Sarcopenia Age-Related Muscle Wasting and Weakness: Mechanisms and Treatments P36 potx

336 D.A. Rivas and R.A. Fielding
2007, the American College of Sports Medicine (ACSM)/American Heart
Association (AHA) released a joint recommendation on physical activity and pub-
lic health recommendations for older adults, the Department of Health and Human
Services (DHHS)/Center for Disease Control (CDC) released the “2008 Physical
Activity Guidelines for Americans” and in 2009 the ACSM updated and expanded
their position stand on “Exercise and Physical Activity for Older Adults”. These
recommendations and guidelines affirm that regular physical activity reduces the
risk of many adverse health outcomes and there are additional benefits as the
amount of physical activity increases with higher intensity, greater frequency and/
or longer duration (see Table 1).
3 Mechanisms of Muscle Atrophy Associated with Sarcopenia
3.1 Protein Synthesis and Degradation
The maintenance of muscle mass is regulated by a balance between protein synthe-
sis and protein degradation and is associated with rates of anabolic and catabolic
processes, respectively. In conditions of atrophy, there is evidence for a shift toward
myofibrillar and non-myofibrillar protein degradation (Mitch and Goldberg 1996)
and a corresponding reduction in protein synthesis (Munoz et al. 1993). When
protein synthesis exceeds protein degradation there is increased muscle mass
(hypertrophy). In contrast, if protein degradation exceeds protein synthesis there is
muscle loss (atrophy). During muscle atrophy as a result of disease processes, dis-
use or aging there is a preferential degradation of intermittently used white muscle
(Type 2) fibers rather than continually used red muscle (Type 1) fibers (Tomlinson
et al. 1969; Larsson 1983; Aniansson et al. 1986). Lexell et al. (1988), when study-
ing 15–83 year old previously healthy men, reported that after the age of 25 years
there is both a loss in the number and size of muscle fibers (Lexell et al. 1988).
These researchers concluded that the fiber size reduction can be explained mostly
by the smaller Type 2 fibers. However, it has been recently reported that there is a
disproportionate loss of muscle function relative to muscle loss (Goodpaster et al.
2006; Haus et al. 2007). Therefore, the loss of muscle mass during aging could be
the result in a decline of protein synthesis, increase in protein degradation or a

combination of both. There is some contention regarding whether the decrease in
protein synthesis associated with aging occurs solely during anabolic stimulation
(Volpi et al. 2001; Cuthbertson et al. 2005; Rennie 2009) or also in the basal state
(Nair 1995; Welle et al. 1993; Rooyackers et al. 1996; Yarasheski et al. 1993). It
was originally reported that old subjects had decreased rates of basal muscle protein
synthesis (Rooyackers et al. 1996; Yarasheski et al. 1993; Welle et al. 1993).
However, others have been unable to reproduce these results and have observed a
decrease only during anabolic stimulation (Rennie 2009; Volpi et al. 2001;
Cuthbertson et al. 2005).
337Exercise as a Countermeasure for Sarcopenia
The concept of aging is also strongly associated with increased protein degradation
leading to muscle atrophy. The effects of aging on protein degradation are difficult
to quantify. This is because in adult humans and animals only 60–70% of skeletal
muscle proteins are made up of myofibrillar protein and these turn over very slowly
making their quantification very difficult [see review: (Attaix et al. 2005)].
Table 1 Summary of physical activity recommendations for older adults from the American
College of Sports Medicine/American Heart Association and the U.S. Centers for Disease Control
and Prevention/ Department of Health and Human Services (Adapted from Nelson et al. 2007;
Chodzko-Zajko et al. 2009; DHHS 2008)
ACSM/AHA Physical activity recommendations for older adults:
Aerobic exercise:
Frequency: For moderate-intensity activities, accumulate at least 30 or up to 60 (for greater
benefit) min/day in bouts of at least 10 min each to total 150–300 min/week, at least 20–30
min/day or more of vigorous-intensity activities to total 75–150 min/week, an equivalent
combination of moderate and vigorous activity.
Intensity: On a scale of 0–10 for level of physical exertion, 5–6 for moderate-intensity and 7–8
for vigorous intensity.
Duration: For moderate-intensity activities, accumulate at least 30 min/day in bouts of at least
10 min each or at least 20 min/day of continuous activity for vigorous-intensity activities.
Type: Any modality that does not impose excessive orthopedic stress; walking is the

