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BLOOD DESTRUCTION DURING EXERCISE.
III. EXERCISE AS A BONE MARROW STIMULUS.
BY G. O. BROUN, M.D.
(From the Laboratories of The Rockefeller Institute for Medical
Research.)
(Received for publication, August 25, 1922.)
Observations already recorded' 2 offer strong evidence for
theoccurrence of blood destruction during exercise. There are
yetother phenomena which point to the same conclusion. It is
wellknown that any considerable loss of blood from hemorrhage or
de-struction of cells within the body is followed in the absence of
com-plications by a definite increase in the number of reticulated
redcorpuscles in the peripheral circulation. This reaction can be
takentherefore as a direct indication that unusual demands for new
cellsare being made upon the hematopoietic tissues. If exercise of
cagedanimals produces such a well marked decrease in the red cell
quantityas blood volume observations indicate,2 a demand for
corpuscles toreplace this loss will inevitably result and this
demand should bereflected in an increase in the number of
reticulated cells.
Methods.
In order to rule out any possible influence upon the
hematopoietic tissueof the methods employed to determine blood
volume, a different series of animalswas used in the present work
from those heretofore reported upon. 1' 2 Treadmillexercise was
given them as already described. Dogs 17, 18, and 19 had beencaged
for only a little over a month at the time observations were begun.
Nos.20 and 21, by contrast, had been confined for over 4 months
before the firstobservations and were caged and sedentary for a
further 2 months prior to thesecond series. In enumerating the
reticulated cells the method of Robertson3
was employed. 10,000 cells were counted in each instance. The
number ofreticulocytes found in 10,000 red cells furnished the
"count" of the animal. On
I Broun, G. O., J. Exp. Med., 1922, xxxvi, 481.2 Broun, G. O.,
J. Exp. Med., 1923, xxxvii, 113.3 Robertson, O. H., J. Exp. Med.,
1917, xxvi, 221.
187
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BLOOD DESTRUCTION DURING EXERCISE. III
the days on which exercise was given, at least two, and in some
instances four,counts were made at intervals during the exercise
period. The average of thesecounts has been employed for charting
purposes. In the control periods beforeand after exercise only
single counts were taken on any 1 day. Great individualdifferences
were noted in the "normal" number of reticulocytes, but the
variationsoccurring in the same animal from day to day, while
considerable, were less marked.
The reticulated elements were followed on all of the dogs for a
week or morebefore exercise. The average of the counts was taken as
the "normal" for theanimal. In the tables, the counts are given as
such, i.e. the number found in10,000 red cells, as well as in
percentages of the previous "normal." In thegraphic representation
in the charts, the variations are expressed in percentagesof this
"normal."
In the single experiment each on Nos. 17, 18, and 19, and in the
last of the twoexperiments on Nos. 20 and 21, hemoglobin,
hematocrit, and red cell determina-tions were made as well as the
reticulated cell counts. Owing to the wide varia-tions which result
from changed cell distribution during a day of exercise, theblood
was examined both before it and afterwards. The average of the
twofindings is used in the tables and charts. The hemoglobin
percentage was deter-mined by the method of Newcomer 4 in the case
of Nos. 17, 18, and 19, and by thePalmer s method in the other two
animals. Blood for the various counts wastaken from the marginal
ear vein of Nos. 20 and 21, and in the other animals fromthe
external jugular.
Reticulated Cell Changes.
The reticulated cell counts are given in Table I and
graphicallyportrayed in Text-fig. 1. No. 17 shows a well marked
response toexercise, first manifest on the 5th day of it, and
maintained throughoutthe following week. Thereafter only occasional
observations weremade; and when a practically normal count had been
secured on the10th day after exercise, they were discontinued. The
animal hadbeen confined but little over a month when exercise was
begun. InNo. 18, confined an equal length of time, the reaction,
while distinct,,assumes less considerable proportions. Only 5 days
of exercisewere given. No. 19, also caged for but a single month,
showed noreaction during the 1st week of exercise. This was
continued, there-fore, into the 2nd week and a distinct increase in
the reticulocytecount manifested itself. Dogs 20 and 21 had been
caged over 4
4 Newcomer, H. S., J. Biol. Chem., 1919, xxxvii, 465.6 Palmer,
W. W., J. Biol. Chem., 1918, xxxiii, 119.
188
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G. O. BROUN
Percent
300
100
700
500
1,300 300
t100 100
900
700
500
300 1300
100 1,1oo00
900
500
300
100
300
100
300
100
300
100I i I I I I .-F 3
Da 14 12 10 8 6 4 2 0 2 4 6 8 10 12 14 16 18 20 22 24 6 30
32
TEXT-FIG. 1. Changes in reticulated red corpuscles during
exercise.
