Sarcopenia Age-Related Muscle Wasting and Weakness: Mechanisms and Treatments P32 potx

296 R. Koopman et al.
seem to represent the main anabolic signals responsible for the post-prandial
increase in muscle protein synthesis. In accordance, recent studies demonstrate that
the attenuated muscle protein synthetic response to food intake in the elderly can,
at least partly, be compensated for by increasing the leucine content of a meal
(Katsanos et al. 2006; Rieu et al. 2006).
Even in the absence of a concomitant increase in plasma insulin, EAA show a
dose-dependent stimulation of muscle protein synthesis (Bohe et al. 2003), and as
a result, some propose that insulin is rather permissive instead of modulatory
(Greenhaff et al. 2008; Rennie 2009; Bohe et al. 2003). Recent data indicate that
insulin in the range of ~30–150 mU/ml does not further stimulate muscle protein
synthesis (Greenhaff et al. 2008). Interestingly, it seems that muscle protein break-
down is very responsive to changes in insulin concentrations. Data from the Rennie
laboratory (Rennie 2009) suggest that insulin levels of 15 mU/ml can almost maxi-
mally reduce muscle protein breakdown and there seems to be no further inhibition
above 30 mU/ml (Greenhaff et al. 2008). These data suggest that protein breakdown
can be already maximally reduced by the intake of a light breakfast in healthy
young men. Resting leg protein breakdown has been reported to be either similar
(Wilkes et al. 2008) or just slightly increased (Volpi et al. 2001) in older men com-
pared with young controls. However, recent data suggest that muscle protein break-
down is not strongly inhibited by insulin in the elderly (Wilkes et al. 2008). These
observations seem to be in line with previous reports suggesting that muscle protein
synthesis is resistant to the anabolic action of insulin in the elderly (Rasmussen
et al. 2006; Volpi et al. 2000), which may be attributed to a less responsive impact
of physiological hyperinsulinemia on the increase in skeletal muscle blood flow
and subsequent amino acid availability in aged muscle (Fujita et al. 2006;
Rasmussen et al. 2006). The latter would also agree with a reduced activation of the
PI-3 kinase/Akt/mTOR signaling pathway and with the lesser increase in the mus-
cle protein synthetic rate following amino acid/protein ingestion in the elderly
(Cuthbertson et al. 2005).
As recent data clearly show that the digestion rate of protein is an indepen-

dent regulating factor of post-prandial protein anabolism (Dangin et al. 2001),
any impairments in protein digestion and/or absorption will attenuate and/or
reduce the appearance rate of dietary AA in the circulation, thereby lowering
the post-prandial muscle protein synthetic rate. Evidence to support the exis-
tence of differences in digestion and absorption kinetics and the subsequent
muscle protein synthetic response to dietary protein intake between young and
elderly humans remains lacking. The latter is largely due to the restrictions set
by the methodology that has been used to assess the appearance rate of AA
from the gut into the circulation. As free AA and protein-derived AA exhibit a
different timing and efficiency of intestinal absorption (Boirie et al. 1996),
simply adding labeled free AA to a protein containing drink does not provide
an accurate measure of the digestion and absorption kinetics of the ingested
dietary protein (Boirie et al. 1995). To accurately assess the appearance rate of
AA derived from dietary protein, the labeled AA need to be incorporated in the
297Exercise and Nutritional Interventions to Combat Age-Related Muscle Loss
dietary protein source (Beaufrere et al. 2000; Boirie et al. 1996; Dangin et al.
2002). A series of studies that have applied specifically produced, intrinsically
labeled protein have been instrumental in the development of the fast versus
slow protein concept (Beaufrere et al. 2000; Boirie et al. 1997a; Dangin et al.
2001, 2002, 2003). These studies show that ingestion of a slowly digested pro-
tein (casein) leads to a more positive whole-body protein balance when com-
pared to the ingestion of a fast digestible protein (whey) or a mixture of free
AA in healthy, young subjects (Dangin et al. 2001). In contrast, ingestion of a
fast protein was shown to result in greater net protein retention when compared
with a slow protein when provided in healthy, elderly men (Beaufrere et al.
2000; Boirie et al. 1997a; Dangin et al. 2002, 2003). The latter might be attrib-
uted to the proposed anabolic resistance of the muscle protein synthetic
machinery to become activated in elderly muscle. However, in a recent study
we did not observe any differences in the appearance rate of dietary phenylala-
nine in the circulation, and plasma amino acid availability between young and

