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News Physiol Sci 18: 196-200, 2003; doi:10.1152/nips.01446.2003
1548-9213/03 $5.00
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News in Physiological Sciences, Vol. 18, No. 5, 196-200, October 2003
© 2003 Int. Union Physiol. Sci./Am. Physiol. Soc.

Riding the Tides: K+ Concentration and Volume Regulation by Muscle Na+-K+-2Cl- Cotransport Activity

Aidar R. Gosmanov1, Michael I. Lindinger2 and Donald B. Thomason1

1 Department of Physiology, The University of Tennessee Health Science Center, Memphis, Tennessee 38163;
2 Department of Human Biology and Nutritional Sciences, The University of Guelph, Guelph, Ontario N1G 2W1, Canada

   Abstract
 
Until recently, the existence of a Na+-K+-2Cl- cotransporter (NKCC) in skeletal muscle was unclear. Recent evidence shows that the NKCC is strongly expressed and provides both K+ and water transport functions in resting and contracting skeletal muscle. The contribution of NKCC activity to K+ and volume regulation in skeletal muscle has potential consequences for muscle contractility and metabolism.


   Introduction
Top
 Introduction
NKCC activity in isosmotic...
 NKCC activity in hyperosmotic...
 Physiological consequences of...
 References
 
Skeletal muscle cells contain 70–75% of the body’s K+ and 45% of the body’s water. Consequently, K+ and water transport by muscle has the potential to affect whole body K+ (12) and water balance. The electrogenic Na+-K+-ATPase is well known for its inward transport of K+ and net efflux of water. Recent evidence indicates that Na+-K+-2Cl- cotransporter (NKCC) expression and activity in skeletal muscle also provides inward transport of K+ and, in contrast to the Na+-K+-ATPase, provides a net influx of water (Fig. 1Go). In many cell types, the inward transport of solute by the NKCC, with water following, helps to maintain the cell volume in the face of a hyperosmotic challenge (3, 7, 13). Thus skeletal muscle NKCC activity may have multifunctional roles for K+ and water transport depending on specific conditions. In the following paragraphs, we discuss the role and regulation of NKCC activity in skeletal muscle under different osmotic conditions and the potential physiological importance of this transport mechanism.



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  		FIGURE 1. Although the Na+-K+-2Cl cotransporter (NKCC) and the Na+-K+-ATPase act in concert for the inward transport of K+, they act in opposition for thebalance of water (A) and Na+ (B) content. Experimental data indicate that muscle strikes a balance between the extremes of water and Na+ balance (C).

 

   NKCC activity in isosmotic conditions
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 Introduction
 NKCC activity in isosmotic...
NKCC activity in hyperosmotic...
 Physiological consequences of...
 References
 
The NKCC couples the inward transport of K+ and Cl- to the Na+ concentration ([Na+]) gradient. As such, the NKCC provides a K+ transport pathway that could complement the Na+-K+-ATPase (Fig. 1Go). For muscle at rest, the bumetanide- and furosemide-sensitive Cl- transport in skeletal muscle produces a plasma membrane depolarization (19); bumetanide specifically inhibits the NKCC, and furosemide inhibits the K+-Cl- cotransporter and, at high concentrations, the NKCC. The tendency of increased NKCC activity to increase intracellular [Na+] and Cl- concentration ([Cl-]) and decrease the membrane potential would necessitate increased Na+-K+-ATPase activity to maintain low intracellular [Na+] and [Cl-]. This combination of NKCC and Na+-K+-ATPase activities would effectively increase the rate at which K+ is transported (unidirectional inward flux, or JinK) compared with a sole reliance on the Na+-K+-ATPase. However, the involvement of the Na+-K+-ATPase in maintaining the activity of the cotransporter has been controversial. Over the long term, the driving force for NKCC activity is clearly the Na+ electrochemical gradient established by the Na+-K+-ATPase. However, in cultured skeletal muscle myocytes, NKCC-mediated JinK is dependent on extracellular [Na+] and [Cl-] but is reported to be ouabain insensitive during short incubations (17); these data indicate that ouabain-sensitive Na+-K+-ATPase activity may not be needed. A striking distinction of these cultured muscle cells is that they appear to exhibit an altered density of NKCC and Na+-K+-ATPase such that NKCC accounts for two-thirds of total JinK (18), compared with 15–20% of JinK in muscle in situ (8). Similarly, in vitro muscle preparations demonstrate that bumetanide inhibits basal ouabain-insensitive JinK over short periods of time. Conversely, in skeletal muscle in situ, ouabain inhibition of Na+-K+-ATPase activity abolishes NKCC-mediated JinK, whereas barium, a nonspecific blocker of cation channels, does not affect NKCC activity (7, 8). Although Na+-K+-ATPase activity must, in the long run, provide the driving force for NKCC activity, the NKCC also apparently provides a inwardly directed Na+ transport mechanism that affects Na+-K+-ATPase activity by its ability to change intracellular [Na+]. Inhibition of basal NKCC activity by bumetanide diminishes ouabain-sensitive K+ uptake into muscle by 35% (7). Interaction between cotransporter activity and Na+-K+-ATPase has been described in several different muscle preparations (as noted in Ref. 7).

