Decreases in active [Ca
2+]
i have been demonstrated in frog semitendinosus and mouse FDB muscle fibers with concomitant decrease in shortening capacity in mouse FDB when [K
+]
e is increased (Lucas et al.
2014; Quinonez et al.
2010). More importantly, a recent study has clearly demonstrated a relationship between AP overshoot and active [Ca
2+]
i in which active [Ca
2+]
i remains stable from + 30 to 0 mV, decreasing rapidly as AP peak became less than 0 mV, with no Ca
2+ release by −40 mV (Wang et al.
2022). The changes in and effects of K
+ on resting E
M and AP and the relationship between AP and Ca
2+ release strongly support a role for K
+ in the decrease in force during fatigue. However, the K
+-force relationships for twitch and tetanic contractions are more complicated than originally thought. For tetanic contractions, there is a range of [K
+]
e for which tetanic force remains close to maximal (≥ 90%) despite significant resting E
M depolarization and lower overshoot, until a [K
+]
e is reached above which force declines abruptly. For twitch and sub-maximal tetanic contractions, small increases in [K
+]
e actually potentiate force, while at higher [K
+]
e, twitch and sub-maximal tetanic force are decreased. In this section, we discuss the K
+-induced force depression on tetanic force and how it is modulated by changes in [Na
+] gradient, G
Cl and NKA activity, then followed by a subsequent section discussing K
+-induced potentiation.
Tetanic force-[K+]
e
relationship
The maximum force a muscle can generate is measured during a completely fused tetanus. For frog sartorius and mouse EDL muscles at 25 °C, peak tetanic force decreases by less than 10–15% when [K
+]
e is raised from 4 to 9 mM and is completely abolished at 12 mM [K
+] (Fig.
1B) (Renaud and Light
1992; Cairns et al.
1997). The critical [K
+]
e, defined as the [K
+]
e above which tetanic force drops abruptly, is 9 mM for these two muscles. Notably, mouse soleus is more sensitive to raised [K
+]
e as the critical [K
+]
e is only 7 mM and no force is generated at 11 mM (Fig.
1B). The differences between mouse soleus and EDL tetanic force-[K
+]
e relationships persist at 37 °C, but with higher critical [K
+]
e, being 9 and 12 mM for soleus and EDL, respectively (Fig.
1B) (Ammar et al.
2015). Similarly for rat muscles at 30 °C, the critical [K
+]
e for soleus and EDL were 9 and 11 mM, respectively (Hansen et al.
2005; Pedersen et al.
2003; Cairns et al.
1995). Soleus is known as a slow-twitch fatigue resistant muscle primarily composed of type 1 fibers, being 87% of all fibers in rat and 67% in mouse; the remaining fibers being type IIA fibers (Banas et al.
2011; Armstrong and Phelps
1984). EDL, on the other hand, is a fast twitch fatigable muscle with fibers being composed primarily of type IIB (56–57% in rat and mouse) and IIX (46% in mouse). Therefore, the most fatigue resistant type I and IIA fibers have lower critical [K
+]
e values than the fatigable type IIB and IIX fibers.
Another observation from the above studies was that the higher the experimental temperature the higher the critical [K
+]
e. This was especially confirmed in rat soleus as the critical [K
+]
e values were 8, 9 and 10 mM at 20°, 30° and 35 °C, respectively (Pedersen et al.
2003). There is one study reporting faster and greater K
+-induced force depression at 37 °C than at 25 °C when mouse soleus were exposed to 10 mM [K
+]
e (Cairns et al.
2011). It is more than likely, however, that the critical [K
+]
e increases with temperature from two points of view. First, the K
+-induced depolarization is less at 37 °C than at 25 °C (Table
2). For mouse EDL, the depolarization per decade change in [K
+]
e is 48 mV at 25 °C and 42 mV at 37 °C; for soleus, the values are respectively 45 and 37 mV. Thus, one should expect that less depolarization at 37 °C results in a higher critical [K
+]
e. Second, as discussed above, the NKA electrogenic contribution is greater at 37 °C, being 15–20 mV, than at 19 °C, being 10 mV (Hicks and McComas
1989; Ammar et al.
2015; Juel
1986; Chibalin et al.
2012). More importantly, if NKA activation with salbutamol reduces the rate and extent of the force loss at high [K
+]
e and increases the critical [K
+]
e (Andersen and Clausen
1993; Clausen et al.
