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J Appl Physiol 88: 346-351, 2000;
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Vol. 88, Issue 1, 346-351, January 2000

The Na+-K+-ATPase alpha 2 gene and trainability of cardiorespiratory endurance: the HERITAGE Family Study

Tuomo Rankinen1, Louis Pérusse2, Ingrid Borecki3, Yvon C. Chagnon2, Jacques Gagnon2, Arthur S. Leon4, James S. Skinner5, Jack H. Wilmore6, D. C. Rao3, and Claude Bouchard1

1 Pennington Biomedical Research Center, Human Genomics Laboratory, Baton Rouge, Louisiana 70808-4124; 2 Physical Activity Sciences Laboratory, Laval University, Ste-Foy G1K 7P4, Québec, Canada; 3 Division of Biostatistics and Departments of Genetics and Psychiatry, Washington University Medical School, St. Louis, Missouri 63110-1093; 4 School of Kinesiology and Leisure Studies, University of Minnesota, Minneapolis, Minnesota 55455; 5 Department of Kinesiology, Indiana University, Bloomington, Indiana 11001; and 6 Department of Health and Kinesiology, Texas A&M University, College Station, Texas 77843-4243


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The Na+-K+-ATPase plays an important role in the maintenance of electrolyte balance in the working muscle and thus may contribute to endurance performance. This study aimed to investigate the associations between genetic variants at the Na+-K+-ATPase alpha 2 locus and the response (Delta ) of maximal oxygen consumption (VO2 max) and maximal power output (Wmax) to 20 wk of endurance training in 472 sedentary Caucasian subjects from 99 families. VO2 max and Wmax were measured during two maximal cycle ergometer exercise tests before and again after the training program, and restriction fragment length polymorphisms at the Na+-K+-ATPase alpha 2 (exons 1 and 21-22 with Bgl II) gene were typed. Sibling-pair linkage analysis revealed marginal evidence for linkage between the alpha 2 haplotype and Delta VO2 max (P = 0.054) and stronger linkages between the alpha 2 exon 21-22 marker (P = 0.005) and alpha 2 haplotype (P = 0.003) and Delta Wmax. In the whole cohort, Delta VO2 max in the 3.3-kb homozygotes of the exon 1 marker (n = 5) was 41% lower than in the 8.0/3.3-kb heterozygotes (n = 87) and 48% lower than in the 8.0-kb homozygotes (n = 380; P = 0.018, adjusted for age, gender, baseline VO2 max, and body weight). Among offspring, 10.5/10.5-kb homozygotes (n = 14) of the exon 21-22 marker showed a 571 ± 56 (SE) ml O2/min increase in VO2 max, whereas the increases in the 10.5/4.3-kb (n = 93) and 4.3/4.3-kb (n = 187) genotypes were 442 ± 22 and 410 ± 15 ml O2/min, respectively (P = 0.017). These data suggest that genetic variation at the Na+-K+-ATPase alpha 2 locus influences the trainability of VO2 max in sedentary Caucasian subjects.

exercise training; sodium-potassium pump; family study


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

THE CAPACITY TO PERFORM high-intensity exercise over an extended period of time is influenced by several factors. The availability of oxygen and energy substrates, as well as the efficiency of muscle energy production mechanisms, is fundamental to maintain a given exercise intensity level. The potential of respiratory and cardiovascular systems to adapt to regular exercise training is also of importance. One factor critically influencing the excitability of skeletal muscles is the concentration gradients for Na+ and K+ across sarcolemma and t-tubular membranes (30). The membrane potential, created by active transport of Na+ out of the fibers and of K+ into the fibers, is essential for the spread of action potentials along the sarcolemma and the t-tubular membranes and, subsequently, for muscle contraction. After contraction, the membrane potential must be restored to facilitate the spread of a new action potential. During exercise, K+ efflux and Na+ influx increase drastically in skeletal muscle, leading to depolarization of the cell membrane and, if not corrected, to a decrease in muscle contractility.

