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J Appl Physiol 83: 323, 1997;
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Journal of Applied Physiology
Vol. 83, No. 1, pp. 323-323, July 1997
EXERCISE AND MUSCLE

RAPID COMMUNICATION

Decreased [3H]ouabain binding sites in skeletal muscle of rats with chronic heart failure

Joel G. Pickar1, John P. Mattson1, Steve Lloyd2, and Timothy I. Musch1,2

Departments of 1 Anatomy and Physiology and 2 Kinesiology, Kansas State University, Manhattan, Kansas 66506

ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES

ABSTRACT

Pickar, Joel G., John P. Mattson, Steve Lloyd, and Timothy I. Musch. Decreased [3H]ouabain binding sites in skeletal muscle of rats with chronic heart failure. J. Appl. Physiol. 83(1): 323-329, 1997.---Abnormalities intrinsic to skeletal muscle are thought to contribute to decrements in exercise capacity found in individuals with chronic heart failure (CHF). Na+-K+-adenosinetriphosphatase (the Na+ pump) is essential for maintaining muscle excitability and contractility. Therefore, we investigated the possibility that the number and affinity of Na+ pumps in locomotor muscles of rats with CHF are decreased. Myocardial infarction (MI) was induced in 8 rats, and a sham operation was performed in 12 rats. The degree of CHF was assessed ~180 days after surgery. Soleus and plantaris muscles were harvested, and Na+ pumps were quantified by using a [3H]ouabain binding assay. At the time of muscle harvest, MI and sham-operated rats were similar in age (458 ± 54 vs. 447 ± 34 days old, respectively). Compared with their sham-operated counterparts, MI rats had a significant amount of heart failure, right ventricular-to-body weight ratio was greater (48%), and the presence of pulmonary congestion was suggested by an elevated lung-to-body weight ratio (29%). Left ventricular end-diastolic pressure was significantly increased in the MI rats (11 ± 1 mmHg) compared with the sham-operated controls (1 ± 1 mmHg). In addition, mean arterial blood pressure was lower in the MI rats compared with their control counterparts. [3H]ouabain binding sites were reduced 18% in soleus muscle (136 ± 12 vs. 175 ± 13 pmol/g wet wt, MI vs. sham, respectively) and 22% in plantaris muscle (119 ± 12 vs. 147 ± 8 pmol/g wet wt, MI vs. sham, respectively). The affinity of these [3H]ouabain binding sites was similar for the two groups. The relationship between the reduction in Na+ pump number and the reduced exercise capacity in individuals with CHF remains to be determined.

sodium; pump; sodium-potassium-adenosinetriphosphatase

INTRODUCTION

REDUCED EXERCISE CAPACITY produced by the early onset of muscular fatigue is arguably the most common symptom experienced by individuals with chronic heart failure (CHF) (7). CHF diminishes cardiac output and renders the heart unable to maintain an output sufficient for the metabolic needs of tissues and organs (28). Early investigations contributed to the idea that muscular fatigue was secondary to an insufficient cardiac output. However, the degree of exercise intolerance often correlates poorly with the degree of cardiac impairment, suggesting that tissues other than the heart contribute to the pathophysiology (11).

Abnormalities intrinsic to skeletal muscle have been linked to the reduced exercise capacity in CHF. These abnormalities include abnormal cellular metabolism, altered mitochondrial enzymes, changes in fiber type composition, and muscle atrophy (2, 17, 19, 21, 29). In addition, abnormalities in excitation-contraction coupling, independent of muscle atrophy, are present in CHF. Ca2+ release and uptake from the sarcoplasmic reticulum are abnormal, and both twitch and tetanic tensions are reduced in the CHF state (13, 26). The sarcolemmal membrane may also be affected in CHF because the concentration of Na+-K+-adenosinetriphosphatase (Na+-K+-ATPase), the Na+ pump, decreases in the vastus lateralis muscle as left ventricular ejection fraction decreases in affected humans (24).

The purpose of the present investigation was to determine whether the number of Na+ pumps is decreased in locomotor muscles of rats with CHF. These studies were undertaken because alterations in transmembrane Na+ and K+ transport can disturb sarcolemmal excitability and skeletal muscle contractility (4). We tested the hypothesis that the number of Na+ pumps is reduced in soleus and plantaris muscles of rats with CHF induced by myocardial infarction (MI).

METHODS

Female Wistar rats were obtained from Charles River Laboratories. All rats received rat chow and water ad libitum and were maintained on a 12:12-h light-dark cycle. All experimental procedures were approved by the Institutional Animal Care and Use Committee at Kansas State University.