1993; Clausen and Everts
1991; Pedersen et al.
2003), then greater NKA activity at 37 °C should give rise to slower and smaller force loss at 37 °C than at 25 °C for a given increase in [K
+]
e.
The most important aspect to consider is the tetanic force-resting E
M relationship because the K
+ effect is not direct but via a depolarization of the sarcolemma. Muscle [K
+]
int have been primarily measured in human studies. For frog sartorius, mouse EDL and soleus muscles at 25 °C, tetanic force remains constant from -95 to −70 mV, drops by about 10% from −70 to −65 mV and reaches zero between −60 and −55 mV (Fig.
1C) (Renaud and Light
1992; Cairns et al.
1997,
2022); i.e., 90% of the force loss occurs over a 5–10 mV range. Notably, the differences between EDL and soleus for the tetanic force-[K
+]
e relationship shown in Fig.
1B are no longer observed for the tetanic force-resting E
M relationship as shown in Fig.
1C; i.e., the greater K
+ sensitivity of soleus is due to greater depolarization at a given [K
+]
e. The tetanic force-resting E
M relationship of mouse soleus is basically the same at 25 °C and 37 °C, while it is slightly shifted toward less negative resting E
M for EDL. The small difference in tetanic force-resting E
M relationship between EDL and soleus at 37 °C may be related to smaller decreases in overshoot when resting E
M becomes less negative than −70 mV (Ammar et al.
2015).
It is important to note that the tetanic force-resting E
M relationships in Fig.
1C are derived from studies using K
+-induced depolarization. If we now take into consideration the Cairns et al.
2022 study discussed above, the critical resting E
M at which force decreases abruptly may be more depolarized than what is shown in Fig.
1C. That is, from the AP overshoot-resting E
M relationship obtained with K
+-induced depolarization a sudden drop in AP peak to −10 mV occurred when resting E
M dropped from −65 to −60 mV (Fig.
1A). Under the same conditions, the critical resting E
M for the abrupt tetanic force decrease occurred between −60 mV and −55 mV (Fig.
1C) suggesting that it occurs when AP peak is −10 mV or more negative. For the shorter microelectrode-induced depolarization, a decrease in AP peak to −10 mV occurred at −50 mV (Fig.
1A) representing a 10 mV shift toward less negative resting E
M compared to the K
+-induced depolarization. Assuming that tetanic force abruptly declines once AP peak becomes −10 mV or more negative, then for shorter depolarization period the critical resting E
M for abrupt tetanic force loss would be −50 mV instead of −60 mV. Thus, to fully understand the role of K
+ in fatigue, future studies are necessary to determine the full time course of the AP depression following increases in [K
+]
e as opposed to when tetanic force reaches a steady state after more than 30 min.
The next question is whether the changes in [K
+]
e and [K
+]
i during fatigue by itself can be considered a major factor in the mechanism of fatigue. In comparing the relationships between [K
+]
e, resting E
M, AP and force in frog sartorius, Light et al. (
1992) demonstrated that while an increase in [K
+]
e to 7 mM in unfatigued sartorius muscles mimicked changes in resting E
M and AP during fatigue, the increased [K
+]
e had little effect on tetanic force of unfatigued muscle. Furthermore, increasing [K
+]
e to 7.5 mM immediately after a fatigue bout did not reduce recovery of force after fatigue despite preventing a recovery of resting E
M (Comtois et al.
1994). In humans, during 30 min moderate (30 Watts, W) knee extension exercise, mean [K
+]
int increased to 10 mM within 5 min but then decreased to a steady state level ranging between 7 and 9 mM; mean [K
+]
int reached 9.7 mM during exhaustive exercise (Nielsen et al.
2004a). Thus, the difference in peak [K
+]
int between a non- exhausting and exhausting exercise was not only small, but slightly less in exhaustive exercise. Most studies in which [K
+]
int was measured by microdialysis in human reported a mean value not exceeding 12 mM (Table
1). Although more studies are needed for [K
+]
int in animal muscles, changes during fatigue in [K
+]
i of human vastus lateralis muscles are within the range reported for mouse and rat muscles (Table
1). So, if the changes during fatigue in [K
+]
int (measured in human muscles) and if the critical [K
+]
e (measured in mouse and rat muscles) are representative of the situation in human, mouse and rat muscles, then 12 mM [K
+]
int at 37 °C is expected to reduce tetanic force by 50% in fatigue resistant muscles such as the soleus, but having little effect in fatigable muscles such as the EDL. Human muscle has a mixed fiber type composition, so the expected effects would be intermediate between these two different types of muscles. Overall, these results do not strongly support the concept that perturbations in K
+ (i.e., both [K
+]
int and [K
+]
i) per se are not a major mechanism for the decrease in force during fatigue at least in muscles with low fatigue resistance. Further studies are necessary to determine [K
+]
int in animal models as well as the critical [K
+]
e in human muscles. However, as discussed below, one cannot exclude K
+ as a potential factor in muscle fatigue without looking at an interaction with Na
+, Cl
− and NKA.