elderly men following the intake of 35 g (Koopman et al. 2009b) of intact
casein protein. Clearly more research is warranted to determine to what extent
anabolic resistance to food (i.e. intact protein) intake exists in elderly humans.
Interestingly, previous studies have suggested that amino acid utilization in the
splanchnic area is elevated in the elderly (Boirie et al. 1997b; Volpi et al. 1999),
which would imply that less of the ingested AA are available for muscle protein
synthesis (Boirie et al. 1997a). Our recently obtained data clearly shows that
this is not the case following the ingestion of a relatively large bolus of intact
casein (Koopman et al. 2009b). In addition, we also recently tested the hypoth-
esis that the ingestion of a protein hydrolysate, i.e. an enzymatically pre-
digested protein, would enhance protein digestion and the absorption rate in
elderly men (Koopman et al. 2009a). The latter should theoretically result in a
greater increase in plasma AA availability and might improve the post-prandial
muscle protein synthetic response. Elderly men were provided with a single
bolus of specifically produced intrinsically L-[1-
13
C]phenylalanine–labeled
intact casein or casein hydrolysate. This is the first study to show that ingestion
of a casein hydrolysate, as opposed to its intact protein, accelerates the appear-
ance rate of dietary phenylalanine in the circulation, lowers splanchnic pheny-
lalanine extraction, increases post-prandial plasma amino acid availability, and
tends to augment the subsequent muscle protein synthetic response in vivo in
humans (Koopman et al. 2009a). These findings may indicate that part of the
proposed anabolic resistance in the elderly might be compensated for in part by
enhancing amino acid availability during the post-prandial period. In accor-
dance, it has been reported that protein pulse feeding (providing up to 80% of
daily protein intake in one meal) leads to greater protein retention than ingest-
ing the same amount of protein provided over four meals throughout the day
(spread-feeding) in elderly women (Arnal et al. 1999, 2000). In agreement,
pulse feeding did not lead to greater protein retention than spread feeding when

applied in young females (Arnal et al. 2000).
298 R. Koopman et al.
4 Exercise and Muscle Protein Turnover
Physical activity, in particular resistance type exercise, is a powerful stimulus to
promote net muscle protein anabolism, resulting in specific metabolic and morpho-
logical adaptations in skeletal muscle tissue. Resistance type exercise training can
effectively increase muscle strength, muscle mass and, as such, improve physical
performance and functional capacity (Evans 1995). Following a single bout of
resistance type exercise, specific signaling pathways are activated, which result in
a temporally increase in muscle IGF-1 gene expression (Chesley et al. 1992),
whereas myostatin expression is reduced (Raue et al. 2006). As a result, mRNA
translation is enhanced (Rommel et al. 2001) and DNA transcription is increased
via activation of transcription factors like MyoD and Myogenin (Willoughby and
Nelson 2002).
A single bout of resistance exercise rapidly (within 2–4 h, (Phillips et al. 1997))
stimulates muscle protein synthesis, and increased protein synthesis rates, in par-
ticular myofibrillar protein synthesis (Welle et al. 1993; Yarasheski et al. 1993;
Wilkinson et al. 2008), have been reported to persist for up to 16 h in trained (Tang
et al. 2008) and 24–48 h in untrained individuals (Chesley et al. 1992; Phillips et al.
1997; Tang et al. 2008). Muscle protein breakdown is also stimulated following
exercise, albeit to a lesser extent than protein synthesis (Biolo et al. 1995; Phillips
et al. 1997). The latter results in an improved net muscle protein balance that per-
sists up to 48 h in untrained individuals (Phillips et al. 1997). Net muscle protein
balance remains negative in the absence of nutrient intake (Phillips et al. 1997), and
as such, both exercise and nutrition are required to obtain a positive muscle net
amino acid balance and, as such, allow muscle hypertrophy. Carbohydrate and
protein/amino acid ingestion during post-exercise recovery forms an effective strat-
egy to enable net muscle protein accretion. Ingestion of carbohydrate following
exercise has been shown to improve net leg amino acid balance without affecting
muscle protein synthesis rates (Borsheim et al. 2004). Ingestion of carbohydrate

