Sarcopenia Age-Related Muscle Wasting and Weakness: Mechanisms and Treatments P21 docx

186 S.E. Alway and P.M. Siu
Karin 2009). However, NF-kB can also promote apoptosis when activated by
pro-apoptotic proteins including p53, Fas and Fas ligand (Burstein and Duckett
2003; Dutta et al. 2006; Fan et al. 2008).
p53 upregulated modulator of apoptosis (PUMA) is a downstream target of
p53 and a BH3-only Bcl-2 family member(Lee et al. 2009; Chipuk and Green
2009; Ghosh et al. 2009b). It is induced by p53 following exposure to DNA-
damaging agents, such as gamma-irradiation and commonly used chemothera-
peutic drugs or oxidative stress (Lee et al. 2009; Chipuk and Green 2009; Ghosh
et al. 2009a). It is also activated by a variety of nongenotoxic stimuli indepen-
dent of p53, such as serum starvation, kinase inhibitors, glucocorticoids, endo-
plasmic reticulum stress, and ischemia/reperfusion (Nickson et al. 2007; Yu and
Zhang 2008). The pro-apoptotic function of PUMA is mediated by its interac-
tions with anti-apoptotic Bcl-2 family members such as Bcl-2 and Bcl-XL which
lead to Bax/Bak-dependent mitochondrial dysfunction mitochondria permeabil-
ity and caspase activation (Chipuk and Green 2009). In addition, PUMA is
directly activated by NF-kB and contributes to TNF-a-induced apoptosis (Wang
et al. 2009).
Fig. 4 The extrinsic (death receptor) pathway is activated in aging and contributes to sarcopenia.
A ligand (e.g., TNF-a) binds to the death receptor and TNFR1, activates procaspase 8 and caspase
8 which in turn activates caspase 3 and DNA fragmentation
187Nuclear Apoptosis and Sarcopenia
Based on the well-documented increase in circulating TNF-a levels with aging
(Bruunsgaard et al. 1999, 2001, 2003a, b; Bruunsgaard 2002; Visser et al. 2002;
Pedersen et al. 2003; Sandmand et al. 2003; Schaap et al. 2006, 2009) and increases
in apoptosis of myonuclei in aged skeletal muscles (Allen et al. 1997; Siu et al.
2005c; Pistilli et al. 2006b), we examined whether apoptotic signalling via the
extrinsic pathway contributed to sarcopenia. Our data show that pro- and anti-
apoptotic proteins in the extrinsic apoptotic pathway are affected by aging in fast
(plantaris) and slow (soleus) skeletal muscles of rats (Pistilli et al. 2006b). Similarly,
Marzetti et al. (2009a, b) report elevated TNF-a and TNF-receptor 1 in muscles of

old rodents. Together, these data suggest that TNF-a mediated signalling may be
an important element triggering the extrinsic apoptotic pathway in and leading to
sarcopenia in aging muscles.
Muscles from aged rats are significantly smaller and exhibit a larger incidence
in fragmented DNA. This suggests that there is a higher level of nuclear apoptosis
in muscles from aged animals. In addition, muscles from aged rodents have higher
TNFR and FADD mRNA content (measured by semi-quantitative RT-PCR) and
protein contents for FADD, Bid, and FLIP, and enzymatic activities of caspase 8
and caspase 3, when compared to muscles from young adult rodents. Although
there is an increase in mRNA expression for the TNFR as measured by the semi-
quantitative approach, the protein content for the TNFR remains unchanged (Pistilli
et al. 2006a, b). This may be explained by the fact that the TNFR antibody utilized
in western immunoblots recognizes the soluble form of the receptor. Thus, the
changes in the membrane bound form of the receptor, measured by PCR, and the
amount of the soluble TNFR may not be equivalent. While fast contracting muscles
are generally more susceptible to apoptosis and sarcopenic muscle loss, the pro-
apoptotic changes have been reported to be expressed in a similar fashion in both
plantaris and soleus muscles; however strong relationships were observed between
markers of apoptosis and muscle loss in the fast plantaris muscle that were not
observed in the soleus (Pistilli et al. 2006a). These data extend the previous dem-
onstration that type II fibres are preferentially affected by aging and suggest that
type II fibre containing skeletal muscles may be more susceptible to muscle mass
loses via the extrinsic apoptotic pathway (Pistilli et al. 2006b).
We have found activation of the extrinsic apoptotic signalling pathway in muscles
of old rats (Pistilli et al. 2006a, 2007; Siu et al. 2008), and therefore we speculate
that circulating TNF-a may be the initiator of this pathway in skeletal muscle.
Nevertheless, we cannot rule out the possibility that other pathways that we did not
examine may have been activated by circulating TNF-a in aging muscle. For exam-
ple, TNF-a has been shown to directly promote protein degradation (Garcia-
Martinez, et al. 1993a, b; Llovera et al. 1997, 1998) and apoptosis within skeletal

