Spectrum of aerobic endurance running performance
in eleven inbred strains of rats
JOHN C. BARBATO, LAUREN GERARD KOCH, AHMAD DARVISH,
GEORGE T. CICILA, PATRICIA J. METTING, AND STEVEN L. BRITTON
Department of Physiology and Molecular Medicine,
Medical College of Ohio, Toledo, Ohio 43614-5804
treadmill; selective breeding; fitness; exercise; cardiac; functional genomics; working heart; cardiac performance
IDENTIFICATION of the genetic basis of the variance
present in mammalian models of complex physiological
traits has become an attainable goal. Inbred strains of
animals that differ widely for a trait of interest have
been a core substrate in the analysis of complex phenotypes, and such strains remain a basic requirement for
progress in functional genomics. An inbred strain is one
that has been brother-sister mated for at least 20
generations. Each generation of brother-sister mating
increases the probability of attaining homozygosity at
any given genetic locus, and by 20 generations ,97.5%
of the loci are homozygous (9, 22). The major value of
inbred strains emanates from their close genetic uniformity that facilitates genotyping and thus identification
of genetic differences between strains.
Inbred strains developed from the low and high ends
of stock that have been selectively bred for a trait of
interest are probably of the greatest value because
genes determining the trait variance will have been
concentrated at the extremes; this concentration increases the power of genetic analysis. Many of the
currently available inbred rat strains, however, were
not developed by selectively breeding for a trait; instead, the strains were simply inbred to increase ge-
530
netic uniformity. Nevertheless, inbred strains developed from nonselected stocks can still be of direct value
in identifying genetic variance for a given trait if
strains that differ widely for that trait can be identified.
The ability of an organism to perform an aerobic
endurance exercise test is a complex trait that is often
used to assess cardiovascular fitness and to estimate
the magnitude of the cardiovascular reserve capacity
(12, 15). It appears that the ability to deliver oxygen to
skeletal muscle via alterations in cardiac output is a
major limiting factor in endurance performance (17,
25). Although a vast literature has developed that deals
with the adaptational aspects of endurance performance (4, 20), the genetic components causative of the
differences between high and low endurance performance have yet to be identified. Nevertheless, it appears that genetic variance accounts for a large portion
of the range observed in endurance performance between individuals. Simple additive models of heredity
plus environment have been utilized to estimate the
genetic contribution to variance in human endurance
performance in monozygotic and dizygotic twins. Although the assumptions in twin studies are often not
completely fulfilled or verifiable (14), Klissouras (19)
estimated that the contribution of heredity to the
interindividual variance in performing an endurance
run to exhaustion in pairs of monozygotic and dizygotic
twins is 93.4% genetically determined.
The two goals of this work were 1) to evaluate the
aerobic running endurance performance of 11 inbred
strains of rats to determine whether any of these
strains differs widely enough to serve as models of low
and high performance for genetic analysis of this trait
and 2) to determine whether a major hypothesized
intermediate phenotype (isolated cardiac performance)
correlated with running performance. We found an
,2.5-fold difference in endurance running capacity
between COP and DA inbred strains of rats. Across
these same 11 inbred strains, the isolated cardiac
performance correlated positively with running capacity. These data suggest there is sufficient difference
between the COP and DA strains to identify chromosomal regions containing genes responsible for inherited differences in endurance exercise performance, i.e.,
endurance exercise quantitative trait loci.
METHODS
Animals
We tested the running endurance performance of six
female and six male rats from each of 11 different inbred
strains. Seven of these strains were purchased from the
8750-7587/98 $5.00 Copyright r 1998 the American Physiological Society
http://www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.33.4 on June 18, 2017
Barbato, John C., Lauren Gerard Koch, Ahmad
Darvish, George T. Cicila, Patricia J. Metting, and
Steven L. Britton. Spectrum of aerobic endurance running
performance in eleven inbred strains of rats. J. Appl. Physiol.