Surgically induced MI. Rats were anesthetized initially with a 5% halothane in oxygen mixture. They were intubated, connected to a rodent respirator (model 680, Harvard Apparatus), and maintained on a 2% halothane in oxygen mixture. The heart was exteriorized through a left-side thoracotomy between the fifth and sixth rib. The pericardial sac was opened, and the heart was exposed. Rats received either an MI or a sham operation as described previously (22). In rats receiving an MI, the left coronary artery was ligated between the pulmonary artery and the left atrium. A 6-0 suture was placed around the left main coronary artery and tied. Sham operations were completed by using the same surgical procedures except that the coronary artery was not ligated. The thoracotomy was closed by using surgical sutures. After these procedures, the lungs were hyperinflated, and the ribs approximated with 3-0 gut. The muscles of the thorax were sewn together with 4-0 gut, and the skin incision was closed with 3-0 silk. Analgesic agents were applied to each animal. Anesthesia was withdrawn, and the animals were extubated. Postoperatively, each rat received 1,000 U of Pen-G/day im for 2 days. All rats were returned to their individual cages, which were 6 in. wide and 9 in. long.

Determination of left ventricular dysfunction. The presence and severity of CHF were evaluated in each rat by using the following structural indexes: changes in left ventricular (LV), right ventricular (RV), and total lung weight normalized to body weight. Hemodynamic indexes included changes in mean arterial pressure (MAP) and left ventricular end-diastolic pressure (LVEDP). Approximately 180 days after surgery, each rat was anesthetized (pentobarbital sodium, 30 mg/kg ip), and the right carotid artery was cannulated with a 2-Fr catheter-tip pressure manometer (Millar Instruments) for recording of arterial pressure and heart rate. While the rat breathed spontaneously, the micromanometer was advanced into the LV in a retrograde fashion for measuring ventricular systolic and diastolic pressures. Immediately after measurement of ventricular pressures, the micromanometer was removed from the animal, and the soleus and plantaris muscles were harvested for the determination of Na+ pump number and affinity. After the skeletal muscles were removed, the rats were killed with an overdose of anesthetic (pentobarbital sodium, 100 mg/kg ip).

Determination of Na+ pumps. The number and affinity of Na+ pumps in the soleus and plantaris muscles were determined by using a radiolabel ([3H]ouabain) binding assay (25, 27). Each muscle was cut into 800-µm-thick transverse sections by using a McIlwain tissue chopper (Brinkman Instruments). Each muscle slice was placed in a separate well of a tissue culture plate. Each well was filled with 2 ml of a standard solution (in mM): 10 tris(hydroxymethyl)aminomethane · HCl, 3 MgSO4, 1 sodium vanadate, and 250 sucrose (pH 7.3).

The binding assay was accomplished in five stages: 1) preincubation wash; 2) incubation with radiolabel; 3) washout of unbound radiolabel; 4) weighing and digestion; and 5) counting of radiolabel. Stages 1-3 were performed in the standard solution with the appropriate concentration of ouabain at constant temperature (37°C). All measurements were performed in triplicate.

Assay protocol. The preincubation wash in the standard solution alone was performed on ice for 20 min to remove extracellular K+. Slices were incubated in fresh standard solution with radiolabel and gently shaken at 37°C for 3 h in a Dubnoff metabolic incubator. Total binding was obtained over a concentration range of 5-1,000 nM ouabain. Nonspecific binding was determined by using an excess of unlabeled ouabain (10-4 M). All wells contained 5 nM [3H]ouabain titrated to the appropriate concentration with unlabeled ouabain. Free ouabain in the incubation solution (Of) was determined at the end of the incubation by removing 250 µl of the incubation medium from the wells with the most dilute concentration of ouabain (5 nM).

Slices were washed on ice for a total of 20 min (2 washes × 10 min). Slices from the total binding wells were washed in standard solution; slices from nonspecific binding wells were washed with an excess of unlabeled ouabain (10-4 M) during the assay. Individual slices were blotted, weighed, placed in liquid scintillation vials, and digested overnight (at least 12 h) in 250 µl of 1 M NaOH.

Three milliliters of liquid scintillation cocktail (Ecolite+; ICN Biomedicals) were added to the scintillation vials, and counting was performed in a Minaxi Tri-carb scintillation counter (4000 series; Packard). Specific binding was determined from the difference between total and nonspecific binding normalized to grams of wet muscle weight. Quench curves were established for the standard and NaOH solution to accurately calculate specific [3H]ouabain binding sites.

Statistical analysis. Structural and hemodynamic indexes were compared by using Student's t-tests. The maximal number of specific ouabain binding sites (Bmax) and the apparent dissociation constant (Kd) for ouabain were determined for each rat and each muscle by using Scatchard analysis. These results were also analyzed by using Student's t-tests. Differences at the P < 0.05 level were considered significant. All values are presented as mean ± SE.

