Sarcopenia Age-Related Muscle Wasting and Weakness: Mechanisms and Treatments P37 pptx

346 D.A. Rivas and R.A. Fielding
aerobic exercise bout in aging humans. This was related to increased endothelial
function and an increase in the insulin-stimulated phosphorylation of mTOR, S6K1
and Akt (Fujita et al. 2007).
4.2 Resistance Exercise
In contrast to aerobic exercise, resistance exercise is based on movements performed
with high resistance and a small number of repetitions over a short period of
time. The purpose of resistance exercise is to provide an overload stimulus that
strengthens muscles. This is usually a training stimulus in the range of 60–70% of
a single repetition maximum (1RM), which can lift 8–12 times to failure and is
performed repeatedly with progressive intensity that induces hypertrophy (Phillips
2007). How resistance exercise is performed is no different between young and
older individuals. Furthermore, studies comparing aerobic exercise-trained (AE)
and resistance exercise-trained (RE) older athletes to sedentary age-matched
controls have reported many physiological advantages associated with the preven-
tion of age-induced diseases (Klitgaard et al. 1990). In a seminal cross-sectional
study of elderly men with different training backgrounds; Klitgaard et al. (1990)
reported older men (69 years), who had been strength-training approximately
12–17 years before being studied, maximal isometric torque and muscle mass, as
measured by computed tomography (CT) scan of the upper arm and mid-thigh,
were significantly greater than those in age-matched swimmers or runners and were
similar to young sedentary controls (Klitgaard et al. 1990). The subjects examined
in this study exercised an average of three times per week at approximately 70–90%
of their 1RM (Klitgaard et al. 1990). Klitgaard and colleagues provide some
evidence that resistance exercise is possibly a superior intervention to aerobic train-
ing for the treatment of sarcopenia.
The effects of resistance exercise in young healthy men and women have been
well described (for early review see Kraemer and Ratamess 2004). Briefly, high
intensity progressive resistance training in young adults has resulted in significant
increases in dynamic strength, explosive power, and muscle mass (McCall et al.
1996; Staron et al. 1991, 1994; Anderson and Kearney 1982). The effect of resis-

tance exercise on the older humans is not a potent when compared to the young.
More recent studies have confirmed these findings (Kraemer et al. 2004; Glowacki
et al. 2004; Campos et al. 2002; McCaulley et al. 2009; Luden et al. 2008). Aged
skeletal muscle does not respond as effectively to resistance exercise, particularly
at the genetic and protein-signaling level, as young skeletal muscle (Kosek et al.
2006; Petrella et al. 2005, 2006; Mayhew et al. 2009; Bamman et al. 2004; Slivka
et al. 2008; Raue et al. 2009). Although there is some attenuation of the effect of
resistance exercise in the old, it is established that resistance exercise is a practical
and effective intervention to increase muscle strength, power and mass in the
elderly even into the ninth decade of life (McCartney et al. 1995, 1996; Kostek
et al. 2005; Valkeinen et al. 2005; Fiatarone et al. 1990; Ferri et al. 2003;
347Exercise as a Countermeasure for Sarcopenia
Adams et al. 2001). These measures are important to the elderly population
because they may reduce the relative stress imposed by activities of daily living.
4.2.1 Improving Strength
A decline in dynamic, isokinetic and static muscle strength has been noted with
advancing age. Muscle strength is defined as the maximum force generation capac-
ity of an individual, it reaches its peak at about the third decade of life and decreases
about 12–15% per decade after the age of 50 years (Larsson et al. 1979). Direct
comparisons of young and older sedentary individuals have shown that older per-
sons of around 70 years have approximately 60% of the force-generating ability of
their younger peers of 20–30 years (Klitgaard et al. 1990). This loss of strength
with aging is observed in both men and women (Lindle et al. 1997). Several studies
of the elderly have suggested that muscle strength is closely associated with
functional activities of daily living (Bassey et al. 1988; Jette and Branch 1981;
Rantanen et al. 1994). The declines in muscle strength with age are related to
impairment in function even in otherwise healthy older individuals.
Investigators have documented gains in strength as a direct result of resistance
training regimens throughout the lifespan (Korpelainen et al. 2006). In the young,
a 2-week isokinetic resistance training program in men effectively increased

