Angiotensin-converting enzyme genotype affects the response of
human skeletal muscle to functional overload
Jonathan Folland*†, Ben Leach‡, Tom Little‡, Kate Hawker‡, Saul Myerson§,
Hugh Montgomery§ and David Jones‡
*Chelsea School Research Centre, University of Brighton, ‡School of Sport and Exercise
Sciences, University of Birmingham and §Centre for Cardiovascular Genetics, University College
London, UK
(Manuscript received 11 May 2000; accepted 27 July 2000)
The response to strength training varies widely between individuals and is considerably influenced by genetic
variables, which until now, have remained unidentified. The deletion (D), rather than the insertion (I), variant
of the human angiotensin-converting enzyme (ACE) genotype is an important factor in the hypertrophic
response of cardiac muscle to exercise and could also be involved in skeletal muscle hypertrophy — an
important factor in the response to functional overload. Subjects were 33 healthy male volunteers with no
experience of strength training. We examined the effect of ACE genotype upon changes in strength of
quadriceps muscles in response to 9 weeks of specific strength training (isometric or dynamic). There was a
significant interaction between ACE genotype and isometric training with greater strength gains shown by
subjects with the D allele (mean ± s.e.m.: II, 9.0 ± 1.7 %; ID, 17.6 ± 2.2 %; DD, 14.9 ± 1.3 %, ANOVA,
P < 0.05). A consistent genotype and training interaction (ID > DD > II) was observed across all of the
strength measures, and both types of training. ACE genotype is the first genetic factor to be identified in the
response of skeletal muscle to strength training. The association of the ACE IÏD polymorphism with the
responses of cardiac and skeletal muscle to functional overload indicates that they may share a common
mechanism. These findings suggest a novel mechanism, involving the renin—angiotensin system, in the
response of skeletal muscle to functional overload and may have implications for the management of
conditions such as muscle wasting disorders, prolonged bed rest, ageing and rehabilitation, where muscle
weakness may limit function. Experimental Physiology (2000) 85.5, 575—579.
The considerable individual variation in human muscular
strength (Hakkinen et al. 1998) reflects the interaction of
environmental factors (e.g. specific training and habitual use)
with genetic elements. In old age, for example, there is a
significant decline in skeletal muscle strength and muscle size
(Grimby & Saltin, 1983; Kallman et al. 1990) that contributes
to a loss of mobility and can inhibit the essential activities of
daily living (Hyatt et al. 1990). Prolonged bed rest (Berg et
al. 1997), space flight (Baldwin, 1996) or immobilisation
(MacDougall et al. 1980) also cause a loss of muscle strength,
largely as a consequence of disuse atrophy. Functional
overload, in the form of strength training is regarded as an
effective means of increasing strength and restoring functional
capacity in all these groups (MacDougall et al. 1980;
Germaine et al. 1995; Tracy et al. 1999). The increase in
strength with training is associated with muscle hypertrophy
(Narici et al. 1989; Garfinkel & Cafarelli, 1992; Hakkinen et
al. 1998), although the relationship between strength gains
and hypertrophy is not always clear (Jones, 1992). The
individual response to strength training is highly variable
(Folland et al. 1998) and strength gains are significantly
affected by inheritance (Thomis et al. 1998), although no
specific genetic locus has been identified. The cause of this
variation may reveal important information on the regulation
of muscular strength.
Angiotensin-converting enzyme (ACE) is a key component
of the circulating human renin—angiotensin system (RAS)
generating angiotensin II, a vasoconstrictor, and degrading
vasodilator kinins. Local ACE expression may also modulate
tissue growth processes as both angiotensin II and kinins
appear to have growth regulatory effects (Geisterfer et al.
1988; Ishigai et al. 1997; Kai et al. 1998). A functional
polymorphism of the ACE gene has been identified, with the
absence (deletion, D) rather than the presence (insertion, I)
of a 287 base pair fragment associated with higher tissue
(Costerousse et al. 1993; Danser et al. 1995) and serum ACE
†To whom correspondence should be addressed at Chelsea School Research Centre, University of Brighton,
Eastbourne BN20 7SP, UK.
