 26.

Do multiple ionic interactions contribute to skeletal muscle fatigue?

S P Cairns  1 , M I Lindinger
Affiliations
Review

Do multiple ionic interactions contribute to skeletal muscle fatigue?

S P Cairns et al. J Physiol. .

Abstract

During intense exercise or electrical stimulation of skeletal muscle the concentrations of several ions change simultaneously in interstitial, transverse tubular and intracellular compartments. Consequently the functional effects of multiple ionic changes need to be considered together. A diminished transsarcolemmal K(+) gradient per se can reduce maximal force in non-fatigued muscle suggesting that K(+) causes fatigue. However, this effect requires extremely large, although physiological, K(+) shifts. In contrast, moderate elevations of extracellular [K(+)] ([K(+)](o)) potentiate submaximal contractions, enhance local blood flow and influence afferent feedback to assist exercise performance. Changed transsarcolemmal Na(+), Ca(2+), Cl(-) and H(+) gradients are insufficient by themselves to cause much fatigue but each ion can interact with K(+) effects. Lowered Na(+), Ca(2+) and Cl(-) gradients further impair force by modulating the peak tetanic force-[K(+)](o) and peak tetanic force-resting membrane potential relationships. In contrast, raised [Ca(2+)](o), acidosis and reduced Cl(-) conductance during late fatigue provide resistance against K(+)-induced force depression. The detrimental effects of K(+) are exacerbated by metabolic changes such as lowered [ATP](i), depleted carbohydrate, and possibly reactive oxygen species. We hypothesize that during high-intensity exercise a rundown of the transsarcolemmal K(+) gradient is the dominant cellular process around which interactions with other ions and metabolites occur, thereby contributing to fatigue.

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Figures

Figure 1
Figure 1. Schematic representation of transsarcolemmal ion fluxes and ion concentration changes in various muscle compartments (interstitial, t-tubular, intracellular) during electrical stimulation or exercise
Sarcolemma includes both surface and t-tubular membranes. Fuzzy space is a microdomain in the subsarcolemmal region. Pathways for ion fluxes include: K+ efflux via delayed rectifier K+, KATP and KCa channels; Na+ influx via voltage-dependent Na+ and stretch-activated channels; Ca2+ influx via L-type Ca2+, stretch-activated and store-operated channels; and Cl− influx via ClC-1 channels. The Na+–K+-pump (depicted) acts to maintain Na+ and K+ gradients. Ionic changes are also predicted for the t-tubular lumen (see text).
Figure 2
Figure 2. The influence of reduced transarcolemmal K+ gradient on contractile force is mediated via depolarization of the resting Em in isolated mouse extensor digitorum longus (EDL) muscle
A, the steady-state peak force-[K+]o relationships for twitch (▪) and tetanic (•) contractions. Tetani were evoked at 200 Hz for 1 s, with supramaximal (20 V, 0.1 ms) pulses delivered via parallel plate electrodes, 25°C. B, the resting Em–[K+]o relationship – determined using surface fibres bathed for 50–80 min at each [K+]o. C, the peak tetanic force–resting Em relationship derived using the data in A and B. All data points are mean values ±s.d. From Cairns et al. (1997) (modified with permission) with inclusion of further experiments.
Figure 3
Figure 3. Interactive effects of raised [K+]o, lowered [Na+]o, and altered [Ca2+]o on peak tetanic force in isolated mouse soleus muscle
Data are from Cairns et al. (1998). Each data point is the mean steady-state value (±s.e.m.). Tetani were evoked at 125 Hz for 2 s, with supramaximal (20 V, 0.1 ms) pulses delivered via parallel plate electrodes, 25°C. The control Krebs solution included 4 mm K+, 147 mm Na+, and 1.3 mm Ca2+. 8K – Krebs solution with 8 mm K+. 100Na – Krebs solution with 100 mm Na+. 10Ca – Krebs solution with 10 mm Ca2+. 0Ca – Krebs solution that is nominally Ca2+ free. #Predicted response (8K + 100Na) if the individual effects of 8K and 100Na were additive (i.e. 88.7%× 96.0%).
Figure 4
Figure 4. Model to illustrate potential integrated physiological mechanisms by which ion–ion interactions, ion–metabolite interactions and catecholamines influence muscle force production during fatiguing exercise
Continuous lines with arrow indicate support for the subsequent process. Dashed lines with arrow indicate resistance to the following process.
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