85(2): 530–536, 1998.—The goal of this study was to identify
inbred rat strains that could serve as useful models for
exploration of the genetic basis of aerobic endurance performance. Six rats of each gender from 11 different inbred
strains were tested for 1) maximal running capacity on a
treadmill and 2) isolated cardiac performance. Running performance was estimated from 1) duration of the run, 2)
distance run, and 3) vertical work performed. Cardiac output,
during constant preload and afterload, was taken as a
measure of cardiac performance from an isolated working
heart preparation. The COP rats were the lowest performers
and the DA rats were the best performers by all estimates of
running performance. Across the 11 strains, the distance run
correlated positively with isolated cardiac performance (r 5
0.87). Estimates of performance were as follows (COP vs. DA
strain, respectively): duration of run, 19.9 6 1.8 vs. 41.5 6 2.2
min; distance run, 298 6 30 vs. 840 6 64 m; vertical work,
15 6 1.7 vs. 40 6 4.4 kg/m. These ,2.5-fold differences in
running performance between the COP and DA suggest that
these strains could serve as models for evaluation of the
genetic basis of variance in aerobic performance.
GENETIC MODELS OF PHYSICAL PERFORMANCE
colonies at Harlan Sprague-Dawley (Indianapolis, IN) at 7–8
wk of age. These seven strains were ACI/SegHsd, AUG/
OlaHsd, BUF/NHsd, COP/Hsd, DA/OlaHsd, F344/NHsd, and
PVG/OlaHsd. The other four strains were obtained from
colonies maintained by John Rapp at the Medical College of
Ohio (Toledo, OH) and included LEW, WKY, SR/Jr, and MNS.
When not being studied, the rats were housed two per cage;
only rats of the same gender, age, and strain shared a cage.
The rats were provided food and water ad libitum and were
placed on a 12:12-h light-dark cycle, with the light cycle
occurring during daytime. All procedures were carried out
with approval by our Institutional Animal Care and Use
Committee and were conducted in accordance with the Guiding Principles in the Care and Use of Animals, as approved by
the Council of the American Physiological Society. The protocol for estimation of running endurance required 2 wk and
was started when the rats were 10 wk old. Rats were killed at
18 wk of age, and isolated cardiac performance was estimated
in each of the 132 rats (6 females and 6 males from 11
strains).
Estimation of Aerobic Running Performance
Estimation of Isolated Cardiac Performance
Preparation of the heart. As a terminal experiment, performed when the rats were 18 wk old, each rat’s heart was
tested by using the Langendorff-Neely isolated working heart
preparation (3, 21). Heparin sodium (300 IU) was injected
intraperitoneally 1 h before the hearts were excised. The rats
were anesthetized with pentobarbital sodium (50 mg/kg body
weight ip), and the abdominal cavity was opened via a
transverse incision. The diaphragm was transected, and a
lateral cut was made along the left side of the rib cage to gain
access to the mediastinum. The heart was pulled away from
the mediastinum to facilitate the removal of the thymus,
pericardium, and other connective tissue. The heart was then
excised by cutting across the aortic and pulmonary vessels,
and the heart was placed in iced Krebs-Henseleit buffer.
Perfusion of working rat heart. With the use of blunt
forceps, the aorta was slipped over the bulbed end of a
16-gauge needle and then held in place with a flat-nosed
alligator clip. Within ,1.5 min after the abdominal cavity
was opened, retrograde perfusion was initiated from a bubble
trap reservoir positioned 108.8 cm above the heart. Retrograde perfusion was maintained for 15 min to allow the buffer
to equilibrate with the interstitial fluid and to wash out
proteinaceous material. Concomitantly, the left atrium was
cannulated with a 16-gauge atrial cannula connected to an
oxygenator set at a fixed fluid level of 20.4 cm above the heart
via an overflow reservoir. This cannulation was secured by a
ligature and checked by momentarily permitting buffer to
flow through the atrial cannula to inflate the left auricle.
The working mode was initiated by clamping the tube
delivering retrograde perfusion and unclamping the tube
delivering buffer to the atrial cannula. In addition, a second
tube, originating from the side arm of the bubble trap, was
unclamped; this permitted buffer to be ejected from the heart
and flow to a second bubble trap 95.2 cm above the heart.
Overflow from this second bubble trap was returned to a
central reservoir located under the heart. To measure aortic
flow, we interrupted this overflow once every 10 min for 1 h. In
addition, coronary effluent was measured (once every 10 min
for 1 h) from the pulmonary artery; the effluent was also
returned to the central reservoir. Thus, overflow from the
oxygenator and second bubble trap was returned to the
central reservoir and pumped back to the oxygenator. Hence,
cardiac output was obtained by adding the aortic and coronary flow values.