Publication of The Physiological Society
2057
Email: [email protected]
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576
activity (Rigat et al. 1990). The D allele has been associated
with growth of vascular smooth muscle at the site of coronary
angioplasty (Ohishi et al. 1993) and human cardiac hypertrophy in response to exercise (Montgomery et al. 1997).
There is considerable ACE activity in skeletal muscle (Reneland
& Lithell, 1994), which raises the possibility that the ACE D
allele might similarly influence the response of skeletal muscle
to functional overload. We therefore studied the influence of the
ACE deletion allele on the response of the human quadriceps
muscle group to specific strength training programmes in
healthy, recreationally active young men.
Subjects
E.xp. Physiol. 85.5
J. Folland and others
METHODS
All the subjects were volunteers from amongst the University staff
and students. They were healthy males (18—30 years), recreationally
active with no history of knee pathology or leg strength training.
Subjects were instructed to maintain their habitual levels of activity
throughout the study period. The study protocol was approved by the
local Ethics Committee and conformed to the Declaration of Helsinki.
Subjects gave their written informed consent to the procedures.
Forty-seven subjects (ACE genotypes: 8 II, 24 ID, 15 DD) were
recruited.
Fourteen subjects, whose ACE genotype distribution and baseline
characteristics did not differ from those who continued, later
withdrew from the study because they were unable to adhere to the
training schedule. Amongst the 33 subjects who completed the
training programme (6 II, 17 ID, 10 DD) baseline physical
characteristics (age, 21.4 ± 0.5 years; mass, 75.9 ± 2.1 kg; height,
180 ± 1 cm; body mass index, 23.3 ± 0.6 kg m¦Â) and activity levels
(2.8 ± 0.3 h exercise per week) were independent of ACE genotype.
Strength training
The training and all of the strength measurements were of the
quadriceps muscle group and the training consisted of three training
sessions per week for 9 weeks. One leg of each subject performed
purely isometric training while the other leg carried out only
dynamic training. Legs were randomly assigned to one form of
training. All of the training was carried out on identical leg extension
machines, one of which was adapted for isometric contractions. In
this case a strain gauge facilitated force measurement and visual
feedback for each contraction. The isometric training was 10
repetitions of 2 s duration at each of four knee joint angles (1.22,
1.57, 1.92 and 2.27 rad). The dynamic training was four sets of ten
repetitions, taking 1 s to lift and 1 s to lower the weight. Each leg
worked at 75% of their respective maxima, and had 2 min rest
between sets. All of the training sessions were supervised with
recording of the training loads and continual verbal encouragement.
Strength testing
A battery of strength measurements was completed on each testing
occasion. Baseline measurements were taken on three occasions,
each 1 week apart, and twice post-training, 3 days apart. The
primary strength measure was unilateral isometric leg extension
strength at a joint angle of 1.57 rad assessed with a conventional
strength-testing chair (Parker et al. 1990). For the three baseline
tests this measure had a coefficient of variation of 3.5%. Each
measurement involved four maximum voluntary contractions with
30 s rest between each. On one occasion electrically stimulated
twitches were superimposed on the maximum voluntary contractions
to calculate the level of voluntary muscle activation (Rutherford et
al. 1986).
Additional strength measurements were taken with a Cybex Norm
isokinetic dynamometer (Lumex Inc., USA). These included peak
isometric torque at four angles (1.22, 1.57, 1.92 and 2.27 rad) and
peak isokinetic torque at three velocities (0.79, 2.62 and 5.24 rad s¢).
ACE genotyping
A saline mouth rinse was used to collect epithelial cells and ACE
genotype was determined by a polymerase chain reaction (O’Dell et
al. 1995). The study was double blind with respect to the subjects’
ACE genotype.