most common type of activity. Aquatic exercise and stationary cycle exercise may be
advantageous for those with limited tolerance for weight bearing activity.
Strength exercise:
Frequency: At least 2 days/week.
Intensity: Between moderate- (5–6) and vigorous- (7–8) intensity on a scale of 0–10.
Type: Progressive weight training program or weight bearing calisthenics (eight to ten exercises
involving the major muscle groups of 8–12 repetitions each), stair climbing, and other
strengthening activities that use the major muscle groups.
Flexibility exercise:
Frequency: At least 2 days/week.
Intensity: Moderate (5–6) intensity on a scale of 0–10.
Type: Any activities that maintain or increase flexibility using sustained stretches for each major
muscle group and static rather than ballistic movements.
Balance exercise: recommended for frequent fallers or individuals with mobility problems.
CDC/DHHS Physical activity recommendations for older adults:
All adults should avoid inactivity. Some physical activity is better than none, and adults
who participate in any amount of physical activity gain some health benefits.
Aerobic exercise:
Frequency: For moderate-intensity exercise, perform 30 min/day for 5 days/week or vigorous-
intensity exercise, perform 20 min/day for 3 days/week. You can do moderate- or vigorous-
intensity aerobic activity, or a mix of the two each week.
Intensity: On a scale of 0–10 for level of physical exertion, 5–6 for moderate-intensity and 7–8
for vigorous intensity.
Duration: For moderate-intensity activities, accumulate at least 30 min/day in bouts of at least
10 min each.
Strength exercise:
Frequency: Ten strength-training exercises, 10–15 repetitions of each exercise 2–3/week.
Balance exercises: perform if at risk of falling.
338 D.A. Rivas and R.A. Fielding
In keeping with this idea, Volpi et al. (2001) were only able to observe a small

increase in basal protein degradation in old versus young humans (Volpi et al.
2001).
There are three known major proteolytic pathways that are revealed to have a
role in skeletal muscle: the lysosomal pathway, the Ca
2+
-dependent pathway com-
prising the m− and m-calpains, and the ubiquitin-proteasome dependent proteolytic
pathway (Attaix et al. 2005). Of these, the pathway that has recently received the
most interest is the ubiquitin-proteasome pathway. In skeletal muscle this pathway
is involved in the breakdown of long-lived myofibrillar proteins. In a variety of
conditions such as cancer, diabetes, denervation, disuse, and fasting, skeletal mus-
cles atrophy through degradation of myofibrillar proteins via the ubiquitin–protea-
some pathway (Edstrom et al. 2006; Attaix et al. 2005; Cao et al. 2005). The
induction of the muscle-specific ubiquitin E3-ligases (atrophy gene-1/muscle atro-
phy F-box (Atrogin-1/MAFbx) and muscle ring-finger protein 1 (MuRF1)) are
thought to be the common mechanism associated with these diseases (Cao et al.
2005). The roles of Atrogin-1 and MuRF-1 in aging related muscle loss are not as
clear cut. For example, some studies reported a small increase (Pattison et al. 2003),
no change (Welle et al. 2003) or even a downregulation of Atrogin-1 and MuRF-1
mRNA in aged muscle (Edstrom et al. 2006). Of interest, Raue et al. (2007)
observed that older women who are experiencing a large degree of sarcopenia
express the MuRF-1 gene at higher levels compared to young adults, but this is
reversed with resistance exercise (Raue et al. 2007). Although there was no differ-
ence in Atrogin-1 expression between the old and young subjects, after resistance
exercise there was a pronounced upregulation of this gene in older women (Raue
et al. 2007).
3.2 Anabolic Resistance
Anabolic stimulators, such as insulin, insulin-like growth factors (IGF1), amino
acids (AA) and muscle contraction, rapidly and significantly increase skeletal
muscle protein synthesis in young healthy tissue. Increased rates of protein synthe-