Perfusion medium. Hearts were perfused with KrebsHenseleit bicarbonate buffer that was aerated with 95%
O2-5% CO2 at 37°C (pH 5 7.4). Concentrations were as follows
(in mM): 118 NaCl, 4.7 KCl, 1.25 CaCl, 1.2 MgSO4, 1.2
KH2PO4, 0.32 EDTA, 25 NaHCO3, and 11 D-glucose.
Data Analyses
For each of the five running trials, three parameters were
used to estimate endurance performance: the duration of the
run (in min), the total distance run (in m), and the vertical
work performed (in kg/m). The distance run was calculated
from the duration of the run. The vertical work performed
was derived, because it incorporates the body weight of the
animal into the estimate of performance. Vertical work was
calculated as the product of the body weight (kg) and vertical
distance (m) the rat reached at the completion of the run that
was performed at a slope of 15° [vertical distance 5 (distance
run)(sin 15°)]. For each rat, the single best daily performance
of the five trials was considered the trial most closely associated with the genetic component of running endurance performance. Heart performance was estimated for each rat by
obtaining the average cardiac output from six measures made
over a 1-h period of perfusion.
Data were evaluated to test for significant differences
between strains and genders. For each parameter, a one-way
analysis of variance was first performed. If analysis of
variance indicated significant differences, the post hoc Dunnett’s t-test was applied to evaluate individual strain differences (26). For each parameter, the strain with the lowest
average value was compared with all other strains for that
parameter to determine which strains differed significantly
from the lowest. Differences between the genders for each
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The first week consisted of introducing each rat to the
treadmill (model Exer-4, Columbus Instruments, Columbus,
OH) for gradually increasing durations each day. The goal of
the first week was to expose each rat to enough treadmill
education so that it could run for 5 min at a speed of 10 m/min
on a 15° slope. This amount of exposure to treadmill running
is below that required to produce a measurable adaptational
change in aerobic capacity (1, 7).
The first 2 days of introduction to treadmill running
consisted of simply placing the rat on the belt that was
moving at a velocity of 5 m/min (15° slope) and picking the rat
up and moving it forward if it started to slide off the back of
the belt. That is, the rats were not allowed to slide onto the
15 3 15-cm electric shock grid located at the back of the
treadmill. During introduction days 3–5, the belt speed was
increased to 10 m/min, and failure to run caused the rats to
slide off the moving belt and onto the shock grid that
delivered 1.2 mA of current at 3 Hz. The rats were left on the
grid for ,1.5 s and then moved forward onto the moving belt.
This process was repeated until the rats learned to run to
avoid the mild shock.
During the second week, each rat was evaluated for
maximal endurance running capacity for 5 consecutive days.
Each daily endurance trial was performed at a constant slope
of 15°, with the starting velocity at 10 m/min. Running
performance was evaluated at about the same time each day
(between 10 AM and noon). Treadmill velocity was increased
by 1 m/min every 2 min, and each rat was run until
exhaustion. Exhaustion was operationally defined as the
third time the rat was willing to slide onto the shock grid and
sustain 2 s of shock rather than run. At the moment of
exhaustion, the current to the grid was stopped, and the rat
was removed from the treadmill.
531
532
GENETIC MODELS OF PHYSICAL PERFORMANCE
strain were evaluated with the Student’s t-test for nonpaired
data. Data are presented as mean values 6 SE.
RESULTS
Combined Female and Male Performances
Fig. 1. Distance run in meters for each
strain; values for females and males in
each strain are combined. Values are
means 6 SE. * Strains that ran significantly (P , 0.05) farther than COP
rats, as evaluated by Dunnett’s t-test.
Performance by Gender
Tables 1 and 2 summarize the average running
performance data for each strain by gender. The range
of performance based on duration run for females
(Table 1) was from 21.2 6 1.0 min for MNS strain to
40.6 6 2.4 min for the AUG strain. The males (Table 2)
recorded a range for duration across the strains similar
to that of females. The COP males recorded the lowest
duration of run (17.7 6 3.2 min), and the DA males
recorded the highest duration run (46.0 6 1.3 min). The
lengths of these durations suggest that this running
test is associated with factors determined primarily by
aerobic capacity (25). For each gender and strain, the
distance run followed the same pattern as for duration
run because distance is a function of duration. The
widest difference (3.69-fold) in distance run was between the male COP and the male DA rats (262 6 51.2
and 969 6 41.3 m, respectively).
