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EDITORIAL FOCUS
Department of Physiology, University of Aarhus, DK-8000 Århus C, Denmark
THE EFFECTS OF AGE AND EXERCISE training on the content of
Na+-K+-ATPase (Na+-K+ pumps) in
skeletal muscle have been characterized by several laboratories in at least
seven different species (for review, see Ref.
1). In the rat,
Na+-K+ pumps as quantified by measuring the capacity for
[3H]ouabain binding to intact skeletal muscle were shown to
increase from birth and to reach a maximum at 
1 mo of age, followed by a
decline of 50-70% over the following 2-20 mo
(6). This age-dependent decline
was confirmed in measurements of the maximum capacity for ouabain-suppressible
86Rb uptake in rat soleus muscle
(2) as well as
K+-stimulated 3-O-methylfluorescein phosphatase
(3-OMF-Pase), an enzyme activity closely related to the
Na+-K+-ATPase
(11). A somewhat similar
age-dependent decline in [3H]ouabain binding capacity was observed
in mice and guinea pigs (6) and
in pigs (compare Refs. 3 and
4) and horses
(12). In contrast, biopsies
from the human vastus lateralis muscles showed only a small downregulation of
the [3H]ouabain binding capacity in the age range 25-80 yr, which
was not statistically significant
(10). Another study showed a
14% decrease from 28 to 68 yr, which was not significant either
(7). Exercise training
increases the content of Na+-K+-ATPase in dog skeletal
muscle (8), and numerous
studies have documented that training or increased muscle activity augments
the content of [3H]ouabain binding sites in skeletal muscle
obtained from rats, guinea pigs, rabbits, sheep, pigs, horses, angoni cattle,
and human subjects (for review, see Ref.
1).
In a study by Ng et al. (9)
in this issue of the American Journal of Physiology-Regulatory,
Integrative and Comparative Physiology, the combined effects of age and
training on the relative abundance of the 
-and 
-subunit isoforms
of Na+-K+-ATPase are characterized in rat skeletal
muscle and compared with the Na+-K+-ATPase activity. The
study tests the hypothesis that endurance exercise training reverses the
age-related changes and is the first to describe these relations in the late
age range of 16-29 mo. This could provide novel information about the
molecular specificity of the regulation of the transmembrane catalytic
-subunit and the -subunit of the
Na+-K+-ATPase. The same research group
(13) previously reported that
in mixed homogenates of the red and white gastrocnemius muscle of the rat,
K+-stimulated 3-O-MFPase activity increased by 50% in 30-mo-old
compared with 18-mo-old animals. In keeping with this, in homogenates of the
red gastrocnemius, [3H]ouabain binding increased by 49% from 18 to
30 mo of age. Inasmuch as the 2-subunit isoform has a high
affinity for ouabain and in the rat seems to be the isoform detected by the
[3H]ouabain binding assay, it would be expected to show about the
same 50% upregulation as the [3H]ouabain binding. Surprisingly,
however, homogenates of the red gastrocnemius muscle prepared from 30-mo-old
rats showed almost the same relative abundance of the
2-subunit isoform as homogenates obtained from 18-mo-old
rats (13). Again, the study
published in this issue of the journal showed no significant upregulation of
the abundance of 2-subunit isoform in the red gastrocnemius
of rats from 16 to 29 mo of age. In keeping with the unaltered levels of
2, the ouabain-suppressible activity of the
Na+-K+-ATPase of a tissue homogenate showed no change
from 16 to 29 mo of age, either in the red or in the white gastrocnemius
muscle, and only a modest increase (20%) in extensor digitorum longus (EDL)
muscle (9).
In contrast, increasing age (from 16 to 29 mo) was associated with a
clear-cut upregulation of the relative abundance of 1 in red
gastrocnemius (25%), white gastrocnemius (77%), and EDL muscles (101%). In the
previous study (13), however,
the relative abundance of the 1-subunit isoform increased
considerably more from 18 to 30 mo of age, by 600% in red gastrocnemius and by
100% in white gastrocnemius, respectively.