sis are a key feature of hypertrophy driving muscle growth. The effect of essential
amino acids on the dose-dependent stimulation of muscle protein synthesis is even
observed when circulating insulin concentrations were clamped (10 mIU/mL)
(Cuthbertson et al. 2005) or when somatostatin was used to inhibit insulin and
insulin-like growth factors in human subjects (Greenhaff et al. 2008). The aging-
induced “resistance” to amino acids to the stimulation of muscle protein synthesis
has previously been observed in humans and rodents (Guillet et al. 2004;
Cuthbertson et al. 2005; Rasmussen et al. 2006; Prod’homme et al. 2005). Rennie
and colleagues (Cuthbertson et al. 2005) termed the age-related inability of nutri-
ents to induce an appropriate anabolic response as “anabolic resistance”. Cuthbertson
et al. (2005) observed in older humans, following introduction of essential amino
acids (EAA), there was a reduced increase in skeletal muscle protein synthesis that
339Exercise as a Countermeasure for Sarcopenia
was correlated with increased concentrations of circulating and intramuscular EAA
(leucine) compared to their young counterparts (Cuthbertson et al. 2005). The
authors hypothesized that this was related to “anabolic resistance” that is
distinguishable in aging muscle (Cuthbertson et al. 2005).
Aging is associated with an inability of insulin to stimulate muscle protein
synthesis and amino acid uptake in otherwise healthy, glucose-tolerant persons
(Rasmussen et al. 2006; Guillet et al. 2004; Bell et al. 2006; Fujita et al. 2009). The
decline in muscle protein anabolic response to insulin is likely to be responsible for
the observed reduction in postprandial muscle protein anabolism in older people.
Rasmussen et al. (2006) observed that protein synthesis does not increase in
response to hyperinsulinemia in older adults, in contrast to young subjects
(Rasmussen et al. 2006). Prod’homme (2005) reported that insulin and EAA had
differential effects on muscle protein synthesis in aging animals (Prod’homme et al.
2005). These researchers observed that young and old animals had a similar
response to insulin, while anabolic stimulation by EAA was completely abolished
in the older animals. Insulin resistance of muscle protein metabolism with ageing
may induce a slow but progressive decline in muscle protein content thereby con-

tributing to the development of sarcopenia in older.
It is well established that within a few hours of muscle contraction there is an
increase in protein synthesis even in the fasted state. The contraction-induced
effects on muscle protein synthesis have been previously shown to be decreased in
older compared to young humans (Kumar et al. 2009; Sheffield-Moore et al. 2004).
Welle et al. (1995) even observed this effect after a 3 week strength exercise pro-
gram in male and female human subjects (Welle et al. 1995). We (Funai et al. 2006;
Parkington et al. 2004) and others (Thomson and Gordon 2005, 2006; Thomson
et al. 2009) have also observed an inhibition of an anabolic signaling in response to
muscle contraction and/or overload in aging skeletal muscle. Funai et al. (2006)
reported that anabolic signaling was increased in skeletal muscle after a single bout
of in situ muscle contractile activity induced by high-frequency electrical stimula-
tion (HFES) in adult animals, but these responses were attenuated in aged animals
(Funai et al. 2006). However, the anabolic resistance attributed to aging muscle has
not been observed in all studies (Reynolds et al. 2004; Paddon-Jones et al. 2004;
Volpi et al. 2003; Drummond et al. 2009a; Short et al. 2003, 2004). Therefore, more
study is needed to elucidate the significance of anabolic resistance to sarcopenia.
3.3 Anabolic Signaling
The mammalian target of rapamycin (mTOR) signaling kinase, which can be acti-
vated by Akt/Protein Kinase B (PKB), has emerged as a necessary effector of
skeletal muscle growth in response to contraction and anabolic agents (for review
see: Wang and Proud 2006; Bodine et al. 2001; Rommel et al. 2001). Insulin, amino
acids and acute contractile activity have all been observed to increase the phospho-
rylation of mTOR and its downstream targets, p70 ribosomal protein S6 kinase 1
340 D.A. Rivas and R.A. Fielding
(S6K1) and 4E binding protein 1 (4EBP1). mTOR is a highly conserved, serine/
threonine kinase of the phosphatidylinositol kinase-related kinase family and is a
key regulatory protein for a multiplicity of cell processes including, but not limited
to, cell growth and differentiation, protein synthesis, and actin cytoskeletal organi-
zation. The primary phosphorylation targets of mTOR are the threonine (Thr)389