isokinetic and isometric right quadricep muscle peak torque at both 60° and 240°
(Akima et al. 1999). In another report in men, a 12-week high resistance strength
training program resulted in an increase in isokinetic concentric (quadriceps) knee
joint strength at a velocity of 30° and eccentric (hamstring) knee joint strength at
velocities of 30°, 120° and 240° (Aagaard et al. 1996). The hamstring/quadriceps
ratio also increased. A dynamic resistance training protocol of similar duration in
men and women resulted in isometric torso rotation strength gains in men and
women who exercised twice weekly (DeMichele et al. 1997). Significant gains in
both upper- and lower-body strength have also been reported for studies of 6
months duration (Kirk et al. 2007).
Strength gains have been reported for shorter (8–12 weeks) duration studies in
older adults. Studies that have utilized similar resistance training protocols (10–12
weeks, 3 days/week, 80% of 1RM), have shown a the mean improvement in muscle
strength of ~80%, post-exercise training (Balagopal et al. 2001; Brown et al. 1990;
Fiatarone et al. 1994; Frontera et al. 1988; Trappe et al. 2000, 2001; Campbell et al.
1994, Harridge et al. 1999). These studies provide evidence there is a substantial
increase in muscle strength in older individuals who resistance exercise. Larsson
et al. (1979) first reported that a selective loss of Type 2 (fast twitch) muscle fibers
is associated with a decline in strength. Frontera et al. (1988) examined the effects
of a high-intensity dynamic-resistance training program in healthy older men
(mean age 64 years; (Frontera et al. 1988)). Their subjects performed knee flexion
and extension exercises 3 days/week at 80% of the 1RM (eight to ten repetitions)
for 12 weeks. They found a 107% increase in knee extensor strength and a 226%
increase in knee flexor strength. In addition, they observed an 11% increase in
348 D.A. Rivas and R.A. Fielding
mid-thigh cross-sectional area as assessed by CT. Muscle biopsy analysis revealed
a 33% and 27% increase in Type 1 and 2 fiber area respectively. This was the first
study to demonstrate that in healthy older men dynamic high-intensity strength-
training can result in marked increases in muscle strength and muscle hypertrophy
(Frontera et al. 1988).

Researchers using a progressive resistance training protocol in older adults
observed a linear increase in dynamic strength at different time points of a 12-week
study (Sousa and Sampaio 2005). In an 8-week comparison between a combined
resistance/gymnasium based functional training regimen and high- and a moderate-
velocity resistance training protocols, significant dynamic strength gains were
reported for the combined resistance/gymnasium indicating a synergistic effect of
exercise (Henwood and Taaffe 2006). However, others report a dose–response rela-
tionship between high-intensity progressive resistance training and functional
capacity that may explain the preponderant use of this type of resistance training
(Galvao and Taaffe 2005; Seynnes et al. 2004). Gains in strength also occur with
low- (Tsutsumi et al. 1997) and variable-intensity resistance training (6 months)
(Hunter et al. 2001).
4.2.2 Increasing Power
Although physical activity interventions that increase or maintain of muscle
strength have important health implications, there is emerging evidence that muscle
power generating capacity (the rate at which muscle force can be generated) may
play a more important role in functional independence and fall prevention, particu-
larly among older adults. Peak muscle power has only recently been examined in
older individuals as a variable distinct from strength and has been shown to decline
earlier and more precipitously throughout the life span (Metter et al. 1997). Lower
extremity muscle power is a strong predictor of physical performance, functional
mobility and risk of falling among older adults (Bean et al. 2002, 2003). Muscle
power is also inversely associated with self-reported disability status in community-
dwelling older adults with mobility limitations (Foldvari et al. 2000; Suzuki et al.
2001) and is a better discriminator of mobility limitations than muscle strength
(Bean et al. 2003). In particular, in two separate studies of older individuals with
self-reported functional limitations, peak lower extremity power has been shown
to be more closely associated with gait speed than strength (Bean et al. 2002;
Cuoco et al. 2004).
Exercise interventions targeted at improving lower extremity muscle power in

