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

Our data show that pro- and anti-apoptotic proteins in the extrinsic anti-apoptotic pathway are affected by aging in fast plantaris and slow soleus skeletal muscles of rats Pistilli et a

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

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 anti-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;

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 casprocas-pase 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)

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

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

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

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 apopapop-tosis 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

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

References

Abmayr, S., Crawford, R W., Chamberlain, J S (2004) Characterization of ARC, apoptosis

repressor interacting with CARD, in normal and dystrophin-deficient skeletal muscle Human Molecular Genetics, 13, 213–221.

Acehan, D., Jiang, X., Morgan, D G., Heuser, J E., Wang, X., Akey, C W (2002) Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding,

and activation Molecular Cell, 9, 423–432.

Adams, G R., Caiozzo, V J., Haddad, F., Baldwin, K M (2002) Cellular and molecular

responses to increased skeletal muscle loading after irradiation American Journal of Physiology Cell Physiology, 283, C1182–C1195.

Adams, V., Jiang, H., Yu, J., Mobius-Winkler, S., Fiehn, E., Linke, A., Weigl, C., Schuler, G., Hambrecht, R (1999) Apoptosis in skeletal myocytes of patients with chronic heart failure is

associated with exercise intolerance Journal of the American College of Cardiology, 33,

959–965.

Adams, V., Doring, C., Schuler, G (2008) Impact of physical exercise on alterations in the

skeletal muscle in patients with chronic heart failure Frontiers in Bioscience, 13,

302–311.

Adhihetty, P J., Hood, D A (2003) Mechanisms of apoptosis in skeletal muscle Basic and Applied Myology, 13, 171–179.

Adhihetty, P J., Irrcher, I., Joseph, A M., Ljubicic, V., Hood, D A (2003) Plasticity of skeletal

muscle mitochondria in response to contractile activity Experimental Physiology, 88,

99–107.

Adhihetty, P J., Ljubicic, V., Hood, D A (2007a) Effect of chronic contractile activity on SS and

IMF mitochondrial apoptotic susceptibility in skeletal muscle American Journal of Physiology Endocrinology and Metabolism, 292, E748–E755.

Adhihetty, P J., O’Leary, M F., Chabi, B., Wicks, K L., Hood, D A (2007b) Effect of

denerva-tion on mitochondrially mediated apoptosis in skeletal muscle Journal of Applied Physiology,

102, 1143–1151.

Adhihetty, P J., O’Leary, M F., Hood, D A (2008) Mitochondria in skeletal muscle: adaptable

rheostats of apoptotic susceptibility Exercise and Sport Sciences Reviews, 36, 116–121.

Adhihetty, P J., Uguccioni, G., Leick, L., Hidalgo, J., Pilegaard, H., Hood, D A (2009) The role

of PGC-1{alpha} on mitochondrial function and apoptotic susceptibility in muscle American Journal of Physiology Cell Physiology, 297(1), C217–C225.

Allen, D L., Linderman, J K., Roy, R R., Bigbee, A J., Grindeland, R E., Mukku, V., Edgerton, V R (1997) Apoptosis: a mechanism contributing to remodeling of skeletal muscle in response to

hindlimb unweighting The American Journal of Physiology, 273, C579–C587.

Allen, D L., Roy, R R., Edgerton, V R (1999) Myonuclear domains in muscle adaptation and

disease Muscle & Nerve, 22, 1350–1360.

Alway, S E (1991) Is fiber mitochondrial volume density a good indicator of muscle fatigability

to isometric exercise? Journal of Applied Physiology, 70, 2111–2119.

Alway, S E., Siu, P M (2008) Nuclear apoptosis contributes to sarcopenia Exercise and Sport Sciences Reviews, 36, 51–57.

Alway, S E., MacDougall, J D., Sale, D G (1989) Contractile adaptations in the human triceps

surae after isometric exercise Journal of Applied Physiology, 66, 2725–2732.

Alway, S E., Coggan, A R., Sproul, M S., Abduljalil, A M., Robitaille, P M (1996) Muscle

torque in young and older untrained and endurance-trained men The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 51, B195–B201.