An important question is whether NKCC-mediated transport is actively regulated and, if so, is the regulation independent of Na+-K+-ATPase regulation? The answers to these questions are apparent under conditions that stimulate K+ uptake by muscle. In contrast to the low NKCC activity in muscle under basal conditions [where muscle water and K+ balance are in steady state (5, 7)], NKCC activity is increased by several stimuli of K+ uptake by muscle. Adrenergic receptor activation causes a robust stimulation of total 86Rb uptake in rat muscle under isosmotic conditions, and NKCC activation accounts for up to one-third of the total stimulated 86Rb transport (7). Muscle contraction produced by either in vitro electrical stimulation or treadmill running also stimulates total 86Rb uptake and NKCC activity independent of cellular shrinkage (3). It is of note that NKCC inhibition by bumetanide does not change muscle cell volume when NKCC activity is stimulated by the ß-adrenergic agonist isoproterenol or by the adenylyl cyclase activator forskolin (3), indicating that NKCC activity does not result in a net transport of solute under isosmotic conditions. Although insulin stimulates Na+-K+-ATPase activity in skeletal muscle (2), insulin in fact inhibits NKCC activity (4). Therefore, although Na+-K+-ATPase activity provides the necessary driving force for NKCC-mediated transport, there is independent regulation of the activity of these two transport processes. A summary scheme of possible interactions between the NKCC and the Na+-K+-ATPase is shown in Fig. 1Go.

The mechanism for NKCC regulation under isosmotic conditions requires the extracellular signal-regulated kinase (ERK) arm of the mitogen-activated protein kinase (MAPK) pathways. Blockade of the ERK MAPK pathway abolishes isoproterenol-, phenylephrine-, and contraction-stimulated NKCC activity (4, 5). However, ERK MAPK pathway activation by the NKCC stimuli is complex, showing apparent compartmentalization and muscle fiber phenotype-specific features. Evidence for compartmentalization comes from experiments in which muscle is stimulated with insulin. Insulin stimulates Na+-K+-ATPase activity and the ERK MAPK pathway but does not stimulate NKCC activity (4). Moreover, insulin inhibits NKCC activity by stimulating phosphatidylinositol 3-kinase/Akt and p38 MAPK pathways that, in turn, apparently inhibit a specific ERK MAPK pathway necessary for NKCC stimulation (4). The importance of the ERK MAPK pathway as an "integrating point" for NKCC regulatory signals is emphasized by fiber phenotype differences in signaling. In slow-twitch fibers, but not fast-twitch fibers, pertussis toxin abrogates isoproterenol-stimulated NKCC activity by allowing activation of Akt and, in turn, inhibition of ERK MAPK pathway (5). Thus different muscle phenotypes contain functionally distinct G protein-coupled signal transduction pathways for NKCC regulation. Also unique to slow-twitch muscle is a p38 MAPK pathway-mediated inhibition of NKCC activity, again through inhibition of the ERK MAPK pathway (5). A summary for known signaling pathways regulating NKCC activity under isosmotic conditions is shown in Fig. 2Go. Because slow-twitch fibers have approximately twice the K+ transport activity as fast-twitch fibers (4, 5), phenotype-specific differences have important physiological consequences. For example, individuals that are physically inactive, obese, or have diabetes mellitus exhibit both an increased reliance on fast-twitch muscle fibers and hyperkalemia during periods of activity. Upregulation of NKCC-mediated JinK in exercise-trained rats demonstrates that regular physical activity may help maintain a slow-twitch phenotype that has a greater capacity for K+ buffering.



