sarcopenia pathophysiology and clinical relevance

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Wien Med Wochenschr (2011) 161/17–18: 402–408
DOI 10.1007/s10354-011-0002-y
� Springer-Verlag 2011
Printed in Austria
Sarcopenia – pathophysiology and clinical relevance
Michael Drey
Institute for Biomedicine of Aging, University of Erlangen-Nürnberg, Nürnberg, Germany
Received December 18, 2010, accepted (after revision) May 18, 2011, published online July 29, 2011
Sarkopenie – Pathophysiologie und klinische
Relevanz
Zusammenfassung. Die Ursachen der Sarkopenie sind multi-
dimensional. Der Verlust an schnell kontrahierenden Muskelfa-
sern übersteigt den Verlust an langsam kontrahierenden
Muskelfasern und endet in einem klinisch relevanten Verlust an
Muskelpower. Auf der subzellulären Ebene führen altersabhä-
ngige Veränderungen der Mitochondrien zu einer Reduktion der
muskulären Performance. Durch einen Rückgang der Anzahl der
motorischen Einheiten der Muskulatur entsteht eine Muskelfa-
seratrophie mit konsekutivem Rückgang der Muskelkraft. Ernie-
drigte Spiel an anabolen Hormonen und ein überwiegen von
proinflammatorischen Zytokinen sind verantwortlich für Verä-
nderungen der Körperzusammensetzung. Ein geringes Maß an
körperlicher Aktivität, Vitamin-D-Mangel und geringe Proteinzu-
fuhr sind stark mit einem Muskelverlust assoziiert. Sarkopenie
verursacht bei den Betroffenen einen Verlust an Unabhängigkeit,
gesteigerten Bedarf an medizinischer Versorgung und erhöhte
Kosten für das Gesundheitswesen.
Schlüsselwörter: Sarkopenie, Pathophysiologie, Alter
Summary. The causes of sarcopenia are multidimensional.
The loss of fast-twitch muscle fibres exceeds the loss of slow-
twitch muscle fibres and ends as a clinical relevant loss of muscle
power. On a sub-cellular level, age associated changes in the
mitochondria lead to functional decline of the muscle. The
reduction of motor units causes muscle fibre atrophy and loss
of muscle strength. Low levels of anabolic hormones and the
imbalance of pro- and anti-inflammatory cytokines are responsi-
ble for changes in body composition of older adults. Reduced
levels of physical activity, vitamin D and protein are highly
associated with muscle loss. Sarcopenia causes loss of indepen-
dence and high medical and nursing needs resulting in great
economic healthcare burden.
Key words: Sarcopenia, pathophysiology, older adults
Pathophysiology
Muscle morphology
Skeletal muscle consists of different fibre types charac-
terized by their specific myosin heavy chain isoforms.
Threemajor different types of fibres (type I, type IIa and
type IIb) can be distinguished. Type I fibre is a slow-
twitch fatigue resistant fibre with greater oxidative
capacity, higher mitochondrial content and greater
capillary density. In contrast, the type II fibre is a
fast-twitch fibre with a high glycolytic capacity. Type II
fibres are subdivided into type IIa that has an interme-
diate oxidative and glycolytic capacity and is more
fatigue resistant then type IIb inwhich glycolytic activity
predominates [1]. Histological human post mortem
studies have shown an age-related loss in fibre num-
bers. Between the ages of 20 and 80 there is about a 50%
reduction in the total fibre number. This loss is more
rapid after the age of 60. Furthermore the loss is selec-
tive, ending in a higher loss of fast-twitch type II fibre
compared to slow-twitch type I fibre [2]. These mor-
phological changes are reflected in muscle function.
Muscle strength decreases approximately 20–40% in
individuals around age 70 compared to young adults
of age 20. The loss of muscle strength even increases to
50% in individuals in their nineties [3]. Fast-twitch type
II fibre is involved in generating muscle power which is
the product of force and velocity of muscle contraction.
As a result of the greater loss of muscle II fibre, muscle
power decreases faster with age than muscle strength
[4]. This observation is clinically relevant, as studies
have shown that muscle power is more strongly related
to physical performance than muscle strength [5].