Statistical analysis
Pre- and post-training mean values were calculated for each leg of
each subject and the difference was expressed as a percentage
increase. The contribution of all factors to the variance of the results
was examined with multivariate analysis. The group data are
expressed as means ± s.e.m. The difference between ACE genotypes
was examined with analysis of variance (ANOVA) and Scheff‹e’s
post hoc test. To analyse the importance of the D allele a protected
Student’s t test was used (critical P < 0.025).
RESULTS
Figure 1
ACE genotype and the response to functional overload.
Percentage increase in isometric strength after 9 weeks of
isometric training for 33 previously untrained healthy young
men (means ± s.e.m.; II, n = 6; ID, n = 17; DD, n = 10).
There were no differences in pre-training strength in relation
to ACE genotype (II, 650 ± 50 N; ID, 657 ± 23 N; DD,
640 ± 30 N; ANOVA, P = 0.91) or between the isometric
and dynamic training legs (Student’s paired t test, P = 0.97).
Prior to the training the level of quadriceps muscle activation
during a maximum voluntary contraction was 97.2 ± 2.1% of
full activation and this was not associated with ACE genotype.
The individual increases in strength as a result of training
varied from 3.2 to 29.7% (average of both legs) and was
unrelated to baseline strength, or any other physical or activity
characteristic.
The response to isometric training was strongly genotype
dependant (increase in isometric strength: II, 9.0 ± 1.7%; ID,
17.6 ± 2.2%; DD, 14.9 ± 1.3%; ANOVA, P < 0.05; Scheff‹e’s
post hoc test, P < 0.05 II and ID; Fig. 1). The gains in
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Exp. Physiol. 85.5
ACE genotype and functional overload
strength were predominantly associated with the presence of
the D allele compared to its absence (ID and DD vs. II,
protected t test, P < 0.025). The ID and DD genotype subjects
improved by 97 and 66% more than the II genotype subjects.
All of the strength measures, taken at different joint angles
and speeds of contraction, showed the same trend with greater
gains for subjects with the D allele genotypes.
The dynamic training was a weaker stimulus to strength gains
than isometric training (increase in isometric strength:
11.5 ± 1.0% vs. 15.2 ± 1.3%; paired t test, P < 0.001) nor
did it produce such a strong training—genotype interaction
(mean increase in isometric strength after dynamic training
was: II, 10.2 ± 1.2%; ID, 11.5 ± 1.6%; DD, 11.8 ± 1.5%). The
interaction was stronger, but still non-significant for a more
specific strength test (mean increase in isokinetic strength at
0.78 rad s¢ after dynamic training was: II, 8.4 ± 3.3%; ID,
11.2 ± 2.6%; DD, 14.9 ± 4.1%).
DISCUSSION
The present results indicate a clear involvement of the ACE
gene in the response of skeletal muscle to functional overload.
This is the first genetic factor to be identified as functionally
important in this context. The consistent genotype and
training interaction we have observed across all of our strength
measures, and both types of training, reinforces the validity of
this finding within the study population. The suggestion of a
gene—environment interaction is enhanced by its marked
dependence on the magnitude of the training stimulus. There
was no association of strength with genotype in the untrained
(pre-training) state, a weak association in limbs exposed to the
lesser (dynamic) training stimulus, and a strong statistically
significant association in limbs undergoing the more effective
isometric strength training. The dynamic training may have
been less effective because it involved lower forces, less uniform
loading and possibly also a shorter duration of loading.
Whilst the ACE gene is a close neighbour of the growth
hormone (GH) gene, and GH may play a role in the response
to functional overload, ACE gene IÏD polymorphism is not
linked to the GH gene (Jeunemaitre et al. 1992; McKenzie et
al. 1995). It is more probable that the ACE gene directly
modulates the adaptation to functional overload through the
pivotal role of ACE within the systemic andÏor local skeletal
muscle RAS by the generation of angiotensin II or the
degradation of kinins.
