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Aging augments interstitial K⁺ concentrations in active muscle of rats

¹Division of Cardiology and ²Department of Pharmacology, Pennsylvania State College of Medicine, Milton S. Hershey Medical Center, Hershey; and ³Lebanon Veterans Affairs Medical Center, Lebanon, Pennsylvania

Submitted 30 May 2005 ; accepted in final form 21 November 2005

	ABSTRACT

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Skeletal muscle performance declines with advancing age, and the underlying mechanism is not completely understood. A large body of convincing evidence has demonstrated a crucial role for interstitial K⁺ concentration ([K⁺]_o) in modulating contractile function of skeletal muscle. The present study tested the hypothesis that during muscle contraction there is a greater accumulation of [K⁺]_o in aged compared with adult skeletal muscle. Twitch muscle contraction was induced by electrical stimulation of the sciatic nerves of 8- and 32-mo-old Fischer 344 x Brown Norway rats. Levels of [K⁺]_o were measured continuously by a microdialysis technique with the probes inserted into the gastrocnemius muscle. Stimulation at 1, 3, and 5 Hz elevated muscle [K⁺]_o by 52, 64, and 88% in adult rats, and by 78, 98, and 104% in aged rats, respectively, and the increase was significantly higher in aged than in adult rats. Recovery for [K⁺]_o, as measured by the time for [K⁺]_o to recover by 20 and 50% from peak response after stimulation, was slower in aged rats. Ouabain (5 mM), a specific inhibitor of the Na⁺-K⁺ pump, was added in the perfusate to inhibit the reuptake of K⁺ into the cells to assess the role of the pump in the overall K⁺ balance. Ouabain elevated muscle [K⁺]_o at rest, and the effect was significantly attenuated in aged animals. The present data demonstrated an augmented [K⁺]_o in aged skeletal muscle compared with adult skeletal muscle, and the data suggested that an alteration in the function of the Na⁺-K⁺ pump may contribute, in part, to the deficiency in K⁺ balance in skeletal muscle of aged rats.

microdialysis; skeletal muscle; potassium

A large body of convincing evidence has demonstrated a crucial role for interstitial K⁺ concentration ([K⁺]_o) in modulating contractile function of skeletal muscle (5, 42), suggesting that a change in interstitial K⁺ balance in aged skeletal muscle, if it occurs, is likely to have important consequences to muscle function. Whether interstitial K⁺ balance is altered in aged skeletal muscle is unknown at present. It has been reported that in elderly men the rate of increase in plasma K⁺ during exercise was greater compared with that in young men, suggesting there is perhaps a deficit in potassium metabolism with age (15). Previous studies from our laboratory showed age-related alterations in the content and expression of the Na⁺-K⁺-ATPase subunit isoforms in the hindlimb muscle of rat (34, 44). Thus skeletal muscle in the aged rats may have an altered Na⁺-K⁺ pump function due to a change in total number of pumps, as well as altered affinity for K⁺ and/or Na⁺ because the Na⁺-K⁺-ATPase isozymes possess different affinity for these ions (2, 6, 21). Because the Na⁺-K⁺ pump is a major regulator of [K⁺]_o (4), those changes may result in altered K⁺ balance in aged skeletal muscle. Therefore, the present study tested the hypothesis that there is a greater accumulation of [K⁺]_o in aged compared with adult skeletal muscle during muscle contraction, and potential underlying mechanism(s) are discussed.