Mitochondria
Muscle contraction is dependent on the production of
ATP in the mitochondria. Since ATP is used for almost
Correspondence: Michael Drey, MD, Institute for Biomedicine of
Aging, University of Erlangen-Nürnberg, Heimerichstraße 58, 90419
Nürnberg, Germany.
Fax: þþ49-911-300 0525, E-mail: michael.drey@gmx.de
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402 � Springer-Verlag 17–18/2011 wmw
all reactions in the cell including muscle contraction,
changes in mitochondria size, the DNA inside the
mitochondria, and mitochondrial proteins directly ef-
fect muscle contraction in aged muscle. With age,
mitochondrial DNA content and protein synthesis are
lower leading to a reduction in mitochondrial proteins
[6, 7]. In addition to the reduction of the amount of
mitochondrial proteins, the proteins have reduced ac-
tivity [7]. This reduction in mitochondrial proteins and
their activity results in a 50% decrease in oxidative
capacity and ATP available for muscle contraction. This
in turn contributes to the age-associated reduction of
aerobic capacity [8].
The decline in mitochondrial DNA content, pro-
tein synthesis and protein activity seen with age maybe
associated with free radical production and oxidative
damage to DNA and mitochondrial proteins [9]. Com-
mon sites of oxidative damage in muscle cells are
nuclear and mitochondrial DNAs. While damaged nu-
clear DNA is quickly repaired, damaged mitochondrial
DNA is not easily repaired [10]. Extensive oxidative
damage to mitochondrial DNA can accumulate over
years diminishing the amount of functional mitochon-
drial DNA. This damage results in decreased levels of
functional mitochondrial protein [9]. Oxidative damage
to mitochondrial proteins also diminishes ATP produc-
tion and oxidative capacity in aged muscle [9].
Neurological factors
Age related changes in the neuromuscular system
might play a role in the onset of sarcopenia. The
number of spinal cord motor neurons and functioning
motor units decline with age [11, 12]. Data indicate that
motor units are preserved until approximately 60 years
of age, at which time there is a dramatic loss [13].
Human nerve cells have a predetermined life span and
the decline in these cells is dependent on the location in
the body, age and presence of disease [14]. The motor
neurons are responsible for sending signals from the
brain to themuscles to initiate movement. Amotor unit
consists of themotor neuron and all of themuscle fibres
innervated by that neuron. The number of the fibres
that a motor neuron innervates depends on the func-
tion of that certain muscle. For example, a muscle that
requires precise movements, such as muscles of the
eye, will have motor units with a motor neuron inner-
vating just a few muscles fibres. Muscles that require
less precise movements and large strength, such as the
quadriceps muscle, will have motor unit with motor
neuron innervating hundreds and possibly over a thou-
sand muscle fibres. The loss of muscle fibres begins
with the loss of motor neurons. Morphological changes
in the anterior horn of the spinal cord, as well as those
in the peripheral axon in older humans and animals,
can be accountable for the older-age muscle atrophy.
Motor neurons will die with age resulting in a denerva-
tion of the muscle fibres within the motor unit. This
denervation causes the muscle fibres to atrophy and
eventually die, leading to decrease in muscle mass [11].
When a motor neuron dies, an adjacent motor neuron,
usually a slow-twitch motor neuron, may reinervate
the muscle fibres, preventing atrophy. This process is
called motor unit remodelling. When compared to fast-
twitch motor units, slow-twitch motor units are slower
to contract and produce much less force. Motor unit
remodelling by slow-twitch motor neurons leads to less
efficient motor units. The remodelled slow-twitch mo-
tor unit will have less precise control movements, less
force productionand slowing of muscle mechanics [11,
12]. Thismay help explain the loss of balance and speed
of movement with age. In addition, denervation rates of
fast-twitch muscle fibres may exceed reinnervation
rates by slow-twitch motor neurons, further explaining
atrophy of fast-twitch muscle fibres in the elderly.