RESULTS

MIs were induced in 8 rats, and sham operations were performed in 12 rats. Body weights were not significantly different between the two groups (432 ± 28 vs. 446 ± 17 g, MI vs. sham operated, respectively). In addition, MI and sham-operated rats were similar in age at the time of muscle harvest (458 ± 54 vs. 447 ± 34 days old, respectively).

Structural and hemodynamic indexes indicative of heart failure were prevalent in the MI rats (Table 1). Left and right ventricular-to-body weight ratios were significantly greater, by 18 and 48%, respectively, in MI rats compared with sham-operated controls. In addition, the presence of pulmonary congestion was suggested by a greater lung-to-body weight ratio (29%). LVEDP was elevated and MAP was lower in the MI rats compared with their sham-operated counterparts.

Table  1.   Comparison of structural and hemodynamic indexes of chronic heart failure in rats with and without surgically induced myocardial infarction
Group n LV/Body Wt, mg/g RV/Body Wt, mg/g Lung/Body Wt, mg/g LVEDP, mmHg MAP, mmHg
Sham 12 1.97 ± 0.07  0.48 ± 0.02  3.43 ± 0.17  1 ± 1  125 ± 3 
CHF 8 2.33 ± 0.09* 0.71 ± 0.05* 4.41 ± 0.4* 11 ± 1* 105 ± 5*
Values are means ± SE; n, no. of rats. CHF, chronic heart failure; LV, left ventricular weight; RV, right ventricular weight; LVEDP, left-ventricular end-diastolic pressure; MAP, mean arterial pressure. * P < 0.05 from sham.

Saturation binding isotherms for specific [3H]ouabain binding sites in soleus and plantaris muscles are shown in Fig. 1. The isotherms were obtained by subtracting the nonspecific binding of [3H]ouabain from the total binding of [3H]ouabain to skeletal muscle slices. The isotherm data were transformed by using Scatchard analysis (Fig. 1, insets). The fit of a first-order linear regression line for both MI and sham-operated rats indicates that there was a single population of high-affinity sites in both soleus and plantaris muscles (Table 2).

Fig. 1. Average saturation binding isotherms for [3H]ouabain binding to soleus (A) and plantaris (B) muscle slices from rats with and without chronic heart failure (CHF). Open symbols, CHF; solid symbols, Sham. Insets: Scatchard analyses derived from average isotherms. Each symbol represents means ± SE. These results demonstrate presence of a single population of [3H]ouabain binding sites in soleus and plantaris muscles.
[View Larger Version of this Image (19K GIF file)]

Table  2.   3[H]ouabain binding sites and binding affinity in muscles from rats with and without CHF
Group n Bmax, pmol/g wet wt Kd, nM Rs
Soleus muscle
Sham 11 175 ± 13  74 ± 19  0.98
CHF 8 136 ± 12* 89 ± 25  0.98
Plantaris muscle
Sham 12 147 ± 8  75 ± 10  0.98
CHF 7 119 ± 12* 71 ± 15  0.99
Values are means ± SE; n, no. of rats. Bmax (maximal binding capacity) and Kd, (apparent dissociation constant) represent mean of individual values obtained from Scatchard analysis for each muscle from each rat; Rs, coefficient of correlation for linear regression of group Scatchard plot from Fig. 1. * P < 0.05 from sham.

The concentration of [3H]ouabain binding sites was reduced 18% in soleus and 22% in plantaris muscles of MI rats compared with their sham-operated counterparts (Table 2). The affinity of the single population of [3H]ouabain binding sites in soleus and plantaris muscles was similar between MI and sham-operated rats. In addition, the volume of distribution available for [3H]ouabain was determined in each muscle (Table 3). The space available for [3H]ouabain in both the soleus and plantaris muscles was similar between the two groups.

Table  3.   Mean volume of distribution for nonspecifically bound 3[H]ouabain in muscle from infarcted and noninfarcted rats
Group n 3[H]ouabain Concentration, nM Specific Activity, Ci/mmol DPM/g wet wt Volume of Distribution, ml/g wet wt
Soleus muscle
Sham 11 5.31 18 19,678 0.12 ± 0.02 
CHF 8 5.35 18 22,585 0.10 ± 0.01 
Plantaris muscle
Sham 8 5.28 18 20,334 0.10 ± 0.01 
CHF 7 5.42 18 26,435 0.10 ± 0.01
Values are means ± SE or means; n, no. of rats. Mean volume of distribution was calculated from volume of distribution for each muscle; DPM, disintegrations/min.