the elderly have been well-tolerated and effective (Henwood and Taaffe 2005;
Earles et al. 2001; Miszko et al. 2003). Indeed, we have previously reported that
an exercise regimen of high-force, high-velocity progressive resistance training
resulted in a twofold increase in muscle power in older women with self-reported
functional limitations, compared to traditional high-force, slow-velocity progressive
resistance training (Fielding et al. 2002). Despite the observed improvements in
musculoskeletal strength, few studies have examined the specific velocity of
349Exercise as a Countermeasure for Sarcopenia
training and its subsequent physiological and functional effects. Fiatarone et al.
(1994) have noted in their nursing home study only a 28% increase in stair
climbing power in response to progressive resistance training despite over a 100%
increase in strength, suggesting a disproportionate and specific rise in strength
versus power with traditional resistance training (Fiatarone et al. 1994).
Skelton et al. (1995) also examined changes in peak leg extensor power in
response to 12 weeks of resistance training in older women (Skelton et al. 1995).
They observed increases in strength of 22–27% with a non-significant increase in
leg extensor power. Recently, Jozsi et al. (1999) noted a modest improvement
(30%) in leg extensor power in response to 12 weeks of RE in healthy older men
and women (Jozsi et al. 1999). These studies suggest that RE results in minimal
improvements in peak power and that training interventions need to be designed to
more closely maximize the capacity to improve peak power in older individuals.
We have shown that a 16 week high velocity high force resistance training to maximize
muscle power intervention is feasible, well tolerated, and can dramatically improve
lower extremity muscle power in older women with self-reported disability (Fielding
et al. 2002). These results have recently been confirmed in two recent randomized
trials (Earles et al. 2001; Signorile et al. 2002). Recently, we have reported (Reid
et al. 2008) that a short-term intervention of high-velocity high-power progressive
resistance training was associated with similar improvements of lower extremity
muscle power compared to traditional slow-velocity strength training in elderly
adults with preexisting mobility impairments. Although both training modalities

yielded similar increases of lower extremity strength in this population, high-
velocity power training was associated with significant gains in specific muscle
power. Future studies should directly quantify neural adaptations and physiological
mechanisms to power training, and further randomized controlled trials are war-
ranted to investigate the optimal training duration and volume required to elicit
significant improvements of muscle power, strength and functional performance in
elderly subjects who are at increased risk for subsequent disability.
4.2.3 Increasing Muscle Mass
The increase in size in response to resistance training is typically given as a change
in the CSA of the muscle, as measured with magnetic resonance imaging, ultra-
sonography, or CT. Changes in muscle strength and size after resistance training are
likely accompanied by alterations in the size of the muscle fibers that are deter-
mined by immunohistochemistry. Studies that have directly compared changes in
muscle mass, CSA or protein synthesis in response to resistance exercise training
have noted significant increases in both males and females (Burd et al. 2009; Staron
et al. 1994; Pansarasa et al. 2009; Holm et al. 2008; Hubal et al. 2005). Increases
in muscle CSA by CT scanning have also been shown to be similar between men
(17.5%) and women (20.4%) in response to 16 week of upper and lower extremity
high intensity resistance training (Cureton et al. 1988). However, one study
employing elastic bands for resistance training noted significant increases muscle
350 D.A. Rivas and R.A. Fielding
fiber cross sectional areas in men but not in women in response to 8 week of training
two to three sessions per week (Hostler et al. 2001). More recently, assessment of
fat free mass by dual energy x-ray absorptiometry and serial CT scans to measure
muscle volume have confirmed similar increases in muscle mass and volume
between young men and women in response to a 6 month whole body program of
progressive resistance exercise training (Roth et al. 2001a). These results suggest
that resistance exercise training can increase muscle strength and mass to similar
extent in both men and women.
Several studies have assessed the optimal dose of resistance training required to