The sarcolemmal Na+-K+-ATPase is a key enzyme for the maintenance of cation-concentration gradients across the cell membrane by transporting three Na+ out of the cell and two K+ into the cell for each molecule of ATP used to drive the process (9). The activity of Na+-K+-ATPase in working skeletal muscles is markedly increased during an acute bout of exercise, mainly because of activation of inactive molecules already present in the sarcolemma (10, 28). However, during high-intensity exercise, the rate of cation fluxes seems to exceed the capacity of the sarcolemmal Na+-K+-ATPase, resulting in a lower membrane potential (10, 17). The activity level of the enzyme remains elevated after cessation of exercise to facilitate the recovery of cation gradients in muscles (27, 28). Regular exercise training has been shown to increase Na+-K+-ATPase concentration in the plasma membrane of trained muscles in sedentary subjects (15, 16, 25), moderately endurance-trained men (22), and endurance athletes (11); this pattern is observed regardless of the mode of exercise training (24). On the other hand, inactivation of the Na+-K+-ATPase by ouabain or by K+ depletion significantly decreases contractile endurance in animal models (18, 26), whereas activation of the Na+-K+-ATPase with insulin or catecholamines or by electrical stimulation restores hyperpolarization of the sarcolemma and force production of rat soleus muscle exposed to altered Na+ and K+ gradients (29, 31).

Genetic factors have been shown to influence the cardiorespiratory fitness level, both in the sedentary state and in response to regular endurance training. Results from twin and family studies have yielded significant heritability estimates for maximal oxygen consumption (VO2 max) in sedentary subjects (7, 12, 21, 23). Similarly, the response of VO2 max to endurance training programs exhibits greater variability between than within pairs of monozygotic twins, with intraclass correlations varying from 0.60 to 0.77 (5, 8, 33). The effects of the genotype on responsiveness to regular endurance training have been investigated in the HERITAGE Family Study, and maximal heritability estimates of 51 and 47% were derived for VO2 max in the sedentary state and in response to training, respectively (3, 4).

Considering the potential role of Na+-K+-ATPase in the contractility of skeletal muscle and the heritability of cardiorespiratory fitness and Na+-K+-ATPase phenotypes, the purpose of this study was to investigate the associations between the Na+-K+-ATPase alpha 2 gene markers (a gene expressed mainly in skeletal muscle) and the responsiveness of VO2 max and maximal power output (Wmax) to a 20-wk endurance training program in 472 Caucasian subjects of the HERITAGE Family Study.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects. The study cohort consisted of 472 Caucasian subjects (230 men and 242 women) from 99 families. The study design and inclusion criteria have been described previously (6). The individuals were required to be in good health (i.e., free of diabetes, cardiovascular diseases, or other chronic diseases) and to be sedentary at baseline (defined as not having engaged in regular physical activity over the previous 6 mo) to be eligible for the study. The study protocol was approved by each of the Institutional Review Boards of the HERITAGE Family Study research consortium. Written informed consent was obtained from each participant.

Exercise training program. The exercise intensity of the 20-wk training program was customized for each participant based on the heart rate-oxygen consumption (VO2) relationship measured at baseline. During the first 2 wk, the subjects trained at a heart rate corresponding to 55% of the baseline VO2 max for 30 min/session. Duration and intensity of the training sessions were gradually increased to 50 min at a heart rate associated with 75% of the baseline VO2 max; these were sustained for the last 6 wk. Training frequency was three times per week, and all training was performed on cycle ergometers in the laboratory. Heart rate was monitored during all training sessions by a computerized cycle ergometer system (Universal Gym Mednet, Cedar Rapids, IA), which adjusted ergometer resistance to maintain the target heart rate. All exercise sessions were supervised by trained exercise specialists.

Fitness phenotypes. Before and after the 20-wk training program, each subject completed two maximal cycle ergometer (SensorMedics Ergo-Metrics 800S, Yorba Linda, CA) exercise tests conducted on separate days. The first test started at 50 W for 3 min, and the rate of work was increased by 25 W every 2 min thereafter to the point of exhaustion. For older, smaller, or less fit subjects, the test was started at 40 W and increased by 10- to 20-W increments. The second test started with a submaximal exercise period, performed at 50 W and at 60% of the initial VO2 max for 12-15 min at each work rate with a 4-min period of seated rest between work rates, and progressed to a maximal level of exertion (4, 36).

For both tests, VO2 was determined every 20 s and is reported as a rolling average of the three most recent 20-s values. All the respiratory phenotypes were measured by using a SensorMedics 2900 metabolic measurement cart. VO2 max was defined as the mean of the highest VO2 values determined in each of the maximal tests, or the higher of the two values if they differed by >5%. The intraclass correlation coefficient for repeated measurements of the VO2 max reached 0.97 (36).

Other phenotypes. Stature was measured to the nearest 0.1 cm with the subject standing erect on a flat surface, with heels, buttocks, and back pressed against the stadiometer and the head positioned in the Frankfort horizontal plane. Body mass was recorded to the nearest 100 g by using a balance scale with subjects clothed only in a light-weight bathing suit.