The work performed by each of the 11 strains,
considered by gender, is also shown in Tables 1 and 2.
For females (Table 1), the AUG and DA were the
highest performers, and the COP and MNS were the
lowest performers based on work. There was a 1.9-fold
difference between the work performed by the female
COP and the female DA rats (14.3 6 1.1 vs. 27.4 6 3.6
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Figure 1 shows the average distance run for each of
the 11 strains; results for females and males are
combined. The COP strain was the lowest performer
and ran for 298 6 30 m. The DA strain was the highest
performer and ran for 840 6 64 m. This 542-m difference in distance run between the COP and DA strains
represents a 2.8-fold difference. The average distances
run by the four highest performing strains (DA, PVG,
AUG, and SR) were significantly different from the
average distance run by the low-performing COP rats.
As an additional measure of performance, and to take
into account variation in body weight, the vertical work
performed up to the point of exhaustion was also
calculated. Figure 2 shows the average work performed
by each of the 11 strains, with results combined for
females and males. To simplify comparison, we have
shown the strains listed in all figures in the same order
(left to right) that they are presented in Fig. 1. On the
basis of work, the COP rats were the lowest performers
and did 15.0 6 1.7 kg/m of work. The DA had the
highest work output and averaged 40.1 6 4.4 kg/m of
work. This 25.4 kg/m difference in work between the
COP and DA represents a 2.7-fold difference. Five of the
strains (DA, PVG, AUG, SR, and LEW) performed a
significantly greater amount of work compared with
work performed by the COP strain (lowest performers).
The data presented in Figs. 1 and 2 demonstrate that
the COP and DA rats recorded a marked difference in
treadmill running endurance capacity, whether the
measure is based on total distance run or work performed.
Figure 3 shows the average cardiac output for each of
the 11 strains and combines results from females and
males. The cardiac outputs ranged from a low of 32.60
ml in the BUF rats to a high of 57.26 ml in the PVG rats
(1.8-fold difference). The strains in Fig. 3 are arranged
in the same order as shown in Fig. 1. It is obvious from
inspection that, in general, cardiac output in each
strain decreased in approximately the same sequence
as did running distance. Figure 4 shows the association
between distance run (data from Fig. 1) and isolated
heart performance (data from Fig. 3). Approximately
75% of the variance in cardiac output was associated
with changes in distance run (r 5 0.868). On average, a
1 ml · min21 · g21 heart weight increase in cardiac output
was associated with a 19.03-m increase in distance run
( y 5 19.03x 2 290.39). The assignment of independent
and dependent variables in Fig. 4 was arbitrary and is
not meant to imply a causative relationship.
GENETIC MODELS OF PHYSICAL PERFORMANCE
533
Fig. 2. Vertical work performed by each
strain; values for females and males
are combined. Values are means 6 SE.
Listing of strains (left to right) is in
same order as in Fig. 1. * Strains that
performed significantly (P , 0.05) more
work compared with COP rats, as
evaluated by Dunnett’s t-test.
puts (in milliliters per minute per gram heart weight).
Only in the COP rats were the male cardiac outputs
significantly greater than in the female cardiac outputs.
The day on which the best running performance was
recorded varied widely among the strains. For example,
most of the male COP rats (Table 2) had their best run on
days 1 and 2 (average 5 1.8), whereas the male PVG
rats almost always performed best on day 5 (average 5
4.7). Despite this variance in the day of best performance, there was no significant relationship between
the duration run and the day on which the best run
occurred for either gender.
Finally, for females there was a significant (P , 0.05)
negative linear association between body weight and
distance run (meters 5 24.47 g 1 1,279 m, r 5 0.76).
That is, lighter rats tended to run a longer distance.
For males there was a similar trend of lesser slope
(meters 5 21.89 g 1 975 m, r 5 0.43) that was not
significant at the 0.05 level (P 5 0.185).
Fig. 3. Isolated cardiac performance
(Langendorff-Neely preparation) for
each strain; values for females and males
are combined. Values are means 6 SE.
Listing of strains (left to right) is same
order as shown in Fig. 1. * Strains that
performed significantly (P , 0.05) more
work compared with BUF rats (lowest
cardiac performers), as evaluated by
Dunnett’s t-test.