effectively increases plasma insulin levels and stimulates muscle protein anabolism,
primarily by reducing muscle protein degradation (Gelfand and Barrett 1987;
Hillier et al. 1998). As explained above, insulin should not be regarded as a primary
regulator of muscle protein synthesis as insulin exerts only a modest effect on
muscle protein synthesis in the absence of elevated amino acid concentrations
(Cuthbertson et al. 2005). In rodent models, it has been reported that an increase in
circulating plasma insulin concentrations does not further enhance mRNA transla-
tion initiation during post-exercise recovery (Fedele et al. 2000; Gautsch et al.
1998; Kimball et al. 2002). In a recent attempt to assess whether carbohydrate
co-ingestion is required to maximize post-exercise muscle protein synthesis, we
observed no surplus effect of carbohydrate co-ingestion on post-exercise muscle
protein synthesis under conditions where ample protein is ingested (Koopman et al.
2007a). Although carbohydrate co-ingestion does not seem to be required to
maximize post-exercise muscle protein synthesis rates, it is likely that carbohydrate
co-ingestion can further inhibit the post-exercise increase in muscle protein
299Exercise and Nutritional Interventions to Combat Age-Related Muscle Loss
breakdown (Borsheim et al. 2004), thereby improving net protein balance (Borsheim
et al. 2004; Roy et al. 1997).
There is a substantial amount of evidence showing that protein/amino acid
administration effectively stimulates muscle protein synthesis in a dose-dependent
manner. Hyperaminoacidemia, following intravenous amino acid infusion, increases
post-exercise muscle protein synthesis rates and prevents the exercise-induced
increase in protein degradation (Biolo et al. 1997). In a more practical, physiologi-
cal setting, oral administration of a large single bolus (Tipton et al. 1999a) or
repeated boluses (Koopman et al. 2005, 2006) of a protein and/or amino acid mix-
ture ingested following resistance type exercise also substantially increases muscle
protein synthesis rates. Moreover, ingestion of smaller amounts of EAA or intact
protein with and without carbohydrate have all been shown to augment post-exer-
cise protein synthesis rates and improve net protein balance (Borsheim et al. 2002;
Dreyer et al. 2008; Drummond et al. 2008a; Miller et al. 2003; Rasmussen et al.

2000; Tang et al. 2008; Wilkinson et al. 2007). In short, it has been well established
that post-exercise amino acid/protein ingestion represents an effective strategy to
augment the anabolic response to exercise and ample amino acid supply to the
muscle is crucial to allow hypertrophy following resistance exercise training.
It has been suggested that the timing of amino acid/protein intake is instru-
mental to further optimize the anabolic response to exercise (Beelen et al. 2008a;
Esmarck et al. 2001; Tipton et al. 2001). As a result, several research groups have
studied the efficacy of protein/amino acid ingestion prior to and/or during exer-
cise to further augment muscle protein synthesis. Recently, we reported that
protein ingestion prior to and during endurance (Koopman et al. 2004) and resis-
tance (Beelen et al. 2008a) type exercise stimulate whole-body (Beelen et al.
2008a; Koopman et al. 2004) and mixed muscle protein synthesis (Beelen et al.
2008a) during exercise. In line with these findings, we have reported that protein
intake prior to exercise augments activation of the PI-3 kinase/mTOR-pathway
during subsequent post-exercise recovery (Koopman et al. 2007b). In addition,
protein ingestion prior to and/or during exercise may further enhance muscle
protein anabolism by blunting the exercise induced increase in protein break-
down. Interestingly, a recent study by Fujita et al. showed no additional benefits
of the ingestion of small amounts of EAA prior to resistance type exercise on
post-exercise muscle protein synthesis rates, despite significantly elevated phos-
phorylation of S6K1 and 4E-BP1 (Fujita et al. 2008). In addition, a recent study
from our lab showed no effect of protein ingestion prior to, during, and after
exercise on muscle protein synthesis measured during subsequent overnight
recovery (Beelen et al. 2008b). The latter might be attributed to the fact that sub-
jects were studied in the fed state, performing exercise in the evening after receiv-
ing a standardized diet throughout the day. Clearly, more research is warranted to
assess the impact of timing of food intake on the skeletal muscle adaptive
response to exercise.
As discussed previously, the increase in extracellular leucine concentration has
been proposed to represent an important nutritional signal that drives the post-