Thus there is a considerable discrepancy between the 3-O-MFPase and
[3H]ouabain binding data and the data on
Na+-K+-ATPase activity and 2-subunit
isoform abundance. Moreover, the data on 1 showed
considerable variation but would suggest substantial age-dependent
upregulation of the tissue content of Na+-K+-ATPase. It
should be recalled, however, that the 1-subunit isoform only
constitutes a minor fraction of the total population of
Na+-K+-ATPase in rat skeletal muscle
(5) and therefore is unlikely
to contribute very much to the sum of Na+-K+-ATPase
content. In all three muscles tested, the relative abundance of
1-subunit isoform showed no significant change with age,
whereas 2 showed a marked decrease.
Endurance training for 13 wk on a treadmill increased the relative
abundance of 2-subunit isoform in red gastrocnemius, white
gastrocnemius, and EDL by 74, 89, and 26%, respectively
(9). The training increased the
relative abundance of the 1-subunit isoform in red
gastrocnemius, white gastrocnemius, and EDL by 15, 3, and 34%, respectively.
These changes would suggest that the training induced similar increases in the
activity of Na+-K+-ATPase in tissue homogenates.
However, training increased the enzyme activity in red gastrocnemius, white
gastrocnemius, and EDL by only 29, 27, and 6%, respectively. The differences
in relative increases in the abundance of Na+-K+-ATPase
activity and the two -isoforms may be related to variations in the
recovery of Na+-K+-ATPase activity in the homogenate as
well as in the tissue contents of 1- and
2-subunit isoforms. It is unsatisfactory that the data on
abundance of subunit isoforms reported in the literature [with one exception
(5)] are only available as
relative values and not in molar units. This makes it very difficult to sort
out what the data mean in terms of maximum capacity for active
Na+-K+-transport as well as in comparisons with other
published values for Na+-K+ pump content.
The general hypothesis tested in this study, whether exercise training
might reverse age-related changes, was only completely confirmed for the EDL,
where increasing age reduced the abundance of 2 by 22%,
which was totally reversed by exercise training. In the red and white
gastrocnemius, increasing age only caused insignificant decreases in
2, whereas training induced considerable upregulation to
levels over and above that of the untrained animals. The age- and
training-induced changes in 1-, 1-, and
2-subunit isoforms were more contradictory. The
1 showed upregulation with age and a small additional
increase with training. In all three muscles tested, 1 showed
no change with age, but training caused a dramatic increase. Training did not
reverse the age-dependent decrease in 2.
Perhaps the most general trend of the study is that exercise training leads
to a rather substantial increase in the abundance of both 1-
and 2-subunit isoforms (in particular the
2) as well as the activity of
Na+-K+-ATPase. This information is original and
important and in keeping with the training-induced upregulation of
[3H]ouabain in skeletal muscle binding reported for several species
in the literature. However, the results raise the question whether studies on
senescent rat muscle are representative for human subjects, who obviously show
much more modest, if any, age-dependent decreases in the content of
Na+-K+ pumps. In 68-yr-old human subjects who had been
training for 12-17 yr, the content of [3H]ouabain binding sites in
the vastus lateralis muscle was 30-40% higher than in age-matched untrained
subjects (7). This upregulation
is larger than that generally seen in younger subjects and seems to have
functional significance
(1).
In a wider perspective, the present observations of Ng and colleagues (9) also indicate that even at an advanced age, training pays off in terms of upregulation of Na+-K+ pump capacity in skeletal muscle.
FOOTNOTES
Address for reprint requests and other correspondence: T. Clausen, Dept. of
Physiology, Univ. of Aarhus, DK-8000 Århus C, Denmark (E-mail:
tc{at}fi.au.dk).
REFERENCES
1 isoform of the Na+,K+-ATPase in
rat soleus and extensor digitorum longus. Acta Physiol
Scand 173: 1-7,
2001.
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