muscle (Carbo et al. 2002; Figueras et al. 2005). Furthermore, intravenous injection
of recombinant TNF-a increases protein degradation in rat skeletal muscles and this
is associated with the increased activity of the ubiquitin-dependent proteolytic path-
way (Garcia-Martinez et al. 1993a, 1995; Llovera et al. 1997, 1998). In addition,
elevated TNF-a concentrations in cell culture for 24–48 h increases apoptosis in
skeletal myoblasts as determined by DNA fragmentation (Meadows et al. 2000;
188 S.E. Alway and P.M. Siu
Foulstone et al. 2001). A reduction of procaspase 8 occurs within 6h of incubating
myoblasts in vitro with recombinant TNF-a, suggesting a TNF-a mediated cleavage
and activation of this initiator caspase in myoblast cultures (Stewart et al. 2004).
Lees and co-workers (Lees et al. 2009) have recently shown that satellite cells
(i.e., MPCs) isolated from hindlimb muscles of old rats have increased TNF-a-
induced nuclear factor-kappa B (NF-kB) activation and expression of mRNA levels
for TRAF2 and the cell death-inducing receptor, Fas (CD95), in response to pro-
longed (24 h) TNF-a treatment compared to in MPCs isolated from muscles of
young animals. These findings suggest that age-related differences may exist in the
regulatory mechanisms responsible for NF-kB inactivation, which may in turn have
an effect on TNF-a-induced apoptotic signalling. Systemic and muscle levels of
TNF-a increase with aging, and this should have an even more profound increase
in activation of apoptotic gene targets through the extrinsic pathway, as compared
to MPCs in muscles of young adult rats (Krajnak et al. 2006; Lees et al. 2009).
The effects of TNF-a on apoptosis are not limited to in vitro conditions, because
a systemic elevation of TNF-a in vivo increases DNA fragmentation within rodent
skeletal muscle (Carbo et al. 2002). Based on the observation that TNF-a mRNA
was not different between muscles from young adult and aged rats, it is reasonable
to assume that muscle-derived TNF-a does not act in an autocrine manner to
stimulate the pro-apoptotic signalling observed in this study. Data from Pistilli and
co-workers (Pistilli et al. 2006b) are consistent with the hypothesis that the well-
documented systemic elevation of TNF-a with age, may increase the likelihood of
ligand binding to the TNFR and stimulate apoptotic signalling of the extrinsic