Hormones
In older adults, anabolic hormone levels decrease,
whereas catabolic hormones increase. As reduced le-
vels of sex hormones are associated with sarcopenia,
testosterone administration in elderly men has been
examined as a pharmacological therapy to preserve
muscle mass and minimize loss of strength [15]. In-
creasing the level of testosterone in old men to the
level of circulating testosterone seen in young men
increased muscle mass but did not result in functional
gains in strength [16]. Recent studies suggest adminis-
tration of supraphysiological dosages of testosterone
in elderly menmay significantly increase lower extrem-
ity strength as well as lean muscle mass [15]. Although
there are significant increases in strength among elder-
ly males when given high doses of testosterone, the
potential risks may outweigh the benefits. Risks associ-
ated with testosterone therapy in older men include
aggressive behavior, thrombotic complications, sleep
apnea, peripheral edema, gyenomastia, and the in-
creased risk of prostate cancer [17].
These side effects have driven the necessity for
drugs that demonstrate improved therapeutic profiles.
Novel, non-steroidal compounds, called selective an-
drogen receptor modulators (SARMs), have shown tis-
sue selective activity and improved pharmacokinetic
properties. Whether these drugs are effective in treating
sarcopenia has to be shown [18]. Dehydroepiandroster-
one (DHEA) is marketed as a nutritional supplement in
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the USA and is available over-the-counter. Unlike tes-
tosterone and estrogen, DHEA is a hormone precursor
which is converted into sex hormones at specific target
tissues [19]. The relationship between DHEA levels and
testosterone/estrogen levels in the human body has
been of particular interest. Since DHEA is a precursor
in the biosynthesis of sex hormones such as testoster-
one and estrogen, DHEA supplementation in both
males and females could potentially aid in increasing
muscle mass and strength without the potential risks
associated with testosterone and estrogen therapy.
Supplementation of DHEA in aged men and women
resulted in an increase in bone density, testosterone
and estradiol levels, libido parameters, but no changes
in muscle size, strength, or function [20, 21]. Research-
ers evaluating the use of DHEA in aging adults suggest
that its effects should be evaluated over a longer period
of time, and it might be more efficacious if the DHEA
dosage administered resulted in circulating androgen
levels exceeding those of young, healthy adults [21].
While there are few known adverse effects associated
with DHEA supplementation, most studies have failed
to demonstrate gains in muscle size or strength that
would address concerns about sarcopenia. Although
DHEA may provide the consumer with other benefits
such as increased bone density and sex hormone levels
which may counter other factors involved with aging, it
has not yet been proven to counter sarcopenia.
As serum growth hormone (GH) levels drop with
aging, its substitution in older adults seems to be logical
consequence [22]. Although GH administration in older
adults appears to improve body composition as evi-
denced as increased muscle mass, decreased fat mass,
and reduced rate of bone demineralization, a strong
body of evidence suggests that GH supplementation
does not result in strength gains, increases in functional
capacity, or positive metabolic changes [23, 24]. The
adverse effects associated with GH supplementation
are significant and are reported at a high rate with
treatment. Such adverse effects include carpal tunnel
syndrome, edema, arthralgia, glucose intolerance and
diabetes [23].
New GH secretagogues activate the receptors of a
putative endogenous ligand in the hypothalamus and
pituitary gland. Acting as functional somatostatin an-
tagonists, GH secretagogues potentiate the actions of
GH-releasing hormone on GH secretion, enhancing
pulsatile GH secretion. It is not clear whether it will be
useful to restore to young levels the activity of the GH-
IGF-I axis in aging. Nevertheless, if beneficial effects
on strength, similar to those demonstrated with GH
can be shown, GH secretagogues could provide a well-
tolerated clinical approach for treating or preventing
sarcopenia, and perhaps, even forestall the inevitability
of age-associated decline in function and indepen-
dence [25].