site of S6K1 and the Thr37/46 sites of 4EBP1 that mediate translational initiation.
The observation of decreased protein synthesis in response to anabolic stimula-
tion with aging is believed to occur as a result of the inhibition of mTOR signaling
(Wang and Proud 2006). Multiple studies that have utilized rapamycin, a highly
potent inhibitor of mTOR activation, have observed decreased protein synthesis
in vivo and in vitro (Drummond et al. 2009; Kubica et al. 2005, 2008; Fluckey et al.
2004; Kimball et al. 2000; Anthony et al. 2000; Grzelkowska et al. 1999). The
inhibitory effect of rapamycin on mTOR activation and protein synthesis can even
occur despite an effective anabolic stimulation (Vary et al. 2007; Rivas et al. 2009;
Kubica et al. 2005; Anthony et al. 2000). Cuthbertson et al. (2005) hypothesized that
the “anabolic resistance” that was observed in their older subjects was related to the
reduced phosphorylation of mTOR and its downstream substrate S6K1 (Cuthbertson
et al. 2005). We and others have observed an age induced attenuation of the Akt/
mTOR signaling pathway in response to contractile stimulation and overload (Funai
et al. 2006; Hwee and Bodine 2009; Thomson and Gordon 2006; Parkington et al.
2004). Recently, Drummond et al. (2009) demonstrated that the contraction-induced
increase of mTOR signaling, protein synthesis and extracellular related kinase sig-
naling (ERK1/2) are reduced with prior rapamycin treatment in humans (Drummond
et al. 2009b). These results provide some understanding for the role of mTOR in the
initiation of protein synthesis in response to anabolic stimuli, such as muscle con-
traction. However, there is some disagreement whether the phosphorylation of
mTOR is responsible for the changes in the protein synthetic rates in response to
an anabolic stimulation (Greenhaff et al. 2008). Greenhaff et al. (2008) recently
demonstrated that changes in signaling protein phosphorylation can be almost
completely be disconnected from protein synthesis with an anabolic stimulus such
as insulin.
3.4 Skeletal Muscle Attenuation
It is well understood that with advancing age there is a change in the composition
of skeletal muscle. Lean muscle mass normally contributes up to 50% of total
body weight in young adults but declines with age to 25% at 75–80 years

(Koopman and van Loon 2009; Short et al. 2004). The loss in lean muscle mass is
usually offset by gains in fat mass. Longitudinal studies have shown that fat mass
increases with age peaking at about 60–75 years (Rissanen et al. 1988; Droyvold
et al. 2006). Aging is associated with the increased accumulation of intramuscular
fat as well as with an increase in the incidence of metabolic disorders such as
insulin resistance (Tucker and Turcotte 2003; Nakagawa et al. 2007). Impaired lipid
341Exercise as a Countermeasure for Sarcopenia
metabolism and increased visceral adiposity associated with aging are thought to
contribute to the muscle atrophy associated with sarcopenia (Nakagawa et al.
2007). Researchers have observed the defects in lipid metabolism, such as
increased intramuscular and circulating lipids, even in lean and otherwise healthy
elderly persons (Nakagawa et al. 2007). Furthermore, studies have found signifi-
cant difference in protein metabolism between obese and non-obese humans
(Guillet et al. 2009; Nair et al. 1983; Jensen and Haymond 1991; Luzi et al. 1996).
Goodpaster et al. (2000) observed that increased mid-thigh muscle attenuation (a
marker of intramuscular lipids with CT scan) was related to the loss of muscular
specific strength in 2,627 older men and women (Goodpaster et al. 2000). The
concomitant age-related changes in body composition, obesity, impaired metabo-
lism and low muscle mass have lead to the hypothesis that there may be a causal
link between obesity and low strength.
Growth factors (i.e. insulin and IGF1), AA and muscle contraction are known
modulators of muscle protein synthesis and inhibitors of protein degradation and
their capacity to stimulate muscle protein synthesis is impaired in both aging and
obesity (Rasmussen et al. 2006; Guillet et al. 2009). Insulin resistance is also highly
coupled with obesity and aging and results in decreased insulin-stimulated glucose
uptake, protein synthesis and the inability to inhibit lipid uptake (Corcoran et al.
2007; Tucker and Turcotte 2003; Hawley and Lessard 2008; Rasmussen et al. 2006;
Anderson et al. 2008; Guillet et al. 2009). Guillet et al. (2009) recently observed
that obese humans had a decreased fractional synthetic rate during an amino acid
infusion and insulin clamp in the basal and insulin-stimulated state compared to