189
700
500
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BLOOD DESTRUCTION DURING EXERCISE. III
M
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G. O. BROUN 191
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BLOOD DESTRUCTION DURING EXERCISE. III
months at the time of the first experiment upon them. The
reticu-locyte curve of No. 20 shows a well marked reaction to
exercise atthis time. On exercise again 2 months later, a definite
reaction wassecured but one much less imposing than had previously
occurred.Prior to exercise the blood of No. 21 showed but a very
small numberof reticulocytes, 2 in 10,000 being the greatest number
noted. Thoughthe actual counts after exercise were not high, they
amount in per-centage terms to a very large increase. This increase
was maintainedpractically throughout the 2 months elapsing before
the secondexperiment. Nevertheless, during the second exercise
period therewas a marked reticulocyte rise above the already
heightened level.
Several interesting points deserve mention in connection with
thecharacter of the reaction. First of all, the irregular wave-like
char-acter of curves derived from successive reticulated cell
counts underordinary circumstances should be noted. A single count
is no reliableindex to this curve. In some instances (Text-fig. 1,
Nos. 21A and20B) a slight increase in the reticulocyte count
occurred during the1st day or two of exercise. This was followed by
a distinct fall inthe count and only towards the end of the
exercise period did a secondrise occur. In practically every
instance the crest of the rise isreached after exercise has been
discontinued, and the curve remainsrelatively high until hemoglobin
and cell count have come backwithin normal limits. It may well be
that the rise noted early inthe course of exercise represents the
appearance of a certain reservesupply of cells held in the bone
marrow for emergency purposes andthat these disappear from
circulation during the following days,when the activity of the
marrow has not yet increased. With thisincrease there occurs a
second rise, near the end of the 1st week ofexercise.
Changes Shown by the Hemoglobinometer, Hematocrit, and Red
Count.
In Tables II to IV and in Text-fig. 2 are given the data
obtainedby the use of hemoglobinometer, hematocrit, and red counts
on theseries of animals already dealt with. It will be noted that
the find-ings are in complete general agreement with the results of
blood volumedeterminations as previously reported upon, in that
they indicatethe disappearance of a considerable quantity of blood
during exercise.2
192
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G. O. BROUN
Taken independently the figures would not offer conclusive
proofof this destruction as they do not deal with total values for
the body.Certain irregular fluctuations that will be noted may be
due eitherto errors in the individual determinations or to local or
generalchanges in the ratio of fluid to cells. For example, a
persistentlyhigh plasma volume will suffice to account for the fact
that thedepression of these curves persisted for nearly 3 weeks
after exercisehad ceased. In Text-fig. 3 is given a composite
picture of the changesin reticulocytes, hemoglobin, hematocrit, and
red count. Whenevercounts were made on more than one dog on the
same day the percent-age figures yielded by these counts were
averaged and used for thecomposite chart. The general features of
the curves leave room forno doubt of the changes.
It is a priori possible that the reticulated cell reaction may
be dueto other causes than the stimulus of blood loss, as for
example, tosome chemical substance engendered or liberated during
exercise.If it be due on the other hand wholly to cell loss, then
on promptreplacement of this loss from outside sources the rise in
reticulocytesshould not occur. To test the point the following
experiment wasperformed.
Preliminary blood volume determinations were made on two dogs
previouslycaged during 2 months. Hemoglobin and reticulated cell
counts were taken for2 days beforehand as well as daily during the
course of exercise. The animalswere exercised on treadmills after
the usual manner for 5 days. The reticulatedcell count showed at
the end of this time an upward trend in both animals. Asecond blood
volume determination was now carried out and the quantity of
cellslost determined. Each animal was now transfused with blood
from a compatibledonor to the amount that should on calculation
exactly replace the loss of hemo-globin. No further exercise was
given.
The results of this experiment are presented in Table V and
Text-fig. 4. It will be seen that the usual increase in
reticulocytes afterexercise did not occur. In fact the cell count
fell below the previouslevel.
Yet another test:-If the increase in reticulated cells is due
toanemia from blood destruction, an animal made plethoric
artificiallyshould on exercise show no rise in reticulocytes so
long as the bloodamount remains abnormally large.
193
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BLOOD DESTRUCTION DURING EXERCISE. III
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G. 0. BROUN 195
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196 BLOOD DESTRUCTION DURING EXERCISE. III
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G. O. BROUN 197
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BLOOD DESTRUCTION DURING EXERCISE. III
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G. . BROUN 199
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BLOOD DESTRUCTION DURING EXERCISE. III
HemnRlobhin
_
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flume of cells _
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Day 1412 10 8 6 4 Z 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
32
TEXT-FIG. 2. Changes during exercise shown by the
hemoglobinometer,hematocrit, and red count.
In Dog 26, a normal animal caged for 3 months, the number of
reticulocytes,per cent of hemoglobin, and number of red cells per
cubic millimeter were followedfor 2 weeks. The animal was then
given intravenously 550 cc. of citrated bloodfrom a compatible
donor. This caused definite plethora. A period of 48 hourswas
allowed for readjustment and then exercise was begun and kept up
for 6 days.The blood volume was not followed.