	METHODS

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Surgical preparation.   All procedures outlined in this study were approved by the Animal Care Committee at The Pennsylvania State University, College of Medicine. Fischer 344 x Brown Norway male rats (six 8 mo old and six 32 mo old) were anesthetized by inhalation of isoflurane-oxygen mixture (2–5% isoflurane in 100% O₂). An endotracheal tube was inserted into the trachea and attached to a ventilator. Polyethylene catheters were inserted into the common carotid artery and external jugular vein for measurement of arterial blood pressure and drug administration, respectively. The intact sciatic nerve of one leg was isolated and then placed on a stimulating electrode. The animals were ventilated, and respiratory parameters were monitored and maintained at normal ranges as previously described (23, 24). Body temperature was maintained between 37.5 and 38°C by a heating pad and external heat lamps, and fluid balance was stabilized by continuous infusion of saline. Decerebration was performed as previously described (23, 24). Once this procedure was completed, anesthesia was removed from the inhaled mixture to avoid any possible confounding effects of the anesthesia may have on the function of the Na⁺-K⁺ pump.

Insertion of microdialysis probes.   The skin directly over the triceps surae muscles of one leg was dissected away, and four microdialysis probes were inserted into the gastrocnemius muscle. Briefly, the probes were inserted into the muscle via a cannula in the direction parallel to the orientation of the muscle fibers. After insertion, the microdialysis probes were attached to a perfusion pump and perfused at a rate of 2.5 µl/min with a physiological saline. The semipermeable fibers with a molecular mass cutoff of 30 kDa (0.20 mm ID, 0.22 mm OD; Spectrum Laboratories, Laguna, CA) were used to construct the microdialysis probes. Each end of a single fiber was inserted 1 cm into a hollow polyamide tube (0.25 mm ID, 0.36 mm OD) and glued. The length of the probe fibers was 2.0 cm. The percent recovery rate of K⁺ for the microdialysis probe was examined in vitro. The rates for 1.0, 2.5, 5.0, and 10 mM of K⁺ were 63–68%. A linear regression analysis for dialysate vs. standard K⁺ concentrations shows that the relationship is linear (r = 0.956, P < 0.001). Thus K⁺ concentrations measured in the dialysate were linearly related to the [K⁺]_o in the rat muscle. It has been shown that probe recovery is not altered by vasoconstrictor maneuvers or twitch contractions of muscle (28). In this report, we present dialysate concentrations without considering the recovery rate of the probes.

[K⁺]_o measurement.   To measure [K⁺]_o, we employed a micro-flow-through K⁺ electrode (Microelectrode, Londonderry, NH), which was modified so that the dead space in the system was <5 µl. The ends of individual microdialysis probes were attached to the electrodes via a modified manifold system, and thus the dialysate from these probes continuously flowed past the electrodes. This approach allowed the continuous online measurement of K⁺ throughout the experiment. Prior reports have illustrated the accuracy and reliability of the online K⁺ electrodes to determine dialysate K⁺ concentrations (25, 28).

Experimental protocol.   A 60-min equilibration period was allowed after the microdialysis probes were inserted. During the experiment, the rats were held in a stereotaxic head-and-spinal unit (Kopf Instrument). The pelvis was stabilized in a spinal unit, and the knee joints were secured by attaching the patellar tendon to a steel post. Contractions induced by electrical stimulation of the sciatic nerve were then performed. Three bouts of rhythmic contraction were conducted at frequencies of 1, 3, and 5 Hz (2.5 times motor threshold and 0.1-ms duration). Each of the stimulations was sustained for 10 min, and there was a 60-min rest period between each bout of contraction. [K⁺]_o before, during, and after each workload was measured, In a final group of studies, 5 mM of ouabain was added to the perfusate, and resting [K⁺]_o levels before and after perfusion of ouabain, without any electrical stimulation, were measured. This concentration of ouabain is expected to occupy and inhibit close to 100% of the Na⁺-K⁺ pump (36). At the end of each experiment, rats were killed by intravenous injection of an overdose of pentobarbital sodium (120 mg/kg) and 1 ml of a saturated solution of KCl.