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  		FIGURE 2. Putative scheme of signal transduction pathways regulating skeletal muscle NKCC activity under isotonic conditions. Activation of NKCC activity requires the extracellular signal-regulated kinase (ERK) arm of the mitogen-activated protein kinase (MAPK) signal transduction pathways. Inhibition of the ERK MAPK pathway can occur through several different mechanisms, depending on muscle fiber phenotype. MEK, MAPK kinase kinase.

 

   NKCC activity in hyperosmotic conditions
Top
 Introduction
 NKCC activity in isosmotic...
 NKCC activity in hyperosmotic...
Physiological consequences of...
 References
 
A well-established function of the NKCC in epithelial cells is to protect cells from water loss during hyperosmotic challenge (a process called a regulatory volume increase, or RVI) (15). Until recently, evidence for a volume-regulatory function of the NKCC in striated muscle was scarce. However, recent ex vivo and in vivo experiments demonstrate that skeletal muscle activates a bumetanide-sensitive RVI in response to hyperosmotic challenge. Intracellular water content of ex vivo skeletal muscle preparations is not affected by 10-min hyperosmotic challenge (indicative of activation of volume-regulatory mechanisms) unless the NKCC is blocked by bumetanide, in which case the muscle loses water (3). Similarly, in perfused rat skeletal muscle inhibition of the NKCC activity before perfusion with hypertonic medium (still containing bumetanide) results in a transient net loss of water from muscle that is gradually followed by a net gain of water after ~20 min (7). These are characteristics of the NKCC in other tissues (13) and indicate that the bumetanide-sensitive JinK and net water uptake can be attributed to cotransporter activity in skeletal muscle also.

Hyperosmotic challenge appears to produce coordinate regulation of NKCC activity and K+ channel conductivity in skeletal muscle. Approximately 30% of total JinK is attributed to passive K+ entry through K+ channels in resting, isotonic muscle (8). However, total JinK does not increase during perfusion of hindlimbs with hypertonic medium despite a doubling of the bumetanide-sensitive component of JinK (Fig. 3Go) (7). The lack of increase in JinK is attributed to a simultaneous decrease in passive influx of K+ through K+ channels, such that a transient increase in JinK in response to cell shrinkage becomes apparent when these cation channels are blocked with barium (Fig. 3Go). Closure of K+ channels is consistent with the report that hypertonic challenge of muscle has a depolarizing influence that is furosemide sensitive (18). Temporally, these data indicate that hypertonic challenge causes a decrease in cellular volume such that cell shrinkage in turn decreases passive K+ flux into the cells via K+ channels in concert with increases in the NKCC-mediated K+ influx. This makes sense with respect to cell volume regulation because the reduction in passive K+ flux, both into and out of the cells, through K+ channels serves to retain osmolytes within the cells. The transience in Jin K when K+ channels are blocked (Fig. 3Go) may result from subsequent deactivation of the NKCC-mediated transport in response to cell volume stabilization that occurs with additional net solute (primarily Na+ and Cl-) and water flux into the cell (7).