maximize gains in muscle strength and mass in young adults. Campos et al. (2002)
compared the responses to 8 weeks of progressive resistance training (Campos
et al. 2002). Young healthy men were randomized to perform low repetition high
intensity, intermediate repetition moderate intensity, or high repetition low intensity
progressive resistance training of the lower extremities (leg press, squat, and knee
extension). These authors found that there was greater muscle fiber hypertrophy
and gains in muscle strength observed low repetition high intensity group and the
intermediate repetition moderate intensity group compared to the high repetition
low intensity group. In young women, Hisaeda et al. (1996) observed similar gains
in peak torque and muscle cross sectional in response to 8 weeks of either high
intensity/low repetition or high repetition/low intensity resistance training (Hisaeda
et al. 1996). Studies have also examined the influence of the number of sets per-
formed at each training session on changes in muscle strength and mass in response
to resistance training. Ronnestad et al. (2007) demonstrated that three sets of lower
body resistance exercise per session compared to one set per session was more
effective in increasing muscle strength and CSA suggesting that the volume of
training per session may drive the gains in muscle strength and mass (Ronnestad
et al. 2007). In contrast, by varying the number of training days per week and the
number of training sets performed while normalizing the total volume of work
performed per week resulted in similar gains in muscle strength and CSA in young
men and women (Candow and Burke 2007). The evidence from these randomized
trials suggests that muscle hypertrophy from resistance training occurs in a dose-
dependent manner that is primarily dependent on the intensity at which the training
sessions are performed. In addition, the total volume of work performed during
resistance training may also influence to magnitude of increase in muscle mass.
Early studies have demonstrated the positive effects of resistance training on
muscle strength and size in healthy older men and women (For background review
see: Fielding 1995). A number of randomized trials have now confirmed these
initial findings (Sipila and Suominen 1996; Ferri et al. 2003; Suetta et al. 2004;
Tsuzuku et al. 2007), and one study has demonstrated that muscle mass can con-

tinue to increase in older adults throughout 2 years of resistance training (McCartney
et al. 1996). More recently, studies have examined the influence of resistance
training on changes in muscle mass and the influence of age per se. Resistance
exercise training interventions (RT) can increase both whole muscle and fiber CSA
in older men and women. However, there is some evidence that this response may
be attenuated with advancing age. Cross sectional studies of older bodybuilders
351Exercise as a Countermeasure for Sarcopenia
who had been performing RE for 12–17 years were reported to have mid-thigh
muscle CSA that were similar to young sedentary controls, suggesting that the
ability to stimulate muscle growth is diminished with age (Klitgaard et al. 1990). In
young men and women, the change in mid-thigh CSA after 4 months of high inten-
sity resistance training is typically 16–23% (Cureton et al. 1988), compared to a
2.5–9.0% increase in institutionalized or frail older individuals in response to simi-
lar resistance interventions (Fiatarone et al. 1990, 1994; Binder et al. 2005).
Few studies have directly compared the effect of age on muscle hypertrophy
utilizing a similar standardized training intervention. Welle et al. (1996) reported
impaired responses of both knee and elbow flexors but not knee extensors after a
whole body RE program in older compared to young men and women (Welle et al.
1996). Data from Hakkinen et al. (1998) suggest a decline in the adaptive response
of the vastus lateralis from middle to old age of approximately 40% (Hakkinen
et al. 1998). Lemmer et al. (2001) reported significant increase in thigh muscle
CSA in both young and older adults following resistance training, however the
magnitude of the increase was greater in the young (Lemmer et al. 2001). Similar
results were also observed by Dionne et al. (2004) following 6 months of resistance
training in young and older non-obese women (Dionne et al. 2004). In contrast,
similar duration resistance training studies have examined changes in total thigh
CSA and have reported similar responses in young and old (Ivey et al. 2000; Roth
et al. 2001a). These findings suggest that progressive resistance training-induced
increases in muscle mass can occur in older individuals but that the magnitude of
this response may be attenuated, particularly in the oldest old.