Modulation of the K+-induced force depression by Na+
Although studies reported faster and greater extent of force decrease when amphibian and mammalian muscles were fatigued at lowered extracellular [Na
+] ([Na
+]
e) compared to control conditions (Cairns et al.
2003; Bezanilla et al.
1972), one must also determine if the [Na
+]
e and [Na
+]
i changes during fatigue significantly affect force in unfatigued muscles. In frog sartorius, mimicking a reduction in [Na
+] gradient observed with fatigue (Table
3) by lowering [Na
+]
e by 1.2 and twofold (i.e., from 120 to 100 and 60 mM) reduced peak force by 10% and 30%, respectively (Bouclin et al.
1995). Mammalian muscles are more resistant to a decrease in [Na
+]
e. In rat soleus and mouse EDL and soleus, a twofold reduction in [Na
+]
e from 147 to 75 mM had no effect on tetanic force as significant decreases in tetanic force occurred at [Na
+]
e below 40 mM, i.e., a 3.8-fold decrease in [Na
+] gradient (Overgaard et al.
1997,
1999; Cairns et al.
2003). Considering that most studies report a less than twofold decrease in [Na
+] gradient during fatigue (Table
3), it would appear that the change in [Na
+] gradient is by itself in most cases too small to be of any major importance in the force decrease during fatigue, despite its effects on AP as discussed above.
Concomitant changes in Na
+ and K
+ gradients, on the other hand, have a synergistic depressive effect on tetanic force; i.e., their combined effects are greater than their additive effects. In frog sartorius, tetanic force decreased by about 8% when either [K
+]
e was increased from 3 to 7 mM to mimic a 2.3-fold decrease in [K
+] gradient, or when [Na
+]
e was decreased from 120 to 110 mM to mimic a 1.2-fold decrease in [Na
+] gradient. If the Na
+ and K
+ effects were additive, the concomitant change in Na
+ and K
+ gradient should lower force by 15% whereas a much greater 31% decrease was actually observed (Bouclin et al.
1995). In rat soleus muscle, tetanic force decreased by 10% when [K
+]
e was increased from 4 to 9 mM (2.3-fold reduction in the [K
+] gradient) and remained constant when [Na
+]
e was reduced from 147 to 85 mM (1.7-fold in the [Na
+] gradient); concomitant changes of both gradients resulted in a 50% force reduction (Overgaard et al.
1999). Finally, in mouse soleus, a 2.0-fold increase in [K
+]
e from 4 to 8 mM decreased tetanic force by 9% and a 1.5-fold decrease in [Na
+]
e (from 147 to 100 mM) reduced force by 3%,while concomitant changes in [K
+]
e and [Na
+]
e resulted in a force depression of 40%, more than threefold greater than a calculated additive effect of 12% (Cairns et al.
2022). Noticeably, Cairns et al (
2022) reported that a similar concomitant change in [K
+] and [Na
+] had an additive and not a synergistic depressive effect on single AP, albeit the effect may be different for a train of APs. Furthermore, they reported that 15% of soleus fibers became inexcitable when [K
+]
e was increased from 4 to 8 mM while a decrease in [Na
+]
e from 147 to 100 mM had no effect; concomitant changes in both [Na
+]
e and [K
+]
e resulted in 20% of fibers becoming inexcitable suggesting that Na
+ and K
+ have a small synergistic effect on sarcolemmal excitability. Thus, reductions in either [Na
+] or [K
+] gradients observed during fatigue have by themselves limited adverse impact on tetanic force, whereas concomitant reductions in [K
+] and [Na
+] gradients result in tetanic force decreases that are large enough to suggest that the combined changes in [K
+] and [Na
+] gradient are important in the mechanism of muscle fatigue.