Inflammation
It is known that muscle tissue is responsive to cytokines
[26]. Some of them do have a catabolic effect like
interleukin-1 (IL-1) [27], interleukin-6 (IL-6) [28], tu-
mor necrosis factor alpha (TNF-a) [28, 29], and myos-
tatin [30]. Some others do have an anabolic effect like
interleukin-15 (IL-15) [31] and insulin-like growth fac-
tor-1 (IGF-1) [32]. On the other side muscle tissue itself
can express certain cytokines and other regulatory
factors, including TNF-a, IL-1, IL-6, myostatin, inter-
leukin-18 (IL-18), granulocyte/macrophage colony
stimulating factor (GM-CSF), and human leukocyte
antigen (HLA) class I and II proteins [33–38]. It is
known that the normal healthy regulation of muscle
protein synthesis and breakdown appears to be depen-
dent, in part, on a balance of expression of cytokines
and other factors [39]. Increasing age has been associ-
ated with changing levels of production for a number of
cytokines in cross-sectional studies. For example the
comparison of cytokine production between 711 elder-
ly participants of the Framingham Heart Study and 21
young healthy volunteers highlighted increased pro-
duction of IL-6 and IL-1Ra, the endogenous receptor
antagonist for IL-1, in peripheral blood mononuclear
cells of the elderly population [40]. Another cross-
sectional study in 790 men and women from the
Framingham Heart Study reported that IGF-1 concen-
trations also declined with age [41]. The significance of
IL-6 as a mediator of sarcopenia was demonstrated in a
longitudinal study of 232 men and 326 women from the
Framingham Heart Study, aged between 72 and 92
years [42]. Cellular IL-6 production proved to be a
significant predictor of sarcopenia in women, but not
in men. High concentrations of IGF-1, also measured in
the study, were associated with a lower loss of fat-free
mass (FFM) compared with low concentrations in men
but not in women. Further, it was shown that IL-6
production was a significant predictor of all-cause
mortality over a 6-year period of observation [43].
Finally, greater loss of FFM was also associated with
increased mortality, highlighting the importance of
sarcopenia as a contributor to the quantity, as well as
the quality, of old age.
Physical activity
Regular physical activity seems to have a positive influ-
ence on the inflammation level, as evident from several
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404 Drey – Sarcopenia – pathophysiology and clinical relevance � Springer-Verlag 17–18/2011 wmw
studies [44]. Higher levels of self-reported physical
activity were associated with lower serum concentra-
tions of several markers of inflammation, including
CRP, IL-6 and fibrinogen, as well as lower white blood
cell counts, after adjusting for age, sex, race, presence of
cardiovascular disease, smoking, body mass index, di-
abetes, and hypertension [45, 46]. Besides a detraining
effect, these data may explain the detrimental effect of
physical inactivity on muscle via protein synthesis
breakdown in the cell induced by inflammation (see
chapter inflammation).
It is well known that muscle strength can beimproved by training, even in older adults [47]. The
most frequently used approach to counteract sarco-
penia is progressive resistance training (PRT). PRT
means participants work against an external force that
is increased as muscle strength increases. Neverthe-
less, investigations have shown that although resis-
tance training (RT) has large benefits on muscle
strength in older adults, it only has a small tomoderate
effect on physical performance [47]. In recent years a
variety of studies indicate that muscle power (genera-
tion of muscular work per unit of time) is more strong-
ly related to physical performance than muscle
strength [5] (see chapter muscle morphology). There-
fore in the recent years the corresponding concept of
power training in older adults has provoked a high
interest. The core element of the power training (PT)
concept is that the concentric portion (lifting or push-
ing) of RT has to be completed as fast as possible,
whereas the eccentric portion (lowering) has to be
completed in approximately 2–3 seconds [48–52]. Un-
fortunately, the studies published until now, compar-
ing effects of RT and PT on physical performance in
older adults have shown inconsistent results [53–59].
For further information see chapter “physical activity
and sarcopenia”.
Nutrition
Until now, a lot of research was done in the field of
nutrition identifying risk factors for sarcopenia. The two
most important factors responsible for the develop-
ment of sarcopenia seem to be a deficiency in vitamin
D status and proteins.