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  		FIGURE 3. Hyperosmotic challenge produces coordinate upregulation of NKCC activity and downregulation of K+ channel conductivity in skeletal muscle. Total inward K+ flux ( Jin K) does not increase during perfusion of hindlimbs with hypertonic medium despite a doubling of the bumetanide-sensitive component of Jin K (squares). In contrast, when K+ channels are first blocked with barium (circles), there is a transient increase in Jin K during hyperosmotic challenge, indicating a decrease in K+ channel-mediated Jin K along with a transient increase in the NKCC-mediated JinK.

 
Independent regulation of NKCC and Na+-K+-ATPase activities in muscle under hyperosmotic conditions appears to be necessary because the Na+-K+-ATPase could actually counteract the consequences of NKCC activation. Na+-K+-ATPase activity in isolation causes a net efflux of solute, counteracting a preservation of cell volume (7) (Fig. 1Go). Indeed, the increase in NKCC-mediated Jin K observed with hyperosmotic challenge (3) accounts for the entire increase in total Jin K (3). Figure 1Go illustrates that NKCC and Na+-K+-ATPase, despite their coordinate inward transport of K+, act in opposition for Na+ and water balance. Na+ content in steady state or water content in steady state are the two extremes for these transport mechanisms in isolation. On the basis of experimental measurements of the relative contribution by each transport mechanism to JinK (5, 7, 8), the balance of activity lies in between the two extremes. This would poise the NKCC and Na+-K+-ATPase transport mechanisms to adjust accordingly for regulation of either Na+ or water content. We can see, then, how these two mechanisms can compensate for resting K+ leakage and the high Cl- conductivity present in muscle while maintaining water content without the accumulation of Na+.

The mechanism(s) for NKCC activation under hyperosmotic conditions is markedly different from isosmotic conditions (3). Inhibition of the ERK MAPK pathway or insulin treatment does not affect hyperosmolarity-stimulated NKCC activity. In addition, insulin has no effect on muscle cell volume, supporting the hypothesis that the distinct roles of the NKCC (K+ uptake vs. volume regulation) use different intracellular signal transduction pathways to activate the NKCC. Paradoxically, whereas isoproterenol and forskolin stimulate NKCC activity in isosmotic conditions, these agents inhibit NKCC activation under hyperosmotic conditions (3). An increase in protein kinase A activity stimulated by these agents can affect the organization of actin cytoskeleton and may affect intracellular translocation or functional characteristics of sarcolemmal proteins. One may speculate that cytoskeletal mechanotransduction events associated with cell shrinkage rapidly activate cotransporter activity (14), increasing Jin K. Lionetto and coworkers (10) have recently implicated cytoskeletal elements together with protein kinase C and myosin light-chain kinase for hyperosmotic activation of NKCC activity in eel intestinal epithelium. Therefore, protein kinase A activity may provide a counterregulatory mechanism to inhibit NKCC activity under appropriate hyperosmotic conditions. Counterregulatory inhibition of muscle NKCC activity under hyperosmotic conditions might be appropriate when preservation of plasma volume and blood pressure must override the preservation of muscle volume.


   Physiological consequences of skeletal muscle NKCC activity
Top
 Introduction
 NKCC activity in isosmotic...
 NKCC activity in hyperosmotic...
 Physiological consequences of...
References
 
Because the NKCC carries K+ in addition to Na+ and Cl-, the potential volume-regulatory role and K+-regulatory role for NKCC are intimately linked. The impact of these dual roles in skeletal muscle is twofold: an effect on composition and volume of fluid compartments and an effect on muscle contractile function.