Genotype determination. Genomic DNA samples isolated from lymphoblastoid cell lines were digested with Bgl II restriction enzyme, and the resulting DNA fragments were separated by agarose gel electrophoresis. DNA fragments were transferred to nylon filters, hybridized with 32P-labeled genomic probes, and visualized with autoradiograms after 1-7 days of exposure at -80°C. Phage lambda DNA digested with Hind III and EcoR I was used as size standard. The genomic probes used were a 2.5-kb DNA fragment of the 5'end of the alpha 2 gene that includes exon 1 (alpha 2 exon 1 marker) and a 1.0-kb DNA fragment of the 3'portion of the alpha 2 gene that includes exons 21 and 22 (alpha 2 exon 21-22 marker) (35).

Statistical analyses. A chi 2 test was used to confirm that the observed genotype frequencies were in a Hardy-Weinberg equilibrium. The normality of the distributions was checked with the Shapiro-Wilk statistic of the UNIVARIATE procedure of the SAS statistical software package (SAS Institute, Cary, NC). Skewed distributions were normalized with logarithmic transformations.

For the sibling-pair linkage analyses, the phenotypes were adjusted for potential confounders by using a stepwise regression procedure separately in four gender-by-generation subgroups, and the standardized (mean = 0, SD = 1) residuals were used for the linkage analyses. The covariates used included age, gender, and baseline body weight for the baseline phenotypes and age, gender, and baseline values of the phenotype and of body weight for the training-response variables. Linkage between the fitness phenotypes and the Na+-K+-ATPase alpha 2 markers was investigated with the sibling-pair linkage procedure (1, 19). Briefly, if there was a linkage between the marker locus and a putative gene influencing the phenotype, siblings sharing a greater proportion of alleles identical by descent at the marker locus would also show a greater resemblance in the phenotype. The squared sibling-pair phenotypic difference was regressed on the expected proportion of marker alleles identical by descent at the locus. A one-sided t-test was then used to test whether the regression coefficient was <0. A significant inverse relationship between the squared sibling-pair phenotypic difference and allele sharing at the marker locus was taken as evidence of linkage. The linkage analysis was performed by using the SIBPAL program of the SAGE Statistical Package (34).

Associations between fitness phenotypes and the genetic markers were tested with analysis of covariance by using the GLM procedure of the SAS package. Baseline phenotypes were adjusted for age, gender, and body weight, and training-response phenotypes for age, gender, baseline body weight, and baseline value of the phenotypes. Possible generation-by-genotype interaction effects were tested by introducing an interaction term in the GLM model in addition to the genotype and generation main effects. If the interaction term was significant, or if a significant sibling-pair linkage was observed between an alpha 2 marker and a phenotype, association analyses were performed separately in parents and offspring. In addition to the fully adjusted models, analyses were also performed without adjustment, by adjusting for each of the covariates separately and by using various combinations of covariates. The results of all of these analyses were globally identical to those of the full model, and, therefore, only the data from the full models are reported in the present study. The results are expressed as means ± SE.

All the family members were included in the association analyses. Although it is commonly believed that the relatedness of the subjects in family studies may cause problems in association analyses, recent evidence (M. Province, T. Rice, and D. C. Rao, unpublished observations) suggests that this is not the case. In that study, simulated data were analyzed by four methods: the least squares method ignored relatedness in the present study, and the other three methods treated the dependencies in different ways. The results showed that, first, failure to incorporate dependencies did not induce any bias and, second, for moderate familial correlations as seen in most family studies (including the present one), ignoring the dependencies in an ANOVA performed quite well. The only negative impact was a small reduction in power. The SEs were slightly larger, but, most importantly, type I error was unaffected. Given this, we do not believe that the dependencies or relatedness of the subjects in families causes any real problems in this type of analysis. However, we repeated the analyses after randomly selecting only one offspring per family, and the results were basically the same as with the whole cohort (see RESULTS).


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The basic characteristics of the subjects are presented in Table 1. The endurance training program increased VO2 max by 16.9 ± 0.7 and 17.0 ± 0.5% and Wmax by 28.6 ± 1.1 and 28.5 ± 0.8% in parents and offspring, respectively. The allele frequencies were 0.89 (8.0-kb allele) and 0.11 (3.3 kb) for the alpha 2 exon 1 marker and 0.79 (4.3 kb) and 0.21 (10.5 kb) for the alpha 2 exon 21-22 marker. Genotype frequencies were in Hardy-Weinberg equilibrium for each marker. Body weight and body composition at baseline were similar across the genotypes (data not shown).