Conflicting evidence has been presented on the effects of gender on the anabolic
response to resistance training among older adults. Several studies that have
enrolled both older men and women have reported similar increases in muscle mass
with resistance training (Hakkinen et al. 1998; McCartney et al. 1996; Roth et al.
2001a; Wieser and Haber 2007). Nine weeks of high intensity resistance training
resulted in lower muscle volume increases in women compared to men (Ivey et al.
2000) and similar findings were reported for whole body fat free mass in response
to 12 week of high intensity resistance training in moderately overweight men and
women (Joseph et al. 1999). Bamman et al. (2003) have also confirmed at the
cellular level a greater degree of hypertrophy of both type I and II fibers in older
men compared to older women in response to 26 weeks of high intensity resistance
training (Bamman et al. 2003). However, in contrast to these reports Hakkinen et al.
(1998) reported a smaller increase in muscle cross sectional area in older men com-
pared to older women (Hakkinen et al. 1998).
4.3 Multi-modal Exercise Therapy
While the preferential mode for strength gains has been strength training (Keeler
et al. 2001; Putman et al. 2004; Sarsan et al. 2006), with a bias towards eccentric
exercises (Hilliard-Robertson et al. 2003), observations indicate that other modes
352 D.A. Rivas and R.A. Fielding
or multi-modal training may also be highly effective in the aging population.
Current guidelines stress the importance of multi-modal exercise for this cohort,
including strengthening exercises, cardiovascular, flexibility, balance training
and the combination of strength and endurance training (Cress et al. 2005; Baker
et al. 2007; Chodzko-Zajko et al. 2009). These include but aren’t limited to:
Nordic training (Mjolsnes et al. 2004), circuit weight training (Harber et al.
2004), balance training (Heitkamp et al. 2001), a combination of strength and
endurance as well as endurance only protocols (Binder et al. 2002; Putman
et al. 2004; LaStayo et al. 2000; Englund et al. 2005; Izquierdo et al. 2004).
Putman et al. (2004) reported that concurrent strength and endurance exercise
training resulted in greater fast-to-slow fiber type transitions and attenuated

hypertrophy of the type I fibers compared with strength training alone (Putman
et al. 2004). Futhermore, multimodal exercise training was associated with a
decreased lipid profile in older women compared to strength training alone
(Marques et al. 2009).
In middle-aged men and women subjected to short duration physical activity
interventions, strength gains were also improved with combinatory aerobics/
weight (Tsourlou et al. 2003) training protocols. The gains in strength persist
throughout longer duration studies (4–6 months) in this age group (Dornemann
et al. 1997; Izquierdo et al. 2005) but demonstrate that greater gains in strength
begin to occur after 8 weeks of a combined resistance and endurance exercise
protocol (Izquierdo et al. 2005). In older adults, investigators have implemented
longer duration (4–12 months) resistance training (Galvao and Taaffe 2005;
Lord et al. 1996a, b) and combinatory resistance/endurance (King et al. 2000;
Izquierdo et al. 2004; Tsourlou et al. 2006; Fahlman et al. 2007; Cress et al.
1999) type regimens to successfully increase strength in an effort to counteract
the late-life decline in physical functioning. While resistance training induces
muscle strength gains, functional-task exercises may be more effective at coun-
teracting declines in function (de Vreede et al. 2005). Investigators have sug-
gested that gains in isometric and dynamic muscle strength (Tsourlou et al.
2006) as well as in isokinetic muscle strength (Galvao and Taaffe 2005) are
associated with improved physical functioning. However, the gains in strength
may be muscle specific and translate into improvements in only select param-
eters of physical functioning as indicated in both long (Schlicht et al. 2001;
Asikainen et al. 2006; Fahlman et al. 2007) and short duration exercise inter-
ventions (Topp et al. 1996). Although there have been some benefits associated
with multimodal exercise regiments in young and older populations. Baker
et al. (2007) recently reported, in a systematic review, that limited available
data suggests that multi-modal exercise has a small effect on physical, func-
tional and quality of life outcomes (Baker et al. 2007). However, more investi-
gation is needed on the efficacy of simultaneous prescription of multi-modal