As the chart shows (Table VI, Text-fig. 5), a slight fall in
redcount and hemoglobin occurred during the exercise period, but
bothremained above the normal level. The reticulated cells
disappeared
17 e2
200
Percent
110
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90
80
70
100
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hematoctit - er cent vo
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xI n 2i0 ed
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Reticulated red corpuscles-- emos bin
-..... HematdP it.--- Copuscles per, c.mm.
TEXT-FIG. 3. General comparison of the changes in the
reticulated red cor-puscles with the hemoglobin, red count, and
hematocrit.
PerC. .,
300
200 110
100 100
0 90
so
Day 2 0 2 4 6 8 10-Reticulated red corpuscles----.......
Hemolobin---- Cell volume
TEXT-FIG. 4. Prevention of the reticulated cell reaction by
transfusion.202
Per
600
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G. . BROUN 203
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BLOOD DESTRUCTION DURING EXERCISE. III
practically completely from the blood stream within 3 days
afterthe transfusion and did not reappear during the exercise nor
for morethan a week thereafter. By this time the red counts and
hemoglobindeterminations had fallen below the normal level and in
the courseof the next few days reticulated cells again
appeared.
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TEXT-FIG. 5. Absence of reticulocyte rise after exercise in a
plethoric animal.
DISCUSSION.
The foregoing observations, in connection with those
previouslyreported, yield a number of suggestions as to the
reaction of the bonemarrow of caged animals to exercise. Obviously
there is at first aperiod in which blood destruction is proceeding
more rapidly thanblood formation. In most animals during this
period the reticulatedcount is increased but little. The need for
new cells is then as greator greater than during the following week
when the animal is againresting. It is possible that reticulated
cells are broken up morequickly during exercise than normal cells.
However, in this casethe counts prior to each day of exercise
should be higher than thoseat the end of it, and this was not
regularly the case. One may believethat during the long period of
confinement which preceded exercisethe bone marrow had become
inert, perhaps even atrophied, as com-
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G. O. BROUN
pared with that of normal animals and it was for a time unable
toproduce new cells to meet the sudden demand. More will be
saidupon the point in a paper that is to follow.'
Unfortunately no reticulated cell observations were made in
whichthe period of exercise was extended over several weeks. It is
probablethat as the marrow adapts itself to the demands upon it,
the numberof reticulocytes will fall to the normal.
The observations of this and the preceding papers taken
togetherstrongly indicate that the rle of exercise as a pace maker
in blooddestruction and formation is an important one. Just as a
disusedmuscle becomes weakened, and atrophied, so presumably may
abone marrow which is not constantly working to replace worn
outcells lessen also in its functional ability. And with the sudden
in-crease in blood destruction brought about by exercise there
ensueswhat may be termed marrow decompensation.
As everyone knows, exercise is good for the body in many
ways.One important effect would seem to be a stimulation of the
hemato-poietic system to a high efficiency. This stimulus need not
take theform of a reduction in the gross number of red cells
through injuryto them, unless indeed the exercise is so overdone
that blood destruc-tion exceeds the reparative abilities of the
marrow. The loss of bloodthat has been demonstrated in sedentary
animals2 produces a tempo-rary anemia in them only because their
hematopoietic tissues are notin a condition to compensate for the
increased corpuscular wear andtear. With mild exercise the
increases in cell destruction and produc-tion should take place
pari passu. And the result will be a marrow fitfor emergencies.
There are, of course, other stimuli to the hematopoietic tissues
fromexercise besides the loss of blood cells. One thinks
immediately of therelative oxygen lack consequent on increased
metabolism. Air-hunger during violent exercise is often as great as
that at high alti-tudes, and the resulting marrow stimulation
should be as considerable.But this and kindred matters need not
enter into present consideration.
The way in which the red cells are destroyed in increased
quantityduring exercise remains undetermined. Rous and Robertson 7
have
6 Broun, G. O., J. Exp. Med., 1923, xxxvii, 207.7 Rous, P., and
Robertson, O. H., J. Exp. Med., 1917, xxv, 651.
205
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BLOOD DESTRUCTION DURING EXERCISE. III
brought forward evidence for the view that normal blood
destruction,and that of some pathological states as well, occur
through a mechani-cal fragmentation of the erythrocytes. It was on
the assumptionthat destruction of this nature would be increased by
the wear andtear incident to the quickened blood flow of exercise
that the presentwork was undertaken. The assumption has been borne
out in thatan increased destruction has been found. But whether the
lattercomes about by corpuscular fragmentation remains to be
seen.
SUMMARY.
A definite increase in the percentage of reticulocytes occurs
afterexercise in animals previously kept to a sedentary life.
Concomitantchanges in the hemoglobin percentage, plasma-cell ratio,
and redcount offer evidence in addition to that already reported by
theauthor of the occurrence of an increase in blood destruction
undersuch circumstances.
Replacement by transfusion of blood destroyed during
exerciseprevents the reticulated cell reaction. Animals rendered
plethoricand then exercised show no increase in reticulated cells
while theplethora persists.
The fact is emphasized that exercise must be an important
factorin the maintenance of an efficient hematopoietic tissue.
206
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