                              
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  		Table 1.   Characteristics of 472 Caucasian subjects in the HERITAGE Family Study

Sibling-pair analysis revealed marginal evidence for linkage between the alpha 2 haplotype and training response in VO2 max (Table 2). The linkage evidence was much stronger between the alpha 2 exon 21-22 marker and the alpha 2 haplotype and Delta Wmax. The alpha 2 exon 1 marker also showed a suggestive linkage with Delta Wmax. The distribution of the squared intrapair differences for each significant phenotype-genotype combination was checked, and no isolated outliers were detected, i.e., there was no sibling pair at least 3 SD above the sibling pair with the next highest value for the squared intrapair difference of a given phenotype. Thus the results of the linkage analyses were not influenced by extreme phenotype values. No linkages were observed between the alpha 2 markers and VO2 max and Wmax in the sedentary state.

                              
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  		Table 2.   Sibling-pair linkage analysis, results for the Na+-K+-ATPase alpha 2 markers, and changes in cardiorespiratory fitness in Caucasian subjects of the HERITAGE Family Study

A significant association between the alpha 2 exon 1 marker and Delta VO2 max was observed in the whole cohort (Table 3). The association was characterized by a smaller training response in the homozygotes for the rarer 3.3-kb allele than in the heterozygotes or the wild-type homozygotes. The alpha 2 exon 21-22 marker was not associated with Delta VO2 max or Delta Wmax in the whole cohort, but, because of the significant findings from the sibling-pair linkage analyses and a suggestive trend for a generation-by-genotype interaction effect for Delta VO2 max (P = 0.075), the analyses were repeated separately in parents and offspring. In offspring, the homozygotes for the 10.5-kb allele showed 29 and 39% greater VO2 max training responses than did the heterozygotes and the wild-type homozygotes, respectively (Table 4). Neither Delta VO2 max nor Delta Wmax was associated with the alpha 2 exon 21-22 genotypes in parents. Baseline VO2 max and Wmax showed no associations with either of the alpha 2 markers. Finally, the analyses were repeated after randomly selecting only one offspring per family. The results were similar to those obtained with the whole cohort, except for the association between the alpha 2 exon 21-22 marker and Delta Wmax in offspring, which was statistically significant (P = 0.011) in the partial cohort (increases of 86.7 ± 10.4, 60.6 ± 4.9, and 53.8 ± 3.5 W in the 10.5/10.5-, 10.5/4.3-, and 4.3/4.3-kb genotypes, respectively).

                              
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  		Table 3.   Associations between the Na+-K+-ATPase alpha 2 exon 1 polymorphism and VO2 max and Wmax in sedentary state and in response to 20-wk endurance training program in 472 Caucasian subjects of the HERITAGE Family Study


                              
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  		Table 4.   Associations between Na+-K+-ATPase alpha 2 exon 21-22 polymorphism and VO2 max and Wmax in sedentary state and in response to 20-wk endurance training program in Caucasian parents and offspring of the HERITAGE Family Study


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The results of the present study suggest that the Na+-K+-ATPase alpha 2 gene locus is associated with the training responses of endurance performance phenotypes in healthy, previously sedentary Caucasian subjects. This is the first time such an association is reported. However, data from human and animal studies support the role of sarcolemmal Na+-K+-ATPase in the skeletal muscle contractility, development of fatigue, and, ultimately, endurance performance (30).

High-intensity exercise leads to increased passive leak of Na+ into and K+ out of the muscle fibers, and K+ concentration in the interstitial fluid can rise two- to fourfold during exercise (30). Loss of cation concentration gradient across the cell membrane leads to depolarization of the sarcolemma, which hinders the spread of new action potentials. To restore the contractility of the muscle, K+ and Na+ concentration gradients must be regenerated, and the sarcolemmal Na+-K+-ATPase is essential in this process. Significantly greater concentrations of Na+-K+-ATPase in vastus lateralis muscle have been reported in endurance-trained subjects than in sedentary age-matched controls (20). Animal studies have shown that inhibition of Na+-K+-ATPase reduces the performance of skeletal muscle (18, 26). However, when the Na+-K+-ATPase was activated with insulin, catecholamines, or electrical stimulation, both membrane potential of the sarcolemma and force production of the muscle were restored (29, 31). Several studies have also shown that exercise training increases the Na+-K+-ATPase concentration in skeletal muscle (11, 15, 16, 22, 25), and the increases take place independently of the changes in oxidative potential of the muscle (15).