their age matched controls (Guillet et al. 2009). In addition to the evidence showing
that high-fat feeding and obesity inhibit protein synthesis in response to an anabolic
stimulus, there is also evidence of altered mTOR signaling in the basal and insulin-
stimulated state (Guillet et al. 2004, 2009; Rivas et al. 2009; Anderson et al. 2008;
Khamzina et al. 2005; Katta et al. 2009). For example, Katta et al. (2009) demon-
strated in obese Zucker rats that mTOR signaling was inhibited in response to in
situ HFES muscle contraction compared to their lean litter mates (Katta et al.
2009). However, studies report there is no relationship between acutely increased
circulating free fatty-acids (artificially-induced with heparin treatment) and
decreased protein synthesis (Katsanos et al. 2009) or impaired mTOR signaling
(Lang 2006) in skeletal muscle. Although there is some contention regarding role
of increased circulating free-fatty acids and reduced protein synthesis, the increased
storage of fat in muscle during aging has been clearly demonstrated to have role in
reduced muscle mass and functional impairment.
3.5 Skeletal Muscle Regeneration
Aging skeletal muscle displays a significant reduction in regenerative capacity
this leads to the inability to adapt to an increased load and is therefore less
responsive to injury. The regenerative capacity of muscle fibers depends on a
342 D.A. Rivas and R.A. Fielding
pool of myogenically specified undifferentiated mononuclear precursor stem
cells called ‘satellite’ cells that appear to function as “reserve” myoblasts (for
review see: Wagers and Conboy (2005), Gopinath and Rando (2008). Satellite
cells (SC) are the primary stem cells in adult skeletal muscle, and are respon-
sible for postnatal muscle growth, hypertrophy, regeneration and repair. SC
were identified ultrastructurally and were named for their peripheral location
beneath the basal lamina of the myofiber (Mauro 1961). SC are primarily in a
quiescent, non-differentiating state, dividing infrequently under normal condi-
tions in the adult but activated (reenter the cell cycle) by regenerative cues such
as injury or exercise. Once activated, the cells will proliferate, increase in num-
ber and the daughter cells (myoblasts) will repair damaged skeletal muscle by

fusing to existing myofibers or generating new myofibers by fusing together
(Hawke 2005).
It is believed that muscle hypertrophy requires the addition of nuclei to existing
myofibers (Adams 2006). This follows the premise that increases in fiber size must
be associated with a proportional increase in myonuclei for the control of mRNA
and protein production per volume of cytoplasm (Hawke 2005). Growth factors
such as, interleukin (IL) 6, testosterone, IGF1 and the IGF isoform, mechanogrowth
factor, have been identified as having a role in post-exercise hypertrophy (Vierck
et al. 2000; Adams 2002; Sinha-Hikim et al. 2003). Of interest, Machida and Booth
(2004) recently demonstrated a key role for the PI3K/Akt pathway in IGF induced
SC proliferation (Machida and Booth 2004).
The potential role of SC in age-induced muscle atrophy is not clear cut. Studies
have either shown a similar (Dreyer et al. 2006a; Roth et al. 2000; Sinha-Hikim
et al. 2006) or lower (Kadi et al. 2004; Renault et al. 2002) SC proportion in older
adults when compared with young adults. It has been demonstrated that SC in aged
muscle display a delayed response to activating stimuli and reduced proliferative
expansion (Schultz and Lipton 1982; Conboy et al. 2003). Verdijk and colleagues
have reported marked decreases in Type 2 versus Type 1 muscle fiber myonuclear
domain size and a specific decrease in the Type 2 fiber satellite cell content in
elderly humans (Verdijk et al. 2007). In a follow up study, these researchers
observed that Type 2 muscle fiber atrophy and the associated lower satellite cell
proportion in Type 2 versus Type 1 muscle fibers in older adults can be reversed by
prolonged resistance type exercise training (Verdijk et al. 2009). Roth et al. (2001)
have also reported that satellite cell proportion in young and older men and women
was significantly increased as a result of 9 weeks of strength training (Roth et al.
2001b). Interestingly, older women demonstrated a significantly greater increase in
SC content and the largest increase in the number of active satellite cells in response
to strength training. Therefore, because of the significant role of SC in skeletal
muscle regeneration, repair and hypertrophy unraveling their role in sarcopenia
remains a high priority.