training as a treatment for improving clinically relevant outcomes, and to
establish whether multi-modal exercise at adequate volumes and intensities is
feasible in older populations.
353Exercise as a Countermeasure for Sarcopenia
4.4 Anabolic Signaling/Protein Synthesis
Exercise of sufficient intensity and duration disrupts homeostasis initiating adaptive
processes to generate new functional protein in skeletal muscle (Coffey and Hawley
2007). An essential process in the regulatory steps controlling protein synthesis
is mRNA translation (Coffey and Hawley 2007). In this regard, mTOR has been
implicated as an upstream mediator of protein synthesis via putative control of
ribosomal biogenesis and Cap-dependent translation (Nader et al. 2005; Hannan
et al. 2003; Besse and Ephrussi 2008). Moreover, the translation repressor
eukaryotic translation initiation factor-4E binding protein 1 (4E-BP1) is a direct
phosphorylation target of mTORC1 which de-represses 4E-BP1 inhibition of
translation initiation (Besse and Ephrussi 2008). Intuitively, both endurance and
resistance exercise would be expected to “switch on” translation following exer-
cise and generate skeletal muscle adaptation, yet clearly identifying increased
mTOR activation and subsequent 4E-BP1 phosphorylation during recovery from
exercise has proved elusive. Indeed, there is limited evidence with regard to these
exercise-induced phosphorylation events being associated with increased protein
fractional synthetic rate (Fujita et al. 2007) likely due to the energy-consuming,
catabolic state of skeletal muscle during and immediately following exercise in
the fasted state. Nonetheless, as a nutrient sensor it is not surprising that amino-
acid ingestion has been shown to augment exercise-induced mTOR activation and
4E-BP1 phosphorylation, and subsequent fractional synthetic rate in skeletal
muscle (Koopman et al. 2007; Dreyer et al. 2008; Drummond et al. 2008; Rivas
et al. 2009).
It is apparent that chronic endurance and resistance training generate
specificity of adaptation and subsequent divergent phenotypes (Coffey and
Hawley 2007). As such, the concomitant increase in mTOR-4E-BP1 mediated

translation initiation with exercise likely contributes to the specificity of training
adaptation. In support of this contention, novel findings by Wilkinson and co-
workers (2008) showed increased translational signalling and fractional syn-
thetic rate following both endurance and resistance training (Wilkinson et al.
2008). Notably, these workers observed specificity of adaptation with chronic
endurance exercise only elevating the mitochondrial protein synthetic response,
while resistance training increased myofibrillar but not mitochondrial fractional
synthetic rate (Wilkinson et al. 2008). Therefore, exercise-induced mTOR
translation initiation following endurance and resistance exercise may enhance
skeletal muscle metabolism via alternate adaptation that promotes muscle qual-
ity (mitochondria) and quantity (cross-sectional area), respectively. Regardless,
the apparent capacity of mTOR to promote global protein synthesis through
translational processes in response to exercise is undoubtedly beneficial for the
metabolic status of skeletal muscle.
Several reports have identified skeletal muscle cell signaling and protein syn-
thesis inconsistencies between young and older subjects after an acute bout of
resistance and aerobic exercise (Kim et al. 2005a, b; Raue et al. 2006; Fujita
354 D.A. Rivas and R.A. Fielding
et al. 2007; Harber et al. 2009). For example, we have previously shown a
decreased phosphorylation of mTOR and S6K1 in response to muscle contrac-
tion by in situ HFES in aged animals (Parkington et al. 2004; Funai et al. 2006).
Rasmussen and colleagues have confirmed our findings in humans and have
further reported that muscle protein synthesis was unchanged in older humans,
after a single bout of resistance exercise (Dreyer et al. 2006b) and the ingestion
of AA (Drummond et al. 2008), compared to young humans. Kumar et al. (2009)
revealed that an acute bout of resistance exercise at different intensities stimulate
myofibrillar protein synthesis and anabolic signalling in a dose-dependent man-
ner in both young and old men during a fasting state (Kumar et al. 2009). The
stimulatory effect of exercise peaked at 1–2 h post-exercise and was suppressed,
but not delayed, in older men. Although the extent of S6K1 phosphorylation