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kg/m, respectively). On the basis of work, the female
DA, AUG, PVG, F344, and BUF performed significantly
better on average than did the female COP. For males
(Table 2), the COP the performed the least work and
the DA performed the most work (15.7 6 3.1 vs. 52.9 6
2.9 kg/m, respectively). This represents a 3.4-fold difference in work performed between the lowest and highest
performing strains. For males, the DA, AUG, PVG,
LEW, WKY, and ACI strains performed significantly
more work than did the COP rats.
Table 3 summarizes the isolated heart performance data
for each gender. The cardiac outputs in the females ranged
from a low of 34.69 6 0.63 ml·min21 · g21 in the BUF rats
to a high of 60.91 6 1.22 ml · min21 · g21 in the DA rats
(1.8-fold difference). For males, the cardiac outputs
ranged from a low of 30.2 6 3.01 ml · min21 · g21 in the
F344 rats to a high of 57.25 6 2.32 ml · min21 · g21 in the
PVG rats (1.9-fold difference). The DA, WKY, F344,
ACI, MNS, and BUF females, compared with the males
of each species, had significantly greater cardiac out-
534
GENETIC MODELS OF PHYSICAL PERFORMANCE
Fig. 4. Correlation between isolated
cardiac performance and distance run
across 11 strains of inbred rats for
males and females combined. Each 1
ml · min21 · g21 increase in cardiac output was associated with an increase of
19.03 m in distance run.
Although a vast literature has developed that deals
with the adaptational aspects of endurance performance (4, 20), the genetic components causative of the
differences between high- and low-endurance performance have yet to be identified. Nevertheless, observations in both humans and animals suggest that genetic
variance accounts for a large portion of the range
observed in endurance performance. Klissouras (19)
estimated the contribution of heredity to the interindividual variance in performing an endurance run to
exhaustion in pairs of monozygotic and dizygotic twins.
He estimated that the variation in maximal aerobic
power is 93.4% genetically determined. Bouchard et al.
(2) estimated that a genetic component accounts for
70% of endurance performance in young adults when
measured as the total work performed during a 90-min
maximal ergocycle test. Other investigators, however,
found only minimal (8) or no heritable components
related to indexes of endurance performance (16). A
finding of no significant genetic component is difficult to
interpret because it could result simply from large
variation in the measure of the trait of interest. This
problem of variation is especially critical for complex
measures, such as maximal oxygen consumption (25).
Although monozygotic twins are almost genetically
identical, and phenotypic variance between twins must
be largely of environmental origin, twin studies should
not be viewed as definitive because the effect of correlated environments would tend to inflate the apparent
genetic contribution. For example, monozygotic twins
may be treated more similarly by people than dizygotic
twins simply because of their similar appearance (14).
Heritability of endurance performance has also been
demonstrated in animals. The magnitude of heritability is often expressed in terms of narrow sense heritability (h2 ) which is the fractional heritability from parent
to offspring in one generation (11, 14). Thus h2 5
Table 1. Summary of average values for endurance
performance in female rats from 11 inbred strains
Table 2. Summary of average values for endurance
performance in male rats from 11 inbred strains
Inbred
Strain
AUG
DA
PVG
F344
LEW
ACI
WKY
SR
BUF
COP
MNS
Day of
Best Duration Run, Distance Run, Vertical Work, Body Weight,
Run
min
m
kg/m
g
3.8
4.2
2.2
4.7
4.5
3.0
2.7
2.8
4.0
2.5
3.5
40.6 6 2.4*†
37.1 6 3.2*‡
36.3 6 2.1*
33.6 6 1.5*†
28.5 6 2.0
27.5 6 1.2
27.0 6 1.3
25.3 6 2.3
24.7 6 1.4
22.1 6 1.2
21.2 6 1.0
805 6 70.7*†
712 6 96.4*
682 6 56.1*
606 6 40.0*†
479 6 50.8
453 6 29.1
441 6 29.0
409 6 53.0
391 6 32.1
333 6 24.4
315 6 20.6
28.3 6 2.7*
27.4 6 3.6*‡
25.6 6 2.1*‡
24.8 6 1.5*†
25.2 6 2.2‡
18.9 6 1.3‡
19.0 6 1.2*‡
19.7 6 2.4‡
19.0 6 1.2‡
14.3 6 1.1
18.5 6 1.0‡
135 6 2.5*‡
149 6 1.2‡
145 6 2.1‡
159 6 1.0‡
206 6 3.8*‡
161 6 2.0‡
167 6 1.8‡
187 6 1.4*‡
189 6 5.2‡
166 6 1.9‡
229 6 3.2*‡
Values are means 6 SE; n 5 6 female rats of each strain. Strains
are listed from highest to lowest performance on basis of distance
run. * Significantly different from COP strain within each gender, P ,
0.05; † female value significantly higher than male value, P , 0.05;
‡ female value significantly lower than male value, P , 0.05.