pathway downstream of the TNFR and contribute to sarcopenia in skeletal muscle
of old rats.
5.2 Cross-talk Between Extrinsic and Intrinsic
Apoptotic Signalling
Cross-talk between extrinsic and intrinsic apoptotic pathways was recently
reviewed (Sprick and Walczak 2004). Cross-talk between these pathways is the
result of the cleavage of the pro-apoptotic BCL-2 family member Bid. Cleaved and
activated caspase 8 cannot only serve to activate caspase 3, which is the execu-
tioner caspase, but also cleave full-length Bid into a truncated version (tBid) (Tang
et al. 2000). tBid then interacts with pro-apoptotic Bax, to stimulate apoptotic sig-
nalling from the mitochondria (Grinberg et al. 2005). As has been previously
shown, apoptotic signalling from the mitochondria stimulates cleavage of procas-
pase 9, which then serves to activate caspase 3 (Johnson and Jarvis 2004). Thus,
both the extrinsic and intrinsic apoptotic pathways converge on caspase 3, which
then fully engages pro-apoptotic signalling. Skeletal muscles from aged rodents
contained a greater protein expression of full-length Bid, which raises the possibil-
ity that cross talk between the extrinsic pathway and the intrinsic pathway may
occur in aged skeletal muscles (Fig. 5).
189Nuclear Apoptosis and Sarcopenia
6 Exercise Modulation of Apoptosis in Sarcopenia
Various perturbations have been used to determine if aging increases the sensitivity
of skeletal muscle to apoptosis and apoptosis signalling cascades. These include
increases in muscle loading, loading followed by a period of unloading, disuse,
denervation or muscle unloading, and aerobic exercise.
6.1 Interventions by Muscle Loading
The evidence presented above indicates that mitochondrial dysfunction is a major
contributing factor to the path physiology of aging including sarcopenia. While
muscle disuse decreases mitochondria function leading to apoptosis (Adhihetty
et al. 2003; Siu and Alway 2005a; Bourdel-Marchasson et al. 2007), chronic exer-
cise improves mitochondria function (Daussin et al. 2008; Lanza et al. 2008) and

reduces apoptotic signalling (Siu et al. 2004).
Fig. 5 The potential cross talk between the extrinsic and intrinsic apoptotic signalling pathways
are shown
190 S.E. Alway and P.M. Siu
Adaptation to chronic loading has been shown to improve anti-apoptotic proteins in
skeletal muscle including XIAP (Siu et al. 2005d), Bcl2 (Song et al. 2006), and reduce
DNA fragmentation (Siu and Alway 2006a) (Song et al. 2006) and lower pro-apoptotic
proteins including Bax (Song et al. 2006), ARC (Siu and Alway 2006a), AIF (Siu and
Alway 2006a). In contrast, models of muscle unloading show most of the appositive
apoptotic signalling such as elevations in Bax, Apaf1, AIF (Pistilli et al. 2006b), cyto-
solic levels of Id2 and p53 (Siu et al. 2006) and the Bax/Bcl2 ratio (Song et al. 2006).
Reduced levels of pro-apoptotic proteins may provide one mechanism to explain
the improvements in muscle mass and force that are observed in humans after a period
of resistance exercise. Our lab (Roman et al. 1993; Ferketich et al. 1998) and others
(Charette et al. 1991; Welle et al. 1995; Parise and Yarasheski 2000; Deschenes and
Kraemer 2002; Mayhew et al. 2009) have shown that resistance exercise is an effective
tool to reduce but not eliminate sarcopenia in aging humans. Although aging has gen-
erally been shown to attenuate the absolute extent of muscle adaptations that are pos-
sible with increased loading (Alway et al. 2002a; Degens and Alway 2003; Degens
2007; Degens et al. 2007), it is not known how much of this might be the result of
increased nuclear apoptosis in skeletal muscle. Interestingly, several studies have
reported unexpected improvements in mitochondrial function in both young adult and
aged subjects as a result of resistance exercise training. For example, the mitochondrial
capacity for ATP synthesis increases after resistance training (Jubrias et al. 2001;
Conley et al. 2007b; Tarnopolsky 2009). Resistance exercise also increases antioxidant
enzymes and decreases oxidative stress (Parise et al. 2005; Johnston et al. 2008).
Furthermore, 26 weeks of whole body resistance exercise was shown to reverse the
gene expression of mitochondrial proteins that were associated with normal aging, to
that observed in young subjects (Melov et al. 2007). Although we have found that
resistance training did not increase the relative volume of mitochondria in muscle