predicted the stimulation of myofibrillar protein synthesis in young men, older
men did not appear to match the changes in anabolic signalling and myofibrillar
protein synthesis, possibly explaining the deficiency in the muscle protein ana-
bolic response.
Prolonged resistance or aerobic type exercise training represent an effective
therapeutic strategy to augment skeletal muscle mass and improve functional
performance in the elderly. Improvements associated with chronic exercise train-
ing are said to be a result of adaptation of skeletal muscle to the additive effect
of an acute exercise bout over a period of time. Exercise training, in addition to
the signaling events that occur with an acute bout of exercise, also leads to the
increased expression of key proteins involved in the adaptation of the muscle.
The compensatory overload model of synergist ablation is an attractive model
because it quickly provides a large and fast hypertrophic response. This is a
commonly used model to study the effects of resistance exercise training on
skeletal muscle adaptations which overloads the plantaris muscle through the
removal of the synergist muscles. This mechanical overload of the plantaris
muscle results in significant inductions of muscle growth of ~30% after 7 days
and ~100% after 35 days in young animals (Spangenburg and Booth 2006;
Spangenburg et al. 2008). In an original study that demonstrated a role for
mTOR phosphorylation in muscle hypertrophy; Reynolds et al. (2002) reported
a ~100% increase in the phosphorylation of mTOR on Ser2448 after 14 days of
muscle overload in young animals (Reynolds et al. 2002). Recently, it has been
shown that anabolic signaling and muscle hypertrophy are impaired in aged
skeletal muscle in response to functional overload (Thomson and Gordon 2006;
Hwee and Bodine 2009; Blough and Linderman 2000; Degens and Alway 2003).
Thomson and Gordon (2006) observed decreased translational signaling and
muscle hypertrophy in aged skeletal muscle in response to 7 days of muscle
overload (Thomson and Gordon 2006). Interestingly, the authors correlated the
inhibition of translational signaling to the activation of AMPK in the aged
muscle. We have recently reported, after 28 days of chronic overload, although

there was an attenuation of hypertrophy in aged animals (30 months) this was
not reflected in the phosphorylation of mTOR signaling components compared
to adult animals (6 months) (Chale-Rush et al. in press).
355Exercise as a Countermeasure for Sarcopenia
5 Conclusion
Specific modes and intensities of physical activity can both act to preserve and also
increase skeletal muscle mass, strength, power, protein synthesis and anabolic sig-
nalling. This effect appears to be pervasive throughout the lifespan and there is
evidence for similar responses in men and women. In general, studies supported the
concept that moderate to high intensity progressive resistance (strength) training
exercise was most effective in improving muscle mass, strength, and power. There
is extensive evidence that specific modes of physical activity can effectively
increase fat free/lean body mass, strength, and power. In particular, there is exten-
sive experimental evidence that performance of regular (two to four times per
week) high intensity (60–80% of the one repetition maximum) progressive resis-
tance (strength) training exercise can result in significant increases in muscle size,
strength, and protein synthesis. Progressive resistance (strength) training has con-
sistently been shown to results in improvements in skeletal muscle mass and muscle
quality. However, resistance training-induced increases in muscle mass can occur
in older individuals but the magnitude of this response may be attenuated, particu-
larly in the oldest of the old. The directionality has been established and the
observed physiological responses are improvements in muscle size, strength and
power. Endurance/aerobic and other more non-traditional forms of physical activity
have not been shown to consistently increase muscle mass or quality but may be
associated with the prevention of loss.
Acknowledgements This chapter is based upon work supported by the U.S. Department of
Agriculture, under agreement No. 58-1950-7-707. Any opinions, findings, conclusion, or recom-
mendations expressed in this publication are those of the author(s) and do not necessarily reflect
the view of the U.S. Department of Agriculture.
The authors would like to thank Dr. Sarah J. Lessard of the Joslin Diabetes Center / Harvard

Medical School for the careful review and insightful comments of the manuscript.
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