Inbred
Strain
DA
PVG
SR
AUG
ACI
LEW
WKY
BUF
F344
MNS
COP
Day of
Best Duration Run, Distance Run, Vertical Work, Body Weight,
Run
min
m
kg/m
g
4.3
4.7
2.5
3.8
3.3
2.7
2.2
4.5
3.8
3.7
1.8
46.0 6 1.3*†
38.9 6 2.2*
33.7 6 2.7*
33.2 6 1.4*‡
27.2 6 1.7
25.5 6 0.6
24.7 6 0.8
23.0 6 1.6
22.0 6 1.0‡
20.4 6 1.6
17.7 6 3.2
968 6 41.3*
754 6 64.5*
615 6 72.4*
594 6 36.1*‡
447 6 39.4
405 6 13.4
387 6 17.7
355 6 32.8
332 6 21.0‡
302 6 33.0
262 6 51.2
52.9 6 2.9*†
41.4 6 3.3*†
47.5 6 5.4†
30.5 6 1.9*
25.9 6 2.1*†
34.0 6 1.2*†
25.3 6 1.2*†
27.9 6 2.7†
18.6 6 1.2‡
25.5 6 2.5†
15.7 6 3.1
211 6 4.4*†
213 6 1.8†
299 6 1.8*†
198 6 5.1*†
225 6 2.9†
324 6 5.5*†
253 6 2.8*†
304 6 4.5*†
216 6 2.9†
330 6 9.1*†
233 6 2.5†
Values are means 6 SE; n 5 6 male rats of each strain. Strains are
listed from highest to lowest performance on basis of distance run.
* Significantly different from COP strain within each gender, P ,
0.05; † male value significantly higher than female value, P , 0.05;
‡ male value significantly lower than female value, P , 0.05.
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DISCUSSION
GENETIC MODELS OF PHYSICAL PERFORMANCE
Table 3. Summary of average values for cardiac output
in female and male rats from 11 inbred strains
Cardiac Output, ml · min21 · g heart weight21
Inbred
Strain
Female rats
Male rats
DA
PVG
AUG
WKY
F344
SR
LEW
ACI
MNS
COP
BUF
60.91 6 1.22*†
57.27 6 0.62*
ND
45.67 6 2.18*†
43.76 6 0.78*†
43.19 6 2.36*
40.04 6 1.53
38.67 6 .060†
37.76 6 1.35†
35.80 6 1.63‡
34.69 6 0.63†
52.91 6 .85*
57.25 6 2.32*
42.28 6 .36*
35.16 6 0.60
30.20 6 3.01
39.27 6 1.72*
38.11 6 0.39*
33.66 6 1.89
34.02 6 0.84
40.00 6 0.49*
30.50 6 .068
(selection response)/(selection differential), where selection response is the average difference for the trait
between the offspring of the high- and low-selected
parents and selection differential is the average difference for the trait between the high- and low-selected
parents.
An h2 of 1 indicates that the phenotype was inherited
with complete fidelity, whereas an h2 of 0 demonstrates
no heritable similarity between parents and offspring.
A significant h2 was found by Garland and colleagues
(6, 10) for endurance performance in both mice (h2 5
0.17–0.33) and garter snakes (h2 5 0.70). We estimated
the heritability of treadmill running performance in a
small test population of Sprague-Dawley (SD) rats by
using the same treadmill test described in the present
study (unpublished observations). The running capacity of 24 SD rats of each gender was measured. Two
pairs of the lowest performers and two pairs of the
highest performers were bred, and the performances of
the four litters of offspring were measured. The first
generation h2 was 0.50, which suggests that the treadmill running test we have adopted to estimate aerobic
endurance performance represents a phenotype with
significant heritability in rats.