DISCUSSION

The present findings support the hypothesis that intrinsic skeletal muscle abnormalities are associated with the CHF state. The concentration of Na+ pumps was reduced in two hindlimb locomotor muscles of rats with CHF compared with their noninfarcted controls. The concentration of pumps decreased significantly by 18% in soleus, a muscle composed predominantly of slow-oxidative fibers and by 22% in plantaris, a muscle composed of relatively equal proportions of fast-oxidative and fast-glycotic fibers (1, 5). Changes in the concentration of Na+ pumps were not due to the age-related reduction in pump number (15), because rats of similar ages were used in these experiments. In addition, the decrease in Na+ pump concentration was not due to a change in the diffusible space available for [3H]ouabain binding, because the volume of distribution for nonspecifically bound ouabain was similar between rats with and without CHF. The affinity of the Na+ pump for ouabain was not affected by the CHF state. These data are the first to demonstrate that Na+ pump concentration is reduced in the locomotor muscles of rats with CHF. Moreover, the reduced concentration of pumps occurred without any changes in affinity. The significant reduction in Na+ pump concentration in skeletal muscle may contribute to the reduced exercise capacity found in CHF (23, 30).

The factors that regulate the concentration of sarcolemmal Na+ pumps are not clear. It might be expected that fibers recruited at the highest alpha -motoneuron frequencies, i.e., fast-twitch muscle fibers, would contain the highest concentration of Na+ pumps. This relationship would enable the most active muscle cells to reestablish their transmembrane Na+ and K+ gradients and maintain their excitability. Such a relationship was demonstrated by Kjeldsen et al. (15). The number of Na+ pumps is greater in the fast-twitch extensor digitorum longus (EDL) compared with the slow-twitch soleus. Chin and Green (3), on the other hand, suggested that muscle's oxidative potential relates better than its contractile characteristics to the number of sarcolemmal Na+ pumps. They report the highest [3H]ouabain binding in muscles with high citrate synthase activity, e.g., soleus, red vastus lateralis, and EDL, and the lowest [3H]ouabain binding in muscles with low citrate synthase activity, e.g., white vastus lateralis (3). The relative importance of a muscle's contractile characteristics compared with its oxidative potential in regulating the number of sarcolemmal Na+ pumps remains controversial.

Our data suggest that long-term regulation of Na+ pump number in skeletal muscle may not necessarily be coupled to the muscle's contractile characteristics or oxidative potential. In rats with CHF, similar to that developed in this study, Duan et al. (8) demonstrated that neither fiber type distribution nor citrate synthase activity changed in soleus or plantaris muscles. Yet, in the present study, the concentration of [3H]ouabain binding sites decreased in both muscles. Several other factors present in the CHF state may contribute individually or as an ensemble to the reduction in Na+ pump concentration. For example, electrolyte disturbances in CHF may contribute to the downregulation of Na+ pump density. K+ and Mg2+ deficiencies decrease the concentration of Na+ pumps in skeletal muscle in rats (14, 24a) and humans (6). Deficiencies in both electrolytes have been noted in humans with CHF (10, 18). The increase in muscle sympathetic nerve activity in CHF (20) may also contribute to the downregulation of Na+ pump density. Catecholamines increase Na+ pump activity via beta -adrenergic receptors located on the muscle membrane (4a). The continued presence of this signal as CHF develops may lead to a desensitization of Na+ pump activity reflected in the decreased concentration of Na+ pumps.

If the decreased concentration of Na+ pumps contributes to the decrements in exercise capacity in individuals with CHF, then this raises several interesting possibilities regarding rehabilitation and treatment. For example, it is known that exercise training for as little as 6 days increases skeletal muscle Na+ pump concentrations by 13.6% in humans (16). Similarly, exercise training for 4-6 wk in rats increases skeletal muscle pump concentration by 22-46% (12). The training effect on the concentration of Na+ pumps in skeletal muscle may offset decreases in Na+ pump concentration associated with CHF. However, the relationship between the reduction in Na+ pump concentration and the reduced exercise capacity found with this pathological state remains to be determined.

ACKNOWLEDGEMENTS

This work was supported by American Heart Association, Kansas Affiliate, Grant KS-95-GB-4 (to J. G. Pickar) and by National Institute of Health Grants HL-49221 (to J. G. Pickar) and AG-11535 (to T. I. Musch).

FOOTNOTES

Address for reprint requests: J. G. Pickar, Kansas State Univ., Dept. of Anatomy and Physiology, VMS 228, Manhattan, KS 66506.

Received 31 December 1996; accepted in final form 14 March 1997.

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