prandial increase in muscle protein synthesis (Kimball and Jefferson 2004).
300 R. Koopman et al.
The dose-dependent relationship between myofibrillar protein synthesis and the
availability of leucine in the plasma (Cuthbertson et al. 2005) has provided a strong
foundation for the hypothesis that the ingestion of additional leucine during post-
exercise recovery could further accelerate post-exercise muscle protein synthesis
rates. Recently, Dreyer et al. reported that ingestion of a leucine-enriched EAA and
carbohydrate mixture following resistance type exercise enhances mTOR signaling
and muscle protein synthesis in vivo in humans (Dreyer et al. 2008). However,
previous observations in our lab showed no surplus value of additional leucine
supplementation in either young (Koopman et al. 2005) or old subjects (Koopman
et al. 2008) when a substantial amount of protein was being ingested during
post-exercise recovery.
5 Aging and the Anabolic Response to Exercise
Muscle protein synthesis is responsive to exercise in both the young and elderly. In
studies performed in young and elderly individuals, resistance and endurance type
exercise have been shown to stimulate mixed muscle protein synthesis (Drummond
et al. 2008b; Fujita et al. 2007; Kumar et al. 2009; Sheffield-Moore et al. 2004;
Welle et al. 1995; Yarasheski et al. 1993). Furthermore, SC content has been shown
to increase following a single bout of exercise and following more prolonged resis-
tance type exercise training in both the young and the elderly. However, the increase
in muscle SC content following eccentric contractions is greater in young compared
with elderly humans, suggesting that SC recruitment in response to exercise is
blunted in the elderly (Dreyer et al. 2006). SC proliferation and/or differentiation
are controlled by the sequential activation and/or suppression of MRFs (i.e. Myf5,
MyoD, Myogenin, and Mrf4). Interestingly, MRF mRNA expression appears to
increase following resistance type exercise in both young and older adults (Costa
et al. 2007; Kim et al. 2005b; Kosek et al. 2006; Raue et al. 2006; McKay et al.
2008; Psilander et al. 2003; Yang et al. 2005). In addition, the impaired Notch sig-
naling in the elderly has been reported to be modulated by strenuous exercise

(Carey et al. 2007). In contrast with the upregulation of MRFs, myostatin mRNA
expression is found to be down-regulated in response to exercise training in both
the young and elderly (Costa et al. 2007; Hulmi et al. 2008; Kim et al. 2005a; Raue
et al. 2006; Roth et al. 2003; Walker et al. 2004). Thus, although some studies have
reported subtle differences in changes in gene expression and anabolic signaling
(Hameed et al. 2003), early studies indicate that the protein synthetic response to
resistance type exercise does not differ considerably between the young and elderly
(Hasten et al. 2000; Yarasheski et al. 1993). In contrast, a more recent study shows
anabolic resistance of anabolic signaling (i.e. 4E-BP1 and S6K1) and muscle pro-
tein synthesis to resistance type exercise in elderly men when compared to young
controls, with measurements being performed in the post-absorptive state (Kumar
et al. 2009). This study is the first to demonstrate that the sigmoidal response of
muscle protein synthesis to resistance exercise of different (increasing) intensities
301Exercise and Nutritional Interventions to Combat Age-Related Muscle Loss
is shifted downward in older men compared with younger men (Kumar et al. 2009).
In addition, it has recently been suggested that mRNA expression of proteolytic
regulators, such as Atrogin-1, are elevated in senescent compared with young
muscle at rest and these levels increased even further in response to resistance type
exercise in the elderly. These findings from Raue et al. (2007) suggest that the regu-
lation of ubiquitin proteasome-related genes involved with muscle atrophy might
be altered in the elderly and protein breakdown may be increased in elderly humans
(Raue et al. 2007). However, there is a paucity of data regarding the measurement
of muscle protein breakdown in response to exercise in the elderly and it is clear
that more work is needed to assess the impact of exercise and specific exercise
modalities on post-exercise muscle protein synthesis and breakdown rates and asso-
ciated myocellular signaling in young and elderly humans.
We have previously shown that muscle protein synthesis rates are lower in
elderly (~75 years) compared with young controls under conditions in which resis-
tance type exercise is followed by food intake (Koopman et al. 2006). However,
combined ingestion of carbohydrate and protein during recovery from physical