Modulation of the K+induced force depression by changes in G
Cl
.
As discussed in the section on AP, there is a net Cl
− influx during both AP depolarization and repolarization phases (Dutka et al.
2008; Heiny et al.
1990; Fahlke and Rüdel
1995). Under normal resting [K
+]
e of ~ 4 mM and [Na
+]
e of ~ 147 mM, reducing [Cl
−]
e to 10 mM had no long-lasting effect on resting E
M, AP or tetanic force in unfatigued mouse soleus, while it increased the rate of fatigue (Cairns et al.
2004). As discussed in the section on resting E
M, a major effect of Cl
− is a slower and lower extent of the K
+-induced membrane depolarization; this effect implies that a decrease in [Cl
−]
e or of G
Cl should increase the K
+-induced force depression and thus the rate of fatigue. However, a series of studies demonstrated that the Cl
− effects are more complex.
In one study, an increase of [K
+] to 11 mM at a normal pH
e of 7.4 reduced tetanic force and M-wave (an extracellular measurement of APs from the muscle surface) to 20–25% of the initial values measured at 4 mM (Pedersen et al.
2005). The extracellular pH (pH
e) was then lowered from 7.4 to 6.8 by raising CO
2 in the gas phase from 5 to 24%, in order to reduce G
Cl, as Cl
− ClC-1 channels are pH-sensitive (Hutter and Warner
1967; Palade and Barchi
1977). Following the decrease in pH
e to 6.8, both tetanic force and M-wave area increased to 80–90% of initial values at 4 mM [K
+]
e and pH
e 7.4. Likewise, at 9 mM [K
+]
e, the same decrease in pH
e increased the number of excitable fibers from 48 to 94% and AP overshoot by 10 mV (Pedersen et al.
2005). Accordingly, lowering pH
e from 7.4 to 6.8 shifted the tetanic force-[K
+]
e relationship by 2 mM toward higher [K
+]
e. These acidic pH
e effects were associated with a 46% reduction in G
Cl (with no effect on G
K). Mimicking the reduction in G
Cl by lowering [Cl
−]
e as well as by exposing soleus to 9-AC at pH
e 7.4 had the same effect on force and M-wave as the low pH
e. The authors concluded that a partial decrease in G
Cl is the mechanism by which acidic pH
e caused an increase in tetanic force and M-wave area during the K
+ -induced depolarization.
The above conclusion was further supported by another study in which mechanically skinned fibers with intact t-tubules were exposed to various [K
+]
i in order to alter t-tubular resting E
M (Pedersen et al.
2004). When contractions were elicited with electrical stimulations to trigger APs in t-tubules, a decrease in intracellular pH (pH
i) from 7.1 to 6.6 shifted the force-[K
+]
i relationship toward lower [K
+]
i, i.e., more depolarized t-tubules. A similar shift was not observed when i) Cl
− was removed from the bathing solution and ii) when contractions were elicited via an activation of the voltage sensor (also known as Ca
V1.1 channel or dihydropyridine receptor). The authors concluded that greater t-tubular depolarization was necessary to induce force loss in the presence of Cl
− (or G
Cl) in acidic than in normal pH
i.
In a third study (de Paoli et al.
2013), rat soleus muscles were stimulated for 30 s train at 60 Hz. Under those conditions, force reached a plateau in about 2 s and decreased constantly thereafter. The extent of the depolarization between APs became greater as [Cl
−]
e was decreased stepwise from 127 to 0 mM. Despite greater depolarization, the rate at which force decreased became slower when [Cl
−]
e was lowered from 127 to 60 mM (to lower G
Cl) and then became faster from 60 to 0 mM Cl
−. The authors concluded that any decrease in G
Cl worsens the K
+-induced depolarization whereas small decrease in G
Cl improves membrane excitability and tetanic force while large decrease in G
Cl worsens the K
+-induced decrease in membrane excitability and force by mechanisms explain below.
The mechanism of action by which decreases in G
Cl affects membrane excitability and tetanic force as [K
+]
e increases have been extensively reviewed (Nielsen et al.
2017; Pedersen et al.