Local RASs have been found in myocardium (Dzau, 1988),
smooth muscle (Gibbons & Dzau, 1990) and skeletal muscle
(Reneland & Lithell, 1994) and the ACE D allele is associated
with higher systemic (Rigat et al. 1990) and cardiac tissue
ACE activities (Danser et al. 1995), although this has not
been examined in skeletal muscle. ACE is responsible for the
production of angiotensin II, which is a potent growth factor
in cardiac and vascular tissue (Geisterfer et al. 1988; Kai et
al. 1998) and ACE also degrades kinins that inhibit growth in
cardiac myocytes (Ishigai et al. 1997). The D allele has recently
been associated with left ventricular hypertrophy in response
to physical training (Montgomery et al. 1997). Thus the ACE
577
genotype that regulates the hypertrophic process in other tissues
may do likewise in skeletal muscle. ACE has been identified as
present within the endothelial cells of skeletal muscle
(Schaufelberger et al. 1998) and both angiotensin II and kinin
receptors are expressed in skeletal muscle (Stoll et al. 1995;
Rabito et al. 1996). Most notably, though, Schaufelberger and
colleagues (1998) found a significant correlation between the
quantity of ACE mRNA transcripts and skeletal muscle fibre
area in a cross-sectional survey of five cardiac patients and
eight control subjects.
Skeletal muscle hypertrophy is associated with strength training
(Narici et al. 1989; Garfinkel & Cafarelli, 1992; Hakkinen et
al. 1998) and is probably the major contributor to the increase
in strength seen with medium to long term training. Hence the
D allele may promote hypertrophy and greater strength gains
in response to functional overload. This suggestion of an effect
of the D genotype influencing strength gains via muscle
hypertrophy may appear in contrast to an earlier report
(Montgomery et al. 1999) where the I (and not D) allele was
associated with a greater relative whole-body anabolic response
to training. However the two studies are not comparable since
the former involved basic army training that consists of varied
physical activity (Williams et al. 1999) compared to the
present study where specific systematic strength training of a
single muscle group was undertaken.
Care should be taken in inferring that hypertrophy is the
only mechanism of strength gain as there are consistent
reports of discrepancies between the increase in strength and
the increase in muscle size, leading to a rise in specific tension
(Garfinkel & Cafarelli, 1992; Hakkinen et al. 1998). This
discrepancy is typically attributed to morphological and
neurological adaptations (Narici et al. 1989; Jones, 1992).
Interestingly, there is evidence that angiotensin II can affect
both sympathetic (Jonsson et al. 1993) and neuromuscular
transmission (Wali, 1986) and could, in theory, influence
neural adaptations to strength training.
The systemic RAS has considerable influence on skeletal
muscle and whole-body metabolism (Montgomery et al. 1999)
which may modulate local tissue responses to overload.
Angiotensin II, which may be related to the ACE D allele,
stimulates systemic growth hormone release, affects steroid
hormone metabolism (Messerli et al. 1977) and, conversely,
may decrease plasma IGF1 concentration (Brink et al. 1996).
However, a functional link between ACE genotype and
systemic (or local) angiotensin II has yet to be demonstrated.
In contrast the ACE I allele has been found to enhance the
plasma insulin response to a glucose load (Cong et al. 1999).
There may be separate and complementary actions of the I
and D alleles. The finding of allele dominance, and even a
suggestion of heterozygote advantage (Fig. 1) is consistent
with this idea. Such an effect could also be due to the lowest
ACE levels (the II genotype) having a rate-limiting effect on
one or more processes.
Ours is the first report identifying a genetic locus that influences
the response to strength training. The association of the ACE
IÏD polymorphism with the responses of cardiac and skeletal
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578
J. Folland and others
muscle to functional overload suggests that they may share a
common mechanism. Although the observed effect of the D
allele is most likely to be due to local hypertrophic actions,
other factors may play a role in the response to functional
overload. The results could have considerable implications for
understanding the genetic basis of muscle wasting diseases and
conditions such as ageing, injury rehabilitation, bed rest and
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