fibres of young adults, resistance exercise stimulated mitochondria biogenesis to main-
tain the myofibrillar to mitochondria volume (Alway et al. 1989; Alway 1991). In
addition, aging attenuates the adaptive response to improve the muscle’s ability to buf-
fer pro-oxidants in response to chronic muscle loading (Ryan et al. 2008). Nevertheless,
there is some improvement in antioxidant enzymes and the ability to buffer oxidative
stress in response to loading conditions (Ryan et al. 2008). Therefore, it is possible
that, resistance training could also improve mitochondria function and stimulate mito-
chondrial biogenesis in aged individuals. If muscle loading improves not only antioxi-
dant enzymes levels but it also reduces Bax accumulation in mitochondria, we would
expect that apoptosis signalling should be decreased. This would lead to improved
muscle recovery following disuse and reduce sarcopenia.
6.2 Apoptotic Elimination of MPCs Reduces Muscle
Hypertrophic Adaptation to Loading
It is thought that myonuclei maintain a constant cytoplasm to nuclei ratio, (i.e.
“nuclear domain”, see Fig. 1), and that hypertrophy requires that fibres add new
191Nuclear Apoptosis and Sarcopenia
nuclei (Schultz 1989, 1996; Schultz and McCormick 1994). Because myonuclei are
post mitotic (Schultz 1989, 1996; Schultz and McCormick 1994), satellite cells/
MPCs provide the only important source for adding new nuclei to initiate muscle
regeneration, muscle hypertrophy, and postnatal muscle growth in muscles of both
young and aged animals (Rosenblatt et al. 1994; Phelan and Gonyea 1997; McCall
et al. 1998; Allen et al. 1999; Hawke and Garry 2001; Adams et al. 2002). MPCs
are critical for muscle growth because muscle hypertrophy is markedly reduced or
eliminated completely after irradiation to prevent MPC activation (Rosenblatt et al.
1994; Hawke and Garry 2001). Growth of adult skeletal muscle requires activation
and differentiation of satellite cells/MPCs and increased protein synthesis and accu-
mulation of proteins, and this necessitates increased transcription of muscle genes
(Dirks and Leeuwenburgh 2002; Pollack et al. 2002; Alway et al. 2002b;
Leeuwenburgh 2003; Dirks and Leeuwenburgh 2004; Siu et al. 2005c). Thus, there
is little doubt that MPC activation and differentiation are critical components in

determining muscle adaptation and growth.
If MPCs are activated normally, but they either do not differentiate or do not
survive to participate in increased protein synthesis, then muscle adaptation would
be compromised. Elevation of apoptosis (lower MPC survival) in muscles from
aged animals (Renault et al. 2002; Siu et al. 2005c) could explain the poorer adapta-
tion to repetitive loading in aging. We have shown that the most recently activated
satellite cells/MPCs during loading are also the most susceptible to apoptosis
(Pollack et al. 2002; Alway et al. 2002a, b; Leeuwenburgh 2003; Dirks and
Leeuwenburgh 2004). Based on these data, we hypothesize that MPC contribution
to chronic loading-induced adaptation (hypertrophy) is lower in muscles of old
animals because apoptosis is higher (Degens and Alway 2003), and fewer MPCs
survive to contribute to muscle adaptation (Chakravarthy et al. 2001).
6.3 Regulation of Apoptotic Signalling by Aerobic Exercise
Although acute endurance exercise has been shown to increase apoptotic signalling
under some conditions including dystrophies and other pathologies (Sandri et al.
1997; Podhorska-Okolow et al. 1998, 1999) long-term adaptation to endurance
exercise has been shown to lower mitochondria-associated apoptosis in heart and
skeletal muscle of rodents (Siu et al. 2004; Kwak et al. 2006; Song et al. 2006;
Peterson et al. 2008); however, it does not improve muscle mass or act as a coun-
termeasure to sarcopenia (Alway et al. 1996; Marzetti et al. 2008a). This might be
in part due to aerobically-induced pathways that are generally inhibitory to muscle
growth (e.g., AMPK).
Apoptosis has been shown to occur in cardiac (Dalla et al. 2001; Hu et al. 2008;
Molina et al. 2009) and skeletal muscles (Dalla et al. 2001; Vescovo and Dalla
2006; Libera et al. 2009) of experimental models of chronic heart failure. Apoptosis
in skeletal muscle has been linked to elevated circulating levels of TNF-a (Adams
et al. 1999; Vescovo et al. 2000). Although nuclear apoptosis has been detected in
192 S.E. Alway and P.M. Siu
muscles of humans with severe chronic heart failure (Conraads et al. 2009), it does
not appear to be a large component of muscle loss associated when the disease is