2016). Briefly, three issues must be taken into account. First, when a stimulation, either electrical during an experiment or at the neuromuscular junction following acetylcholine binding to its receptor, depolarizes the membrane toward AP threshold, there is a constant Cl
− influx that counteracts the stimulation-induced depolarization. AP threshold becomes less negative following prolonged depolarization, induced either by higher [K
+]
e or continuous stimulations as Na
V channels become inactivated. As a consequence of a less negative threshold, greater stimulation current is needed to reach it. Lowering G
Cl reduces the Cl
− influx that opposes the stimulatory depolarization. This explains why the number of excitable fibers increases at 9 mM K
+ when G
Cl is lowered by decreasing pH
e. Second, as discussed in the section on AP, there is a constant Cl
− influx during AP depolarization and repolarization phases. Under normal conditions, G
Na during the AP depolarization is substantial and largely overwhelms the counteracting Cl
− current that opposes the depolarization; i.e., the G
Na:G
Cl ratio is very high. This is no longer the case when Na
V channels are inactivated by prolonged membrane depolarization. However, small decreases in G
Cl has two opposing effects: it allows (i) for greater K
+-induced depolarization and (ii) greater G
Na:G
Cl ratio. If small decrease in G
Cl improves AP amplitude and force at raised [K
+]
e, then one can suggest that the increase in AP amplitude due to greater G
Na:G
Cl ratio largely overcomes the expected lower AP amplitude due to the greater K
+-induced depolarization. Third, there is an optimum decrease in G
Cl for which the extent of the depressive effects of any depolarizations on excitability and force is at its lowest. As shown by de Paoli et al. (
2013), small decreases in G
Cl, induced by decreases in [Cl
−]
e from 127 to 60 mM, reduce the extent of the depressive effects of any membrane depolarization because the increased G
Na:G
Cl ratio improves AP threshold and allows greater AP depolarization. Further decreases in G
Cl not only worsen the K
+-induced depolarization but it may do it to the point at which the depolarization depressive effects as Na
V channel inactivation becomes too great resulting in further decrease in membrane excitability and force.
Modulation of the K+-induced force depression by NKA
NKA is largely responsible for the maintenance of the [Na
+] and [K
+] gradients across the muscle membrane. The NKA mechanisms of action, molecular isoforms and activity regulation in muscle have been extensively reviewed (Pirkmajer and Chibalin
2016; Clausen
2003,
2013; McKenna et al.
2023). Here, we briefly discuss how NKA, its activation and inhibition, modulates the K
+ effects on force depression. Exposing unfatigued soleus muscles to 12.5 mM K
+ reduced tetanic force to zero within 20 min, while in the presence of 10 µM ouabain, a NKA-specific inhibitor, the decrease occurred in only 2 min; conversely, NKA activation with 10 µM salbutamol, a β
2-adrenergic receptor agonist, reduced the rate of force decrease, reaching zero after 40 min (Clausen and Everts
1991). Slower force decrease also occurred when NKA was activated by insulin, epinephrine and calcitonin gene related peptide (CGRP) (Andersen and Clausen
1993; Clausen and Everts
1991; Clausen et al.
1993; Clausen and Flatman
1977). Furthermore, activating NKA after force had decreased to a steady level at elevated [K
+]
e or after a concomitant increase in [Na
+]
i and decrease in [K
+]
i allowed for large force recovery (Andersen and Clausen
1993; Clausen et al.
1993; Macdonald et al.
2005; Pedersen et al.
2003). Improvement of tetanic force in the presence of salbutamol correlated with improvement of M-waves, which suggest an improvement of membrane excitability (Overgaard et al.
1999). Thus, activation of NKA has the capacity to reduce the rate and extent of the K
+-induced force depression in unfatigued skeletal muscle.
NKA activity increases during muscle activity (see review by (McKenna et al.
2023). This for example was shown as 2 Hz stimulation for 10 min or 60–120 Hz stimulation for 10 s increased ouabain-suppressible Na
+ efflux and K
+ influx in rat soleus muscle (Everts and Clausen
1994; Nielsen and Clausen
1997). More importantly, stimulating soleus muscle with 1.5–2 s long 30 Hz tetanic contractions every min after force had been depressed at 10 mM K
+ allowed for full force recovery; for soleus exposed to 12.5 mM K
+ the stimulation allowed for a partial recovery (Overgaard and Nielsen
2001; Nielsen et al.