Our results suggest that the homozygotes for the variant allele of the alpha 2 exon 1 decreased the VO2 max response to regular endurance training, whereas the variant allele of the alpha 2 exon 21-22 is associated with greater VO2 max responsiveness. Although these two markers are in significant linkage disequilibrium in the HERITAGE cohort, it is unlikely that the variant alleles reflect the same underlying functional gene variant. A more detailed inspection of the markers revealed that all of the 10.5-kb homozygotes of the alpha 2 exon 21-22 marker were also alpha 2 exon 1 wild-type homozygotes, whereas 87% of the alpha 2 exon 1 variant allele carriers and all of the variant allele homozygotes were alpha 2 exon 21-22 wild-type homozygotes. Thus it seems plausible that these two markers index two different mutations: one associated with a decreased and the other with an increased responsiveness to endurance training. However, these markers explain a relatively small proportion of the variance in Delta VO2 max (1.5-2.4%), which is in line with the polygenic nature of cardiorespiratory fitness phenotypes.

A role for the Na+-K+-ATPase alpha 2 locus in the training responsiveness was further supported by the sibling-pair linkage results. Although neither of the individual markers showed significant linkages with Delta VO2 max, the haplotype revealed a suggestive linkage. This is most likely due to the low information content of the individual markers. With the use of the haplotype, it was possible to increase the polymorphic information content value of the marker from 0.174 (exon 1) and 0.306 (exon 21-22) to 0.411.

Although Na+-K+-ATPase alpha 2 gene markers used in the present study were described 10 years ago (35), it is still unclear whether these variants have any effect on the function of the Na+-K+-ATPase alpha 2 subunit. However, exons 19-22 of the Na+-K+-ATPase alpha 2 gene encode hydrophobic, probably transmembrane, domains (35). In vitro studies have shown that artificially induced mutations in this region alter the pump current of the rat alpha 2 subunit (38) and decrease catalytic function and affinities of Na+ and K+ in the sheep alpha 1 subunit (2, 13, 37).

We observed an association between the alpha 2 exon 21-22 marker and Delta VO2 max in offspring but not in parents. The exact explanation for this difference is unclear, but it is possible that the skeletal muscle cation balance is a less important determinant of endurance capacity in older individuals. One could speculate that the energy production pathways in skeletal muscle, the availability of oxygen and substrates for energy production, or the ability of the cardiorespiratory system to adapt to increased levels of physical activity become more dominant performance-limiting factors with advancing age. Some studies have shown that the erythrocyte Na+-K+-ATPase activity decreases with age (14, 32) and that this decrease is associated with age-related reduction in resting metabolic rate (32). However, it is not known whether a similar phenomenon takes place in skeletal muscles or if it has any relevance to the generation difference observed in the present study.

In summary, these data from the HERITAGE Family Study suggest that DNA sequence variation at the Na+-K+-ATPase alpha 2 locus, or a locus in close proximity, is associated with the responsiveness of VO2 max and Wmax to a 20-wk endurance training program in healthy, sedentary Caucasian subjects.


    ACKNOWLEDGEMENTS

The HERITAGE Family Study is supported by the National Heart, Lung, and Blood Institute through Grants HL-45670 (to C. Bouchard), HL-47323 (to A. S. Leon), HL-47317 (to D. C. Rao), HL-47327 (to J. S. Skinner), and HL-47321 (to J. H. Wilmore). A. S. Leon is partially supported by the Henry L. Taylor endowed Professorship in Exercise Science and Health Enhancement. C. Bouchard is partially supported by the Donald B. Brown Research Chair on Obesity funded by the Medical Research Council of Canada and Hoffmann-La Roche Canada. T. Rankinen is a fellow from the Medical Research Council of Canada. Some of the results of this paper were obtained by using the program package SAGE, which is supported by US Public Health Service Resource Grant 1 P41 RR0365 from the National Center for Research Resources.


    FOOTNOTES

Original submission in response to a special call for papers on "Molecular and Cellular Basis of Exercise Adaptations."

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. §1734 solely to indicate this fact.

Address for reprint requests and other correspondence: C. Bouchard, Pennington Biomedical Research Center, 6400 Perkins Rd., Baton Rouge, LA 70808-4124 (E-mail: bouchac{at}pbrc.edu).

Received 13 July 1999; accepted in final form 27 August 1999.


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RESULTS
DISCUSSION
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