Data acquisition and analyses.   Mean arterial pressure (MAP) during electrically stimulated muscle contraction was continuously recorded on an MacIntosh computer using PowerLab software. K⁺ data were collected every 5 s and were recorded on a PC-based computer. MAP, resting [K⁺]_o data, and the time for [K⁺]_o to recover by 20% (T₂₀) and 50% (T₅₀) from peak response were expressed as absolute value. The response for [K⁺]_o during contraction and ouabain perfusion was determined by the percent change from control. The control values were determined by analyzing at least 30 s of the data immediately before the interventions, and subsequent K⁺ responses were determined by each minute. This data analysis normalizes the slight variations in resting muscle [K⁺]_o between rats, and we found the statistical analysis results to be the same whether the data were analyzed by using percentage changes or absolute values. The data were analyzed with a one-way repeated-measures ANOVA. Tukey post hoc analysis was utilized to determine differences between groups. All values are expressed as means ± SE. For all analyses, differences were considered significant at P < 0.05. All statistical analyses were performed using SPSS for windows version 11.5.

	RESULTS

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[K⁺] levels in adult and aged rats at rest and after twitch contraction.   Within 60 min after the insertion of microdialysis probe, [K⁺]_o gradually returned to a steady-state resting level (Fig. 1). Between the adult and aged rats, there was no significant difference in the resting [K⁺]_o levels. Twitch muscle contraction induced by electrical stimulation quickly increased [K⁺]_o. The peak [K⁺]_o level was significantly higher in the aged rats compared with the adult rats (8-mo-old rat = 2.21 ± 0.42 mM; 32-mo-old rat = 2.83 ± 0.52 mM, P < 0.05) (Fig. 2). Furthermore, the T₂₀ and T₅₀ from peak response were analyzed. There was a trend for the recovery time to be longer in aged than in adult rats, and the differences reached significance at 3 and 5 Hz of stimulation (Fig. 3). Basal MAP before contraction was not different between the animals of the two age groups, and electrical stimulations did not significantly increase blood pressure in either group (Table 1).

View larger version (13K): [in this window] [in a new window]   Fig. 1. Interstitial K+ concentrations after insertion of microdialysis probes. There were no significant differences in baseline values for muscle interstitial K+ concentrations between 8-mo-old (n = 6) and 32-mo-old (n = 6) rats. Values are means ± SE.

View larger version (18K): [in this window] [in a new window]   Fig. 2. Percent increases of interstitial K+ concentrations during twitch muscle contraction induced by electrical stimulation of the sciatic nerve. A: 1-Hz stimulation. B: 3-Hz stimulation. C: 5-Hz stimulation. Stimulations elevated muscle interstitial K+ concentrations in both 8-mo-old (n = 6) and 32-mo-old (n = 6) rats. The increase in interstitial K+ concentrations was greater in the aged rats than in adult rats. Values are means ± SE. , Change. *P < 0.05, significance vs. adult rats.

View larger version (8K): [in this window] [in a new window]   Fig. 3. Recovery rates of interstitial K+ concentrations after electrical stimulation. A: 1-Hz stimulation. B: 3-Hz stimulation. C: 5-Hz stimulation. T20 and T50 represent the time for interstitial K+ concentrations to recover by 20% and 50% from peak response, respectively. The recovery was significantly slower in aged rats compared with adult rats. Values are means ± SE. *P < 0.05, significance vs. adult rats.

View larger version (10K): [in this window] [in a new window]   Fig. 4. Interstitial K+ concentrations after perfusion of 5 mM of ouabain. In 8-mo-old (n = 6) and 32-mo-old (n = 6) rats muscle interstitial K+ concentrations were significantly elevated after ouabain perfusion. However, the effect was smaller in the 32-mo-old rats. Values are means ± SE. *P < 0.05, significance vs. adult rats.

