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 The Author 2008. Published by Oxford University Press on behalf of the British Geriatrics Society.
All rights reserved. For Permissions, please email: [email protected]
ACE inhibitors for sarcopenia—as good as
exercise training?
Sarcopenia is a major health problem for older people.
Progressive impairment in muscle strength and loss of
muscle mass are key contributors to falls, fractures and
reduced physical function, is a key risk factor for death, and
for the need for assistance with activities of daily living [1, 2].
Finding effective ways to prevent and reverse sarcopenia,
therefore, has great importance as a way of attempting to
reduce falls and immobility, avoid institutionalisation and
enhance healthy ageing.
No consensus threshold for diagnosing sarcopenia has
yet been arrived at, but the pathophysiological hallmarks
of the condition are becoming better defined. Reduced
cross-sectional muscle area, fibre loss and reduced muscle
quality all play a part; mitochondrial dysfunction occurs
together with preferential loss of type II (fast twitch)
fibres and changes in calcium handling by the sarcoplasmic
reticulum [3]. These changes lead to reductions in maximal
muscle strength, affecting predominantly explosive power
but also leading to increased fatigability.
The biological mechanisms underlying the pathophysiological changes of sarcopenia are still not well understood,
but basic science and epidemiological studies have given
us important insights in the last few years. Satellite cells
in muscle, which usually provide the substrate for muscle regeneration, are lower in number in older people [4].
Chronic inflammation is linked to sarcopenia, with proinflammatory cytokines, including IL-6 and TNF alpha,
thought to have deleterious actions on muscle [5]. Hormonal
363
Editorials
changes are also thought to play a role, and there are emerging
links between the metabolic syndrome and sarcopenia [6].
Finally, a number of lines of epidemiological evidence now
link the renin-angiotensin-aldosterone (RAAS) system to
skeletal muscle function. Individuals with the II genotype of
the ACE gene have greater endurance and greater skeletal
muscle trainability in some studies [7]; hypertensive patients
taking ACE inhibitors have greater cross-sectional muscle
mass and a slower decline in walking speed than those taking
other antihypertensives in epidemiological studies [8].
What works in sarcopenia? The best evidence to date
is exercise. Both endurance and resistance exercise improve
skeletal muscle function and cross-sectional area, even in very
old patients [9]. These benefits are not simply abstract but
can translate into an enhanced ability to perform activities
of daily living [10]. However, as many older people are
unwilling or simply unable to engage in exercise training
other avenues need to be explored. The appealing prospect
of a pill which might confer improved exercise capacity has
led to a number of pharmacological interventions being
evaluated. These include testosterone [11], which shows
moderate effects on muscle strength in older men, growth
hormone, which is expensive, shows only modest effects and
has problematic side-effects [12], and vitamin D [13], which
has shown improvements in muscle function in some, but
not all studies.
Following on from recent observational data suggesting
a beneficial effect of ACE inhibitors, we recently reported
results from a randomised controlled trial of ACE inhibitors
on physical function involving 130 older patients with
impairment of daily activities [14]. Patients were all aged
65 years and over, and were excluded if they had concurrent
heart failure or LV systolic dysfunction. At baseline, patients
had a wide range of comorbid conditions and had significant
impairment of physical function—the baseline six-minute
walk distance was only 300 metres and the median baseline
timed-up and go time was 13 seconds. The intervention group
received 4 mg of perindopril daily for 20 weeks; the control
group received placebo. The intervention group achieved a
31 m improvement in the six-minute walk distance compared
to placebo at 20 weeks (p = 0.003); quality of life as measured
by the EuroQol 5D tool also improved by a clinically
significant 0.09 points relative to placebo (p = 0.046), and
there was a nonsignificant improvement in the timed-up
and go time (1.3 seconds, p = 0.08). The improvement in
exercise capacity recorded is equivalent to that reported after
six months of exercise training [15], and the intervention
was well tolerated with nonsignificantly fewer falls in the
treatment group.
What remains less clear from these results is the
mechanism of action. ACE inhibitors are known to
have effects on cardiac function, and it is possible that
they improved cardiac output, and hence, muscle blood
supply—many patients in this study had cardiovascular
disease, and a high proportion of older people display
disturbances of diastolic cardiac dysfunction even in the
absence of an overt diagnosis of heart failure. ACE inhibitors
364
are also known to improve endothelial function, muscle
glucose uptake, increase potassium levels and modulate
other hormonal systems including IGF-1, all of which could
contribute to improved skeletal muscle function. Finally,
ACE inhibitors could of course be mediating a direct effect
on skeletal muscle structure and function; they are known to
have trophic effects on myocardial tissue.
What does this mean for the treatment of older people?
Firstly, it should give us reassurance that older people treated
with ACE inhibitors for other cardiovascular conditions are
very unlikely to suffer from worsening physical function as a
result of therapy. More excitingly, it promises to reinvigorate
attempts to find pharmacological approaches to the difficult
problem of sarcopenia. More work is now needed to
understand the precise mechanisms underlying the observed
clinical effect, to test how best to combine interventions
such as exercise and ACE inhibitors for treating sarcopenia,
and to explore whether other interventions suggested by
observational work and basic science might have beneficial
effects on this problem that afflicts vast numbers of older
people.
MILES D. WITHAM∗ , DEEPA SUMUKADAS ,
MARION E. T. MCMURDO
Section of Ageing and Health, University of Dundee,
Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
E-mail: [email protected]
∗ To whom correspondence should be addressed
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