Some possible mechanisms that contribute to sarcopenia are outlined in Fig. 1.
Sarcopenia is a multifactorial process and the mechanisms that underlie it are only
beginning to be elucidated. More research is needed determine their roles in the
onset of sarcopenia.
343Exercise as a Countermeasure for Sarcopenia
4 Exercise as an Intervention for the Modulation
of Sarcopenia
As discussed earlier in this chapter, life-long habitual physical activity is the most
effective preventative treatment for age-induced sarcopenia. Multiple groups have
studied the effects of exercise training on energy metabolism and as a treatment for
metabolic disorders such as, insulin resistance, obesity and type 2 diabetes (Hawley
and Lessard 2008; Berger and Berchtold 1979; Wallberg-Henriksson and Holloszy
1984, 1985; Zierath 2002; Goodyear and Kahn 1998; Kelley and Goodpaster 2001;
Musi and Goodyear 2006). Exercise training, with respect to substrate metabolism,
is associated with enhanced oxidative capacity and insulin sensitivity, decreased
intramuscular lipid storage and improved body composition (Hawley and Lessard
2008; Toledo et al. 2007; Richter and Ruderman 2009; Tanaka and Seals 2003;
Lessard et al. 2007).
There is growing evidence demonstrating the benefits of exercise late in life as a
countermeasure for sarcopenia and its related functional limitations (Keysor 2003;
Henwood and Taaffe 2005; Galvao and Taaffe 2005; Galvao et al. 2005). Regular
physical activity is associated with greater functional capacity, increased appendicular
muscle mass and reduced incidence of metabolic diseases and this is particularly
observed in middle-aged and older adults (Sugawara et al. 2002; Harber et al. 2009b).
Since the 1980s, numerous intervention studies have reported the benefits of resistance,
aerobic and a combination (aerobic and resistance) of these exercise modalities for the
treatment muscle loss and disability as a result of aging (Frontera et al. 1988; Tanaka
and Seals 2003). The purpose of this section is to review the molecular events and
whole-body benefits of the different modes of exercise for the treatment of sarcopenia.
Fig. 1 A few possible mechanistic contributors to sarcopenia and its consequences

344 D.A. Rivas and R.A. Fielding
4.1 Aerobic Exercise
Aerobic exercise is a widely recommended therapeutic agent for older adults
because of its beneficial effects on cardiovascular and metabolic health, body com-
position and improved function. Endurance exercise is based on movements per-
formed with a high number of repetitions and low resistance. Maximal aerobic
capacity (VO
2
max) is generally thought to be the best indicator of the capacity to
perform aerobic exercise. Maximal oxygen consumption declines about 1% per
year after the age of 25 in sedentary individuals. This is important since low aerobic
capacity has been highly correlated with increased rates of all-cause mortality in
numerous epidemiological studies (Paffenbarger et al. 1993, 1970; Leon et al.
1987; Morris et al. 1953a, b). However, in master athletes who participate in regular
aerobic activity the decline in VO
2
max is only 0.5% per year (Tanaka and Seals
2003, 2008; Paffenbarger et al. 1993).
It is thought that the key contributors to a decline in maximal aerobic capacity
in sedentary individuals are a decrease in maximal cardiac output (Ogawa et al.
1992; Proctor et al. 1998), a decrease in muscle oxidative capacity (Ljubicic et al.
2009; Short et al. 2003; Conley et al. 2000a, b; Harber et al. 2009) and a decrease
in metabolically active muscle mass with a concomitant increase in metabolically
inactive fat mass (Paffenbarger et al. 1970; Goodpaster et al. 2000, 2006; Short
et al. 2003; Proctor and Joyner 1997; Fleg and Lakatta 1988). When measuring VO
2

max normalized to muscle mass (as indexed by 24 h urinary creatinine excretion)
in old and young men and women, Fleg and Lakkata (1988) reported that the age-
induced decrease in VO