Alway, S E., Degens, H., Krishnamurthy, G., Smith, C A (2002a) Potential role for Id myogenic

repressors in apoptosis and attenuation of hypertrophy in muscles of aged rats American Journal of Physiology Cell Physiology, 283, C66–C76.

Alway, S E., Degens, H., Lowe, D A., Krishnamurthy, G (2002b) Increased myogenic repressor

Id mRNA and protein levels in hindlimb muscles of aged rats American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 282, R411–R422.

Alway, S E., Degens, H., Krishnamurthy, G., Chaudhrai, A (2003a) Denervation stimulates

apoptosis but not Id2 expression in hindlimb muscles of aged rats The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 58, 687–697.

Alway, S E., Martyn, J K., Ouyang, J., Chaudhrai, A., Murlasits, Z S (2003b) Id2 expression during apoptosis and satellite cell activation in unloaded and loaded quail skeletal muscles

American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 284,

R540–R549.

Antonsson, B., Montessuit, S., Lauper, S., Eskes, R., Martinou, J C (2000) Bax oligomerization

is required for channel-forming activity in liposomes and to trigger cytochrome c release from

mitochondria The Biochemical Journal, 345(Pt 2), 271–278.

Attaix, D., Ventadour, S., Codran, A., Bechet, D., Taillandier, D., Combaret, L (2005) The

ubiq-uitin-proteasome system and skeletal muscle wasting Essays in Biochemistry, 41, 173–186.

Basanez, G., Nechushtan, A., Drozhinin, O., Chanturiya, A., Choe, E., Tutt, S., Wood, K A., Hsu, Y., Zimmerberg J., Youle R.J (1999) Bax, but not Bcl-xL, decreases the lifetime of planar

phos-pholipid bilayer membranes at subnanomolar concentrations Proceedings of the National Academy of Sciences of the United States of America, 96, 5492–5497.

Benayoun, B., Baghdiguian, S., Lajmanovich, A., Bartoli, M., Daniele, N., Gicquel, E., Bourg, N., Raynaud, F., Pasquier, M A., Suel, L., Lochmuller, H., Lefranc, G., Richard, I (2008) NF-kappaB-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3,

the protein involved in limb-girdle muscular dystrophy type 2A The FASEB Journal, 22,

1521–1529.

Bernardi, P (1999) Mitochondria in muscle cell death Italian Journal of Neurological Sciences,

20, 395–400.

Bhuiyan, M S & Fukunaga, K (2007) Inhibition of HtrA2/Omi ameliorates heart dysfunction

following ischemia/reperfusion injury in rat heart in vivo European Journal of Pharmacology,

557, 168–177.

Blink, E., Maianski, N A., Alnemri, E S., Zervos, A S., Roos, D., Kuijpers, T W (2004) Intramitochondrial serine protease activity of Omi/HtrA2 is required for caspase-independent

cell death of human neutrophils Cell Death and Differentiation, 11, 937–939.

Bourdel-Marchasson, I., Biran, M., Dehail, P., Traissac, T., Muller, F., Jenn, J., Raffard, G., Franconi, J M., Thiaudiere, E (2007) Muscle phosphocreatine post-exercise recovery rate is

related to functional evaluation in hospitalized and community-living older people The Journal of Nutrition, Health & Aging, 11, 215–221.

Brack, A S & Rando, T A (2007) Intrinsic changes and extrinsic influences of myogenic stem

cell function during aging Stem Cell Reviews, 3, 226–237.

Brack, A S., Bildsoe, H., Hughes, S M (2005) Evidence that satellite cell decrement contributes

to preferential decline in nuclear number from large fibres during murine age-related muscle

atrophy Journal of Cell Science, 118, 4813–4821.

Brack, A S., Conboy, M J., Roy, S., Lee, M., Kuo, C J., Keller, C., Rando, T A (2007) Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis

Science, 317, 807–810.

Bruunsgaard, H (2002) Effects of tumor necrosis factor-alpha and interleukin-6 in elderly

popu-lations European Cytokine Network, 13, 389–391.