1998). The force recovery was associated with a partial recovery of resting E
M and membrane excitability, with the latter determined by M-waves. Furthermore, Nielsen et al. (
1998) provided evidence that resting E
M and force recovery were associated with increases in NKA activity brought about by the release of CGRP from neurons innervating skeletal muscle. Salbutamol, epinephrine, insulin and CGRP, all NKA activators, substantially reduced the rate at which force declined when rat soleus was continuously stimulated at 60 Hz for min while exposed at various [K
+]
e (Clausen and Nielsen
2007). Finally, when soleus muscles were stimulated with 400 ms long tetanic stimulation at 40 Hz every 3rd s for 5 min and compared to control, 10 µM, terbutaline, a β
2-adrenergic receptor agonist, reduced the extent of the resting E
M depolarization by 35%, the [K
+]
i decrease by 31%, the [Na
+]
i increase by 25% and the force decrease by 10% (Juel
1988). Juel (
1988) suggested that the terbutaline effects involved a NKA activation. Thus, muscle contractions induce NKA activation, which then has the capacity to minimize perturbations in muscle E
M, [K
+]
i, [Na
+]
i and force.
In resting unfatigued skeletal muscle, the electrogenic NKA contribution to resting E
M under normal [K
+]
e conditions (i.e., 4–5 mM K
+) is 12–20 mV in EDL, soleus and diaphragm muscles (Ammar et al.
2015; Chibalin et al.
2012; Clausen and Flatman
1977). Furthermore, several studies have reported that under normal [K
+]
e conditions and in the resting state, a 3 to 9 mV hyperpolarization occurs when NKA is activated by β
2-adrenergic receptor agonists or insulin (Clausen and Flatman
1977; Kuba
1970; Kuba et al.
1978; Kuba and Nohmi
1987; van Mil et al.
1995; Juel
1988). Finally as discussed above, muscle contractions increase NKA activity, which then modulates resting E
M and membrane excitability (Juel
1988; Hicks and McComas
1989; Nielsen et al.
1998; Overgaard and Nielsen
2001). Thus, one mechanism of action for NKA is via its electrogenic effects making resting E
M more negative and counteracting the K
+-induced depolarization and the subsequent decrease in force.
It is important to note, however, that while NKA activation during muscle activity with or without an exposure to catecholamines leads to more negative resting E
M and smaller force loss, the same does not always apply when resting muscles are exposed to elevated [K
+]
e. First, some studies reported that in rat diaphragm, mouse soleus and lumbrical muscles the extent of the catecholamine-induced hyperpolarization decreased as [K
+]
e was increased; the hyperpolarization near 0 mM [K
+]
e being 10–20 mV and becoming zero at 10 mM [K
+]
e (Uwera et al.
2020; Kuba and Nohmi
1987; van Mil et al.
1995). In the study of Uwera et al. (
2020), salbutamol triggered an increase in tetanic force at 10 mM [K
+]
e in soleus muscle despite no effect on resting E
M. Second, an exposure of resting muscle under normal [K
+]
e conditions (4–5 mM) to catecholamines/agonists results in a hyperpolarization (Clausen and Flatman
1977; Kuba
1970; Kuba et al.
1978; Kuba and Nohmi
1987; van Mil et al.
1995; Juel
1988) and increase in twitch force (Holmberg and Waldeck
1980; Reading et al.
2003; Cairns et al.
1995,
1993; Bowman and Zaimis
1958; Cairns and Dulhunty
1993a,
b). However, the hyperpolarization cannot be the mechanism by which twitch force increases because the changes in resting E
M are not within the range that affects twitch force; i.e., under normal conditions resting E
M is more negative than −75 mV while twitch force depression occurs when resting E
M becomes less negative than −60 mV. Together these results suggest that the mechanism of action by which catecholamine improves force, regardless of [K
+]
e, cannot be solely due to an effect on resting E
M. Indeed, catecholamines also increases Ca
2+ release. This mechanism involves (i) phosphorylation of SR Ca
2+ release channels, known as the ryanodine receptors (RyR1) and (ii) in some muscles, such as diaphragm and amphibian muscle but not mammalian limb muscles, a phosphorylation of the t-tubular voltage sensor/Ca
2+ Ca
V1.1 channels (for more details see review by Cairns and Borrani
2015).
Overall, NKA activation by muscle contraction, catecholamines and CGRP is most likely crucial at protecting skeletal muscle from the K+-induced force depression. As discussed in greater detail in the section below entitled “A new perspective about the role of K+, Na+ and Cl− on muscle performance from the onset of exercise to fatigue”, this protection is important at the onset of, or during mild exercise, when [K+]int is high but there is no metabolic stress triggering fatigue.