	DISCUSSION

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Our data showed that in the resting state there was no discernable difference in [K⁺]_o between adult and aged skeletal muscle. However, with induction of muscle contraction, between 1 and 5 Hz, [K⁺]_o rose to a significantly higher level in aged than in adult skeletal muscle, suggesting a potential deficit in the regulation of [K⁺]_o in aged skeletal muscle. Accumulation of K⁺ in the interstitium can be viewed as a function of three interacting factors, namely, the K⁺ leak/release from the muscle cells, the reuptake of K⁺ into the cells by the Na-K pump, and the clearance of K⁺ from the interstitium due to blood flow. The latter two factors are mainly responsible for the recovery of [K⁺]_o to its basal levels. Therefore, the elevated [K⁺]_o in aged skeletal muscle could be the result of an increased K⁺ leak/release, a decreased reuptake by the Na⁺-K⁺ pump, a decreased clearance of K⁺ due to blood flow, or a combination of these factors. Although the design of the present study does not allow us to unequivocally identify mechanisms underlying the altered K⁺ balance in aged skeletal muscle, potential involvements of the factors may be appraised.

First, our data showed that in the resting state when the Na⁺-K⁺ pump was inhibited by infusion of ouabain, levels of [K⁺]_o were lower in aged than in adult skeletal muscle (Fig. 4). The result is consistent with a lower K⁺ leak/release and/or a higher K⁺ clearance from blood flow in aged skeletal muscle. By contrast, in the presence of functional Na⁺-K⁺ pump, levels of resting [K⁺]_o did not differ between the two age groups (Fig. 1). These data suggest, but do not prove, that the Na⁺-K⁺ pump in aged skeletal muscle may be less effective in the reuptake of K⁺, such that despite a lower K⁺ leak/release and/or a higher clearance, the basal [K⁺]_o level in aged skeletal muscle was not different from that of adult skeletal muscle. Second, at higher frequency of stimulation (3 and 5 Hz), the T₂₀ and T₅₀ were significantly longer in aged than in adult skeletal muscle. This deficiency in the recovery of [K⁺]_o could be the result of a less efficient K⁺ uptake by the Na⁺-K⁺ pump and/or a decreased clearance of K⁺ in aged skeletal muscle. We cannot clearly discern the contribution of the two potential mechanisms on the basis of the present results. However, the latter possibility does not seem to be congruent with the ouabain infusion result discussed earlier. Taken together, the present data are consistent with the notion that a decreased Na-K pump function plays a role, at least in part, in the age-related deficit in K⁺ balance in skeletal muscle. It is of interest to note, Musch et al. (33) have shown that, at rest, blood flow to the total hindlimb musculature and to all of the individual muscles or muscle parts (with the exception of the plantaris) was not different between young (6–8 mo old) and old (27–29 mo old) rats. However, submaximal exercise elicited a differential redistribution of blood flow in individual hindquarter muscles between young and old rats. Thus, to definitively determine a contribution of an altered K⁺ clearance in aged skeletal muscle, or lack thereof, future studies should aim to measure [K⁺]_o under a condition where skeletal muscle blood flow is maintained by constant perfusion. Finally, the present results do not allow us to determine whether the K⁺ leak/release from actively contracting muscle is different between adult and aged skeletal muscle.

A somewhat unexpected observation is that there was an apparent decline in [K]_o toward the end of electrical stimulation and the reason is unclear at present. However, in the report by Nielsen et al. (35), [K⁺]_o levels also declined during intense exercise after an initial rise. Thus we speculate a possible reason for the decline observed in our study may be due to diminution of intracellular K⁺ levels after prolong electrical contraction stimulation.

Changes in [K⁺]_o could have important impacts on the performance of the skeletal muscle by direct and indirect mechanisms. An augmented accumulation of [K⁺]_o could result in reduced membrane excitability, and, consequently, contractile force (3, 16). According to the membrane hypothesis of muscle fatigue, during maximal muscle activity when the sarcolemmal Na⁺-K⁺ pump is unable to keep up with the K⁺ efflux, contractile function declines due to declining membrane potential and cell excitability (14). Furthermore, Overgaard et al. (39) suggested a direct role of K⁺-Na⁺ gradients in modulating contractile function of skeletal muscle by demonstrated that an increase in [K⁺]_o (and a decrease in interstitial Na concentration) reduces M-wave and consequently tetanic force.