Bruunsgaard, H., Andersen-Ranberg, K., Jeune, B., Pedersen, A N., Skinhoj, P., Pedersen, B K (1999) A high plasma concentration of TNF-alpha is associated with dementia in

centenari-ans The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 54,

M357–M364.

Bruunsgaard, H., Pedersen, M., Pedersen, B K (2001) Aging and proinflammatory cytokines

Current Opinion in Hematology, 8, 131–136.

Bruunsgaard, H., Ladelund, S., Pedersen, A N., Schroll, M., Jorgensen, T., Pedersen, B K (2003a) Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old

people Clinical and Experimental Immunology, 132, 24–31.

Bruunsgaard, H., Andersen-Ranberg, K., Hjelmborg, J B., Pedersen, B K., Jeune, B (2003b)

Elevated levels of tumor necrosis factor alpha and mortality in centenarians The American Journal of Medicine, 115, 278–283.

Bruusgaard, J C., Liestol, K., Gundersen, K (2006) Distribution of myonuclei and microtubules

in live muscle fibers of young, middle-aged, and old mice Journal of Applied Physiology, 100,

2024–2030.

Burstein, E & Duckett, C S (2003) Dying for NF-kappaB? Control of cell death by

transcrip-tional regulation of the apoptotic machinery Current Opinion in Cell Biology, 15, 732–737.

Cacciapaglia, F., Spadaccio, C., Chello, M., Gigante, A., Coccia, R., Afeltra, A., Amoroso, A

(2009) Apoptotic molecular mechanisms implicated in autoimmune diseases European Review for Medical and Pharmacological Sciences, 13, 23–40.

Campisi, J & Sedivy, J (2009) How does proliferative homeostasis change with age? What

causes it and how does it contribute to aging? The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 64, 164–166.

Cande, C., Cecconi, F., Dessen, P., Kroemer, G (2002a) Apoptosis-inducing factor (AIF): key to

the conserved caspase-independent pathways of cell death? Journal of Cell Science, 115,

4727–4734.

Cande, C., Cohen, I., Daugas, E., Ravagnan, L., Larochette, N., Zamzami, N., Kroemer, G (2002b) Apoptosis-inducing factor (AIF): a novel caspase-independent death effector released

from mitochondria Biochimie, 84, 215–222.

Carbo, N., Busquets, S., van, R M., Alvarez, B., Lopez-Soriano, F J., Argiles, J M (2002)

TNF-alpha is involved in activating DNA fragmentation in skeletal muscle British Journal of Cancer, 86, 1012–1016.

Cartron, P F., Moreau, C., Oliver, L., Mayat, E., Meflah, K., Vallette, F M (2002) Involvement

of the N-terminus of Bax in its intracellular localization and function FEBS Letters, 512,

95–100.

Chabi, B., Ljubicic, V., Menzies, K J., Huang, J H., Saleem, A., Hood, D A (2008) Mitochondrial

function and apoptotic susceptibility in aging skeletal muscle Aging Cell, 7, 2–12.

Chakravarthy, M V., Spangenburg, E E., Booth, F W (2001) Culture in low levels of oxygen

enhances in vitro proliferation potential of satellite cells from old skeletal muscles Cellular and Molecular Life Sciences, 58, 1150–1158.

Chang, H Y & Yang, X (2000) Proteases for cell suicide: functions and regulation of caspases

Microbiology and Molecular Biology Reviews, 64, 821–846.

Chao, D T., Korsmeyer, S J (1998) BCL-2 family: regulators of cell death Annual Review of Immunology, 16, 395–419.

Chao, D T., Linette, G P., Boise, L H., White, L S., Thompson, C B., Korsmeyer, S J (1995)

Bcl-XL and Bcl-2 repress a common pathway of cell death The Journal of Experimental Medicine, 182, 821–828.

Charette, S L., McEvoy, L., Pyka, G., Snow-Harter, C., Guido, D., Wiswell, R A., Marcus, R

(1991) Muscle hypertrophy response to resistance training in older women Journal of Applied Physiology, 70, 1912–1916.