The distance run (in m) and the vertical work accomplished (in kg/m) at exhaustion were taken as the
estimates of endurance performance for each of the five
trials. For each rat, the single best daily trial of the five
performed was used as the estimate of endurance
performance most related to genetic composition. This
idea of estimating the genetic component from the one
best day of performance, rather than the average for all
trials, for example, has two origins. 1) The environment
can have an infinite negative influence upon performance (i.e., take the distance run to zero). Factors such
as subtle differences in housing or daily handling could
cause a genetically superior rat to perform below its
normal level on a given day. 2) The environment can
have only a finite positive influence on endurance
performance.
The almost threefold difference in endurance performance between the COP and DA strains (Figs. 1 and 2)
should provide a suitable genetic substrate for identification of quantitative trait loci and, ultimately, genes
associated with the extremes of endurance performance. This approach is based on two related and
apparently immutable facets of biology: 1) genes are
causative of traits and not vice versa; and 2) in a
segregating F2 population, genes causative of a given
trait (such as endurance performance) will remain
associated with that trait and other genes will segregate randomly relative to the trait. Inbred models of
hypertension in rats have served as a prototype for
exploring the genetic basis of complex traits in this
species, as exemplified by the work of Rapp and colleagues (5, 23, 24).
Given the complexity underlying endurance performance, one cannot predict the exact nature of the
various individual traits that would be found in divergent inbred strains. Nevertheless, one view supports
the hypothesis that endurance performance is determined largely by two factors: 1) the rate at which
oxygen and nutrient substrates can be utilized to
produce energy in the form of ATP, and 2) the efficiency
with which this energy is transferred into work (20).
Oxygen utilization is governed by the cardiac output
and the ability of peripheral tissues to extract oxygen.
Efficiency is the ratio of work performed to total energy
expended and is determined by the complex interaction
of all factors that translate energy into movement, such
as skeletal mechanics, neuromuscular coordination,
and heat dissipation. Joyner (17) has described a more
explicit model of endurance running performance that
in its simplest form is the product of three physiological
factors: 1) the maximal rate at which oxygen and
nutrient substrates can be utilized (V̇O2 max) to produce
energy in the form of ATP, 2) the percentage of V̇O2 max at
the threshold for lactate release, and 3) the efficiency of
running. Each of these intermediates is polygenic in
origin and highly complex in physiological expression.
We hypothesize that allelic variation for each of these
three intermediate phenotypes will largely account for
the magnitude of the difference in performance between the COP and DA strains of rats. The correlation
across strains between the magnitude of isolated heart
performance and distance run (Fig. 4) provides preliminary data suggesting that heart performance may be a
primary intermediate phenotype that determines the
difference in aerobic capacity between the strains.
An endurance exercise test is often used clinically to
assess cardiovascular fitness and as a general test of
overall health status. If indeed there is a large genetic
component to a phenotype as fundamental to health
and survival as endurance performance, identification
of the genes responsible for these differences would be
of major importance. Obviously, divergent inbred strains
that originated from selective breeding for aerobic
endurance performance would be better models because the genes for these traits would be concentrated
in the low- and high-selected lines (13, 18). Such
concentration would allow for identification of a larger
Downloaded from http://jap.physiology.org/ by 10.220.33.4 on June 18, 2017
Values are means 6 SE; n 5 6 rats of each gender in each strain;
ND, not done. Strains are listed from highest to lowest performance
on basis of cardiac output for females. * Significantly different from
BUF strain within each gender, P , 0.05; † female value significantly
higher than male value, P , 0.05; ‡ female value significantly lower
than male value, P , 0.05.
535
536
GENETIC MODELS OF PHYSICAL PERFORMANCE
number of genes causative of the differences between
low- and high-endurance performance (9). To our knowledge, such models of physical performance are not
available. The wide divide in performance between
COP and DA strains of rats represents a currently
available substrate for exploration of the functional
genomics of endurance performance.
Address for reprint requests: S. L. Britton, Physiology and Molecular Medicine, Medical College of Ohio, 3035 Arlington Ave., Toledo,
OH 43614-5804 (E-mail: [email protected]).
Received 29 December 1997; accepted in final form 1 April 1998.
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