Exercise studies provide a good illustration of the integrative nature of skeletal muscle’s impact on fluid compartments. Within contracting muscle cells, the rapid hydrolysis of phosphocreatine consumes water and results in the production of two osmotically active molecules: creatine and inorganic phosphate. At the same time, hydrolysis of glycogen results in the production of lactate, another osmolyte, and the release of bound water. Contractile activity causes muscle to lose osmotically active K+ and lactate, which accumulate within the interstitial fluid compartment and enter the venous circulation, raising plasma osmolality (Fig. 4Go). The classic study of Lundvall and coworkers (11) demonstrates that the increase in plasma osmolality during exercise is due to "the delivery of osmoles from the exercising muscle." Because the net loss of K+ and lactate from muscle approximately balances the net accumulation of lactate within contracting skeletal muscle (9), the increase in intracellular osmolality can be approximated from the increase in intracellular creatine concentration. The study by Lundvall et al. (11) demonstrates that the increase in the volume of active muscle is primarily "caused by osmosis resulting from increased muscle tissue osmolality"; also, capillary hydrostatic pressure plays only a minor role in fluid accumulation of active muscles. The increase in fluid accumulation within active muscle greatly exceeds the fluid loss from the vascular compartment (9), further contributing to the increase in plasma osmolality. Accordingly, fluid from noncontracting tissues moves, primarily by osmotic forces, into the vascular compartment, in part defending vascular volume (Fig. 4Go). It can now be appreciated that an increase in NKCC activity within noncontracting muscle would counteract the net loss of water from these cells, preventing excessive cellular dehydration with impairment of force-producing ability (6). When modeled in situ, perfusion of skeletal muscle with hypertonic medium simulating that seen in blood during high-intensity exercise results in a rapid loss of water from muscle, followed within 2 min by a more prolonged increase in net water and solute uptake that is sensitive to NKCC inhibition with bumetanide (7). Activation of the NKCC by contractile activity also would help the contracting muscle accumulate osmolytes and preserve cell volume (3).



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  		FIGURE 4. Metabolic events accompanying exercise results in fluid shifts within working and nonworking muscles. Osmolytes accumulating in the working muscle cause water to move from the interstitium to the working muscle. Osmolyte release from the muscle increases plasma osmolality and draws water from the nonworking tissue. NKCC activation helps to defend the nonworking muscle from shrinkage through a regulatory volume increase (RVI). PCr, phosphocreatine; Pi, inorganic phosphate.

 
A muscle cell’s ability to maintain cell volume and K+ content has contractile consequences. Although hypertonic challenge leads to an increase in resting tension (1), maximum isometric force production is dramatically reduced (6). An increase in cytosolic Ca2+ concentration resulting from increased entry of extracellular (1) and sarcoplasmic reticulum Ca2+ into the cytoplasm may increase resting tension. The decreased magnitude of isometric force development is apparently due to a slowed rate of myosin-actin cross-bridge formation resulting from increased intracellular ionic strength (20). Impaired contractile activity also occurs with loss of K+ from contracting muscle (16). As outlined in Fig. 1Go, NKCC activity could contribute significantly to JinK to maintain or restore intracellular K+ concentration and indeed appears to do so under isosmotic and hypertonic conditions (3, 7, 8). However, a significant loss of K+ could also trigger a regulatory volume increase, making it difficult to assign separate volume- and K+-regulatory roles for the NKCC in isolation.

In summary, the skeletal muscle NKCC appears to have multifunctional roles for K+ and water transport. Mechanisms regulating NKCC activity are complex and largely unexplored but depend on muscle phenotype, local conditions, and whole body conditions. The multifunctional roles of the NKCC in skeletal muscle may occur simultaneously within an animal. For example, in humans and other animals, exercise results in a redistribution of water and ions among the tissues in response to rapid and pronounced changes in fluid osmolality, ion concentrations, and capillary hydrostatic pressure. The NKCC in working muscle could act to help restore intracellular K+ concentration and volume, whereas in the nonworking muscle the NKCC would preserve cell volume against hyperosmotic plasma and interstitial fluid. Given the importance of skeletal muscle on whole body K+ and water balance, the coordinated control of NKCC activity to meet multiple cellular demands is of physiological significance.


   Acknowledgments
 
We are grateful to our colleagues for their work that we were unable to cite.

M. I. Lindinger’s research was supported by grants from the National Sciences and Engineering Research Council, Canada. D. B. Thomason’s research was supported by grants from the American Diabetes Association and the American Heart Association.


   References
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 Introduction
 NKCC activity in isosmotic...
 NKCC activity in hyperosmotic...
 Physiological consequences of...
 References
 

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