activity resulted in similar increases in mixed muscle protein synthesis rates in
young and elderly men (Koopman et al. 2006). In line with these findings,
Drummond et al. recently reported similar post-exercise muscle protein synthesis
rates over a 5 h recovery period in young versus elderly subjects following inges-
tion of carbohydrate with an EAA mixture (Drummond et al. 2008b). However,
their data indicated that the anabolic response to exercise and food intake was
delayed in the elderly. During the first 3 h of post-exercise recovery the young
subjects showed a substantial increase in muscle protein synthesis rate, which was
not observed in the elderly. The latter may be attributed to a more pronounced
activation of AMPK and/or reduced ERK1/2 activation during exercise, which
seems to be in line with the recently reported attenuated rise in 4E-BP1 phospho-
rylation following resistance type exercise in the elderly (Kumar et al. 2009). The
mechanisms responsible for the delayed intramyocellular activation of the mTOR
pathway remain unclear, but might include differences in muscle recruitment,
muscle fiber type composition, capacity and/or sensitivity of the muscle protein
synthetic machinery, the presence of an inflammatory state, and/or the impact of
stress on the cellular energy status of the cell between the young and the elderly.
6 Exercise Training in the Elderly
The clinical relevance of nutritional and/or exercise intervention in the elderly natu-
rally resides in the long-term impact on skeletal muscle mass and strength, and the
implications for functional capacity and the risk of developing chronic metabolic
disease. In accordance with the previously discussed work it has been well estab-
lished that the ability of the muscle protein synthetic machinery to respond to
anabolic stimuli is preserved, albeit maybe to a lesser extent (Rennie 2009), until
very old age (Fiatarone et al. 1990; Frontera et al. 1988). Resistance type exercise
302 R. Koopman et al.
interventions have been shown effective in augmenting skeletal muscle mass,
increasing muscle strength, and/or improving functional capacity in the elderly
(Ades et al. 1996; Bamman et al. 2003; Fiatarone et al. 1990, 1994; Frontera et al.
1988, 1990, 2003; Lexell et al. 1995; Vincent et al. 2002; Brose et al. 2003; Ferri

et al. 2003; Godard et al. 2002; Iglay et al. 2007; Kosek et al. 2006; Martel et al.
2006; Verdijk et al. 2009a; Haub et al. 2002). In addition, endurance (Ades et al.
1996; Bamman et al. 2003; Fiatarone et al. 1990, 1994; Frontera et al. 1988, 1990,
2003; Lexell et al. 1995; Vincent et al. 2002) type exercise activities have been
shown to enhance skeletal muscle oxidative capacity, resulting in greater endurance
capacity (Short et al. 2003, 2004).
The muscle regenerative capacity seems to decline at a more advanced age (i.e.
decline in SC number and/or activation status). However, it is obvious that a
reduced SC pool size does not prevent the capacity to allow extensive muscle
hypertrophy even at an advanced age (Dedkov et al. 2003; Shefer et al. 2006;
Thornell et al. 2003). Moreover, resistance type exercise training has been shown
to increase muscle fiber size with a concurrent increase in SC content (Kadi et al.
2004b; Kadi and Thornell 2000; Petrella et al. 2006; Olsen et al. 2006). Some
(Mackey et al. 2007; Roth et al. 2001; Verdijk et al. 2009a; Verney et al. 2008)
but not all (Hikida et al. 1998; Petrella et al. 2006) studies report a substantial
increase in SC content following 9–16 weeks of resistance type exercise training
in older adults. Recently, we assessed the effects of 12 weeks resistance type
exercise training on fiber type specific hypertrophy and SC content in healthy,
elderly men (Verdijk et al. 2009a). Elderly men show a reduced type II muscle
fiber size and SC content when compared with the type I muscle fibers.
Interestingly, prolonged exercise training resulted in a 28% increase in type II
muscle fiber size and a concomitant 76% increase in type II muscle fiber SC
content in elderly males (Verdijk et al. 2009a). The apparent differences in fiber
size and/or SC content between type I and type II muscle fibers prior to interven-
tion were no longer evident after 12 weeks of training. Overall, these findings
suggest that SC are instrumental in the generation of new myonuclei to facilitate
muscle fiber hypertrophy.
Numerous studies have highlighted the need for protein/amino acid ingestion
before, during, and/or after exercise to stimulate muscle protein synthesis and
reduce muscle protein breakdown. Remarkably, little evidence exists that dietary