2
max is explained by the selective loss of muscle mass that
accompanies aging. Recently, Proctor and Joyner (1997), when examining the
effect of reduced muscle mass (and increased fat mass) on VO
2
max in the elderly,
expressed maximal oxygen consumption relative to appendicular muscle mass
(Proctor and Joyner 1997). They observed that 50% of the decline in VO
2
max, as
a result of aging, was attributed to the age-induced decreases in muscle mass and
increases in fat mass. Therefore, understanding the possible benefits from aerobic
exercise for increasing maximal oxidative capacity and/or muscle mass in older
adults could have implications for healthy aging.
4.1.1 Improving Oxidative Capacity
Aerobic exercise of sufficient intensity and duration can significantly increase VO
2

max in middle aged and older adults (Huang et al. 2005; Malbut et al. 2002; Lanza
et al. 2008). It has been hypothesized that increases in mitochondrial number,
increases in the expression of mitochondrial proteins and/or an increase in the
expression of transcription factors involved in mitochondrial biogenesis are mecha-
nisms for the enhancement in post-exercise VO
2
max. Lanza et al. (2008) observed
increases in mitochondrial ATP production rate (MAPR), citrate synthase (CS)
activity, pparg-coactivator 1 a (PGC1a), mtDNA abundance. Of interest, the
345Exercise as a Countermeasure for Sarcopenia
researchers also reported an increase in sirtuin 3 (SIRT3), a protein deacetylase that
has been associated with the life prolonging benefits of caloric restriction, in aero-

bically trained older individuals compared to their sedentary peers (Lanza et al.
2008).
There is some evidence of a reduction in the activation of the energy sensor,
AMP-activated protein kinase (AMPK), in response to endurance exercise in aging
muscle (Reznick et al. 2007). However, Ljubicic and Hood (2009) observed no dif-
ference with endurance-like contraction induced AMPK activation in high-oxida-
tive red muscle between old and young animals (Ljubicic and Hood 2009). The
researchers did observe an inhibition of AMPK activity in the less oxidative white
muscle in the acute response to endurance-like contraction. This may be an impor-
tant consequence because of AMPK has recently been observed to have a critical
role in the regulation of muscle hypertrophy as a result of muscle overload (McGee
et al. 2008; Thomson et al. 2009).
4.1.2 Increased Muscle Mass
There has been minimal study on aerobic exercise and its effects on improving
muscle function, increasing muscle mass and protein synthesis in the elderly. Some
researchers have provided evidence that aerobic exercise was as proficient as resis-
tance training at improving functional limitations associated with aging (Wood
et al. 2001; Davidson et al. 2009; Coggan et al. 1992; Verney et al. 2006). For
example, Davidson et al. (2009) reported that 6 months of resistance and aerobic
exercise was associated with similar improvements in functional limitation in 136
previously sedentary, obese older men and women (Davidson et al. 2009).
Researchers have previously reported that aerobic exercise does not alter muscle
size in older individuals (Ferrara et al. 2006; Verney et al. 2006; Short et al. 2004;
Weiss et al. 2007). However, Harber et al. (2009) have recently shown that a 12
week aerobic training intervention induced a 16.5% increase in single fiber cross
sectional area (CSA) and a 20% increase in quadriceps muscle volume that was
accompanied by improvements in whole muscle power and force production in
healthy older women (Harber et al. 2009). The investigators hypothesized that their
results differed from previous studies because their subjects were in good health
and the body weights of their subjects were maintained throughout the intervention.

Also, habitually endurance-trained elderly males have higher appendicular muscle
mass, relative to body mass, compared to their sedentary controls (Sugawara et al.
2002). The increased muscle hypertrophy and appendicular muscle mass observed
in these studies could be as a result of increases in protein synthesis observed after
aerobic exercise (Harber et al. 2009a, b; Short et al. 2004; Fujita et al. 2007). Short
et al. (2004) reported that men and women have a decline in whole-body protein
metabolism as a result of aging. A 4 month aerobic exercise program had no effect
on whole-body protein turnover but, significantly increased mixed muscle protein
synthesis in the older subjects (Short et al. 2004). Fujita et al. (2007) have further
shown an increase in insulin-stimulated muscle protein turnover as a result of an acute