Studies of various populations show that vitamin D
deficiency is highly prevalent in older adults. 80–100% of
nursing home residents in Europe, Australia and North
America have been shown to be deficient, with a high
proportion of severe deficiency. An epidemiological
study of community-dwelling adults, aged 71–76, in
Europe showed that 36% of males and 47% of females
are deficient [60–62]. This deficiency in older adults was
shown to be associated with sarcopenia, muscle weak-
ness, poor physical performance, balance problems
and falls, although findings from different studies are
somewhat inconsistent [63–70]. In randomized con-
trolled trials with older adults, investigating the effects
of vitamin D substitution on physical performance has
shown a clear tendency towards improvement in phys-
ical performance and muscle strength [71–74]. One
rationale for that effect is that vitamin D receptors are
present in the cell membrane and the core of muscle
cells [75]. The genomic effect of vitamin D results in
changes of mRNA concentrations and consecutively in
de novo protein synthesis in the muscle cell. Non-
genomic effects include the activation of protein kinase
C releasing Ca into the cytosol which is essential for
muscle contraction.
Besides the vitamin D deficiency, it seems that
protein intake plays an important role in older adults.
Epidemiological studies show that protein intake
is positively associated with preservation of muscle
mass [76, 77]. In the Health, Aging and Body Composi-
tion longitudinal study the authors found an associa-
tion of protein intake and changes in lean mass (LM)
and appendicular LM (aLM) over a 3-year period [78].
In this study aLM is the sum of lean mass of both legs
and arms, whereas LM is whole body lean mass. It was
reported that individuals in the highest quintile of
protein intake lost approximately 40% less LM and aLM
than those in the lowest quintile. These findings suggest
that the current recommended daily allowance (RDA)
for protein intake (0.8 g/kg per day) is not adequate for
older persons. It does not take into account the changes
that occur with age, such as reduced muscle mass,
increased fat mass, changes in food intake, reduced
physical activity and more frequent illness [79].
Reassessments of the nitrogen balance studies
show that a protein intake of 1.0–1.3 g/kg per day is
needed to offset the typically lower energy intake and
impaired insulin response in older adults [79]. Further
studies have demonstrated that not only the global
increase in protein intake but also the amount of pro-
tein intake per meal seems to be important [80]. It was
shown that ageing is associated with an inability of
skeletal muscle to respond to low doses (�7.5 g) of
essential amino acids whereas higher doses (10–15 g)
are capable of stimulating muscle protein synthesis to a
similar extent as the young [81]. Further, Katsanos et al.
[82] have revealed that especially an increased propor-
tion of leucine in a mixture of essential amino acids can
reverse an attenuated response of muscle protein syn-
thesis in elderly. For detailed information see chapter
“nutrition and sarcopenia”.
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Clinical relevance
Sarcopenia with regard to its role as a key player in
the development of physical frailty defined by Fried and
colleagues [83] results in a reduction of physical
strength and ability to perform activities of daily living.
These consequences of sarcopenia were the reason for
including a measurement of physical performance to
the latest definitions of sarcopenia [84, 85]. Further the
loss of muscle and strength with aging results in risk of
falling, difficulty in recovering from illness, prolonga-
tion of hospitalizations and long-term disability requir-
ing assistance in daily living. Further, the reduction of
muscle mass and physical strength leads to diminished
quality of life, loss of independence, and mortality [86,
87]. This loss of independence represents a high eco-
nomic healthcare burden and area of high medical/
nursing need. The estimated direct healthcare cost
attributable to sarcopenia in the United States in 2000
was $18.5 billion ($10.8 billion in men, $7.7 billion in
women), which represented about 1.5% of total health-
care expenditures for that year. The excess healthcare
expenditures were $860 for every sarcopenic man and
$933 for every sarcopenic woman. A 10% reduction in
sarcopenia prevalence would result in savings of $1.1
billion per year in U.S. healthcare costs [88]. As a
consequence of the expansion of this population seg-
ment along with increased longevity, the number of the
older adults who will become sarcopenic and frail and
require long-term institutionalization will consume a
high amount of healthcare funds.
Conflict of interest
The author declares that there is no conflict of
interest that could be perceived as prejudicing the
impartiality of the research reported.
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main topic
408 Drey – Sarcopenia – pathophysiology and clinical relevance � Springer-Verlag 17–18/2011 wmw
	Sarcopenia – pathophysiology and clinical relevance
	Sarkopenie – Pathophysiologie und klinischeRelevanz
	Pathophysiology
	Muscle morphology
	Mitochondria
	Neurological factors
	Hormones
	Inflammation
	Physical activity
	Nutrition
	Clinical relevance
	Conflict of interest
	References