co-interventions can further augment the adaptive response to prolonged exercise
training in the elderly. Even the proposed importance of ample dietary protein
intake in the long-term adaptive response to resistance training in the elderly has
been a topic of intense debate (Campbell and Evans 1996; Morais et al. 2006;
Campbell and Leidy 2007). The current Recommended Dietary Allowance (RDA)
for habitual protein intake of 0.8 g/kg/day (Rand et al. 2003; Trumbo et al. 2002)
has been suggested to be marginal to allow lean mass accretion following resistance
exercise training in the elderly (Campbell et al. 2002). Moreover, it has been sug-
gested that the RDA is even insufficient for long term maintenance of skeletal
muscle mass in sedentary elderly (Campbell et al. 2001). However, more recent
work by the same research group indicates that dietary protein requirements do not
303Exercise and Nutritional Interventions to Combat Age-Related Muscle Loss
increase with age, and that a dietary protein allowance of 0.85 g/kg/day is adequate
(Campbell et al. 2008).
When habitual dietary protein intake is standardized at 0.9 g/kg/day, exercise
induced increases in muscle mass become apparent and a further increase in protein
intake does not seem to have any additional effect (Iglay et al. 2007). In addition,
data from a recent study by Walrand et al. (2008) indicated that although increased
protein intake in the elderly further improved nitrogen balance (by increasing
amino acid oxidation), no beneficial effects on muscle protein synthesis and muscle
function were observed in that study(Walrand et al. 2008). These observations
might explain why most studies fail to observe any additional benefit of nutritional
co-intervention on the skeletal muscle adaptive response to prolonged resistance
type exercise training in the elderly (Campbell et al. 1995; Fiatarone et al. 1990,
1994; Freyssenet et al. 1996; Frontera et al. 1988; Godard et al. 2002; Haub et al.
2002; Iglay et al. 2007; Meredith et al. 1992; Verdijk et al. 2009b; Welle and
Thornton 1998). However, the absence of any benefits of nutritional co-intervention
may be attributed to a less than optimal timing of amino acid and/or protein supple-
mentation. Esmarck et al. (2001) concluded that an early intake of a protein supple-
ment immediately after each bout of resistance type exercise, as opposed to 2 h

later, is required for skeletal muscle hypertrophy to occur following 12 weeks of
intervention in the elderly. However, the absence of any hypertrophy in the control
group receiving the same supplement 2 h after cessation of each exercise bout
seems to be in conflict with previous studies that show muscle hypertrophy follow-
ing resistance training without any dietary intervention (Esmarck et al. 2001).
Nevertheless, the proposed importance of nutrient timing is supported by more
recent studies investigating the impact of amino acid or protein co-ingestion prior
to, during, and/or after exercise on the acute muscle protein synthetic response
(Beelen et al. 2008a; Tipton et al. 2001). To study the proposed impact of timed
protein supplementation during prolonged exercise intervention, we recently com-
pared increases in skeletal muscle mass and strength following 3 months of resis-
tance type exercise training with or without protein ingestion prior to and
immediately after each exercise session in elderly males (Verdijk et al. 2009b).
However, timed protein supplementation prior to and after each exercise bout did
not further increase skeletal muscle hypertrophy in these healthy, elderly men who
habitually consumed ~1.0 g protein/kg/day.
Altogether, the available data suggest that sufficient habitual protein intake (~0.9 g/
kg/day) combined with a normal meal pattern (i.e. providing ample protein three
times per day) will allow substantial gains in muscle mass and strength following
resistance type exercise training in the elderly. Additional protein supplementation
does not seem to provide large surplus benefits to exercise intervention in healthy,
elderly males. Additional protein intake may reduce subsequent voluntary food
consumption in the elderly (Fiatarone Singh et al. 2000) and as a consequence some
have suggested that supplementation with EAA would be more efficient (Timmerman
and Volpi 2008). Clearly, acute studies have shown benefits of timed supplemen-
tation with small (~7–15 g) amounts of EAA on muscle protein synthesis
(Katsanos et al. 2005; Paddon-Jones et al. 2004, 2006). However, well designed,
304 R. Koopman et al.
double-blind, placebo-controlled long-term studies to investigate beneficial and
adverse effects of long-term EAA supplementation in the elderly have yet to be