less severe (Dirks and Jones 2006; Yu et al. 2009a). Complicating the treatment of
heart failure and related cardiovascular diseases is the likelihood that drugs includ-
ing statins which are routinely prescribed to reduce hypercholesterolemia, may
themselves have a pro-apoptotic role in skeletal muscle (Adams et al. 2008). Such
increases in apoptosis are likely to have devastating effects when statins are
combined with sarcopenia, where muscle loss is already high. Although aerobic
exercise appears to reduce several skeletal muscle problems of persons suffering
from severe chronic heart failure (Linke et al. 2005) and an exercise-induced
improvement in antioxidant enzymes is correlated to reduced apoptosis in muscles
of patients with chronic heart failure (Siu et al. 2004, 2005a; Song et al. 2006),
currently there are no data to definitively address if aerobic exercise reduces apop-
tosis in heart failure patients. The role or aerobic exercise on nuclear apoptosis of
skeletal muscle has not been well-studied but limited data suggest that apoptosis
signalling is reduced by aerobic exercise in cardiac and skeletal muscle of young,
diseased and aged animals (Siu et al. 2004; Kwak et al. 2006; Song et al. 2006;
Peterson et al. 2008; Marzetti et al. 2008a, b).
7 Summary and Conclusions
Sarcopenia involves complex of several cellular mechanisms which together con-
tribute to muscle loss during aging. Among them, nuclear apoptosis has recently
emerged as an important factor involved in the pathophysiology of sarcopenia.
Several lines of evidence support the hypothesis that mitochondrial (intrinsic),
extrinsic (death receptor) and endoplasmic reticulum-calcium stress activated apop-
totic signalling, occurs in skeletal muscles of old mammals. Nevertheless, it has not
been determined to what extent sarcopenia would be reduced, if apoptotic signal-
ling could be fully blocked. Although there is evidence that reducing Bax markedly
reduces apoptosis associated muscle loss with denervation (Siu and Alway 2006b),
it is not known if this is also the case with aging. We cannot rule the possibility that
the apoptotic signalling events may occur to simply eliminate dysfunctional nuclei
and/or damaged muscle fibres, whose perseverance would be detrimental for organ
function.

Even though a cause and effect relationship between apoptosis and sarcopenia
has not been unequivocally determined, evidence that muscle loss is reduced in Bax
null mice (Siu and Alway 2006b), and experimental interventions to accelerate
muscle loss in aged animals also elevates apoptosis (Siu and Alway 2005a; Siu
et al. 2005b, c, d, 2006, 2008; Pistilli et al. 2007) strongly suggests that a causal
relationship likely exists between nuclear apoptosis and muscle loss, and this may
also extend to aging associated muscle loss. Furthermore, activation of mitochon-
drial apoptotic signalling during the early phases of disuse muscle atrophy (Siu and
Alway 2005b; Siu and Alway 2009) suggests that this may exist to balance muscle
193Nuclear Apoptosis and Sarcopenia
size and the metabolic or functional needs of the animal. If this is true, nuclear
apoptosis may be a fundamentally important mechanism that regulates myonuclei
number and, therefore controls the extent of muscle growth (or atrophy) in aging.
Apoptotic signalling may be modified by loading and aerobic forms of exercise, but
it remains to be seen how effective exercise might be in slowing or preventing
apoptosis in sarcopenia. Clearly further research is required to better understand the
complex cellular mechanisms underlying muscle atrophy that occurs in sarcopenia,
and the importance of apoptosis in this process. Unravelling the regulatory factors
in the apoptotic pathways will be a necessary step prior to having the ability to
design effective interventions and countermeasures for sarcopenia.
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