In the present study a physiology saline solution without K⁺ was used as perfusate in the dialysis probe, similar to the method described by Green et al. (17) in their measurement of interstitial K⁺. This undoubtedly, to a large part, accounts for the seemingly low [K]_o levels in our study compared with previous reports (18, 28, 35, 38). However, it should be noted that we present the dialysate K⁺ concentrations without considering the recovery rate of the probes (60%). If we take this into account, then resting [K⁺]_o will be 2–2.5 mM in our study, a [K]_o level that is closer to what have been reported previously.

Although the magnitude of augmentation in [K]_o in aged rats after electrical stimulation does not appear to be very large, the increase may ultimately be able to influence contractile function of the skeletal muscle. As suggested by Nielsen et al. (37), it is possible that an increase of [K⁺] in the t-tubular system may reach a critical level earlier due to the relative small volume of the t-tubular system. Furthermore, these authors suggested that the expected increase in interstitial Na⁺ concentration after repeated stimulation may further interfere with the ability of the t-tubular system to support successive action potentials at close intervals, conditions that may reduce tetanic force responses and thus contribute to muscle fatigue.

[K⁺]_o can also affect the sympathetic nervous system activity. In skeletal muscle, afferent nerves, such as the group III and IV afferents, have been shown to be activated by [K⁺]_o (41). This activation results in the stimulation of cardiovascular nuclei in the brain stem, an increase of sympathetic activity, and rises in blood pressure, which is part of the exercise pressor response (32). Therefore, an augmented [K⁺]_o in aged skeletal muscle could result in a higher pressor response, consistent with the clinical observation that the pressor response is greater in older people (30). It has been shown that the decline in exercise performance associated with aging may be partly due to decreased blood flow to active skeletal muscles (20, 31). Interstitial norepinephrine released from sympathetic nerves regulates vascular smooth muscle tone and thus muscle blood flow. Previous data showed [K⁺]_o may play a role in modulating exocytotic release of norepinephrine (43). Thus it may be speculated that during intense physical activity, a greater increase in [K⁺]_o with muscle contraction in aged animals may induce a larger release of norepinephrine and evoke vasoconstriction, which could reduce blood flow to muscles. On the other hand, an increased [K⁺]_o may relax vascular smooth muscle and evoke vasodilation (7). This action opposes the effects of norepinephrine but may benefit the clearance of metabolites in the interstitium. Whether the increase in [K⁺]_o that we have detected is capable of causing such a vasodilation in skeletal muscle remains to be determined. The relative contributions of these competing factors should be the aim of future studies.

In conclusion, the present data demonstrated an augmented [K⁺]_o in aged skeletal muscle compared with adult skeletal muscle with twitch muscle contraction. An alteration in the function of the Na⁺-K⁺ pump may contribute, in part, to the deficiency in K⁺ balance in the skeletal muscle of aged rats.

	GRANTS

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This study was supported by National Institutes of Health grants RO1 AG-16822 (Y.-C. Ng), RO1 HL-75533 (J. Li), and RO1 HL-60800 (L. I. Sinoway).

	ACKNOWLEDGMENTS

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The authors express gratitude to Val Kehoe for excellent technical assistance. The authors also thank Nick King for help in using potassium microelectrode technique, Liz Chambers and Oze Henig for help in making dialysis probes and preparing experiments. We also thank Linda Chung for careful reading of the manuscript.

	FOOTNOTES

 

Address for reprint requests and other correspondence: Y.-C. Ng, Dept of Pharmacology, College of Medicine, The Pennsylvania State Univ., Milton S. Hershey Medical Center, 500 Univ. Dr., Hershey, PA 17033 (e-mail: ycn1{at}psu.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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This Article Abstract Full Text (PDF) Free All Versions of this Article: 100/4/1158    most recent 00639.2005v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Li, J. Articles by Ng, Y.-C. Search for Related Content PubMed PubMed Citation Articles by Li, J. Articles by Ng, Y.-C.