performed (Henderson et al. 2009).
7 Future Research
Over the last ~30 years our understanding about the regulation of muscle protein
synthesis and degradation and their response to exercise and nutrition has increased
tremendously. However, despite significant technical evolution during this time, the
sensitivity of the measurement and large inter-subject variance in (basal) muscle
protein synthesis rates limit the ability to detect small, but potentially physiologically
relevant differences between groups. It should be noted that even minor differences
in, for example basal muscle protein synthesis and/or breakdown rate (<10%) would
be clinically relevant when calculating their impact over one or more decades before
sarcopenia becomes evident. Therefore, more sensitive methods should be developed
to assess both muscle protein synthesis and breakdown rates in vivo in humans.
In particular, more work is needed to develop valid tracer-models to assess muscle
protein breakdown rates in various settings to complement currently used measure-
ments of proteasome and calpain activity.
Even though it has been demonstrated that satellite cell (SC) content is reduced
in the elderly, little is known about changes in activation status that occur when we
get older. Moreover, the molecular mechanisms controlling SC activation, prolif-
eration, differentiation and self-renewal in vivo in humans remain to be established.
The identification of molecular key signatures of quiescent and activated SC may
help to determine the precise signaling pathways leading to SC activation.
Discovery of these key-regulatory proteins can potentially result in the identifica-
tion of new targets for nutritional and pharmacological strategies to improve skeletal
muscle development in pathological conditions.
Most of the data provided in this chapter agree with the concept that the post-
prandial muscle protein synthetic response is set-off by a specific nutritional signal,
most likely the post-prandial rise in plasma availability of one or more specific EAA
and/or the concomitant insulin response allowing the AA to reach the extracellular
matrix of the target tissue, and that the sensitivity and/or capacity of this signaling
process is impaired with aging. Much effort is presently being directed toward the

discovery of such an extracellular amino acid sensing mechanism in skeletal muscle
tissue. The latter will further increase our understanding of the proposed impact of
the anabolic resistance to food intake in the etiology of sarcopenia.
Nutrient availability throughout day and night likely plays an important role in
the differential response to acute versus long-term exercise intervention. We specu-
late that potential benefits of (timed) protein and/or amino acid supplementation in
the elderly might be restricted to specific elderly subpopulations, e.g. malnourished
or frail elderly, and various patient populations. So far, it is evident that the
combination of resistance type exercise training with or without post-exercise
305Exercise and Nutritional Interventions to Combat Age-Related Muscle Loss
protein administration represents a feasible and effective strategy to improve
muscle mass, strength, and functional performance in the elderly. More research is
necessary to study the interaction between exercise and nutrition in the elderly, and
the implications for the acute and long-term adaptive response to intervention.
8 Conclusions
The loss of skeletal muscle mass with aging is associated with reduced muscle
strength, the loss of functional capacity, and an increased risk of developing
chronic metabolic disease. The progressive loss of skeletal muscle mass does not
seem to be attributed to age-related changes in basal muscle protein synthesis and/
or breakdown rates. Recent work suggests that the muscle protein synthetic
response to the main anabolic stimuli, i.e. food intake and/or physical activity, is
blunted in the elderly. Despite this proposed anabolic resistance to food intake
and/or physical activity, resistance type exercise substantially stimulates net
muscle protein accretion when protein is ingested prior to, during, and/or follow-
ing exercise in both the young and the elderly. In accordance, prolonged resistance
type exercise training has proven an effective interventional strategy to prevent
and/or treat the loss of muscle mass and strength in the elderly. Research is war-
ranted to provide more insight in the interaction between nutrition, exercise and
the skeletal muscle adaptive response. The latter is needed to define more effective
nutritional, exercise, and/or pharmaceutical interventional strategies to prevent

and/or treat sarcopenia.
Acknowledgements Dr. Koopman was supported by a Rubicon Fellowship from the Netherlands
Organisation for Scientific Research (NWO). Dr. Koopman is a C.R. Roper Senior Research
Fellow of the Faculty of Medicine, Dentistry and Health Sciences at the University of Melbourne
(Victoria, Australia).
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