Sarcopenia Age-Related Muscle Wasting and Weakness: Mechanisms and Treatments P22 pot

196 S.E. Alway and P.M. Siu
Chipuk, J. E. & Green, D. R. (2009). PUMA cooperates with direct activator proteins to promote
mitochondrial outer membrane permeabilization and apoptosis. Cell Cycle, 8(17),
2692–2696.
Chowdhury, I., Tharakan, B., Bhat, G. K. (2008). Caspases – an update. Comparative Biochemistry
and Physiology. Part B: Biochemistry & Molecular Biology, 151, 10–27.
Combaret, L., Dardevet, D., Bechet, D., Taillandier, D., Mosoni, L., Attaix, D. (2009). Skeletal
muscle proteolysis in aging. Current Opinion in Clinical Nutrition and Metabolic Care, 12,
37–41.
Conley, K. E., Amara, C. E., Jubrias, S. A., Marcinek, D. J. (2007a). Mitochondrial function, fibre
types and ageing: new insights from human muscle in vivo. Experimental Physiology, 92,
333–339.
Conley, K. E., Jubrias, S. A., Amara, C. E., Marcinek, D. J. (2007b). Mitochondrial dysfunction:
impact on exercise performance and cellular aging. Exercise and Sport Sciences Reviews, 35,
43–49.
Conraads, V. M., Hoymans, V. Y., Vermeulen, T., Beckers, P., Possemiers, N., Maeseneer, M. D.,
Vrints, C., Martinet, W. (2009). Exercise capacity in chronic heart failure patients is related to
active gene transcription in skeletal muscle and not apoptosis. European Journal of
Cardiovascular Prevention and Rehabilitation, 16, 325–332.
Dalla, L. L., Sabbadini, R., Renken, C., Ravara, B., Sandri, M., Betto, R., Angelini, A., Vescovo, G.
(2001). Apoptosis in the skeletal muscle of rats with heart failure is associated with increased
serum levels of TNF-alpha and sphingosine. Journal of Molecular and Cellular Cardiology,
33, 1871–1878.
Dalla, L., Ravara, B., Gobbo, V., Betto, D.D., Germinario, E., Angelini, A., Evangelista, S.,
Vescovo, G. (2009). Skeletal muscle proteins oxidation in chronic right heart failure in rats:
can different beta-blockers prevent it to the same degree? International Journal of Cardiology,
143, 192–199.
Danial, N. N. & Korsmeyer, S. J. (2004). Cell death: critical control points. Cell, 116, 205–219.
Daussin, F. N., Zoll, J., Ponsot, E., Dufour, S. P., Doutreleau, S., Lonsdorfer, E., Ventura-Clapier, R.,
Mettauer, B., Piquard, F., Geny, B., Richard, R. (2008). Training at high exercise intensity
promotes qualitative adaptations of mitochondrial function in human skeletal muscle. Journal

of Applied Physiology, 104, 1436–1441.
Degens, H. (2007). Age-related skeletal muscle dysfunction: causes and mechanisms. Journal of
Musculoskeletal & Neuronal Interactions, 7, 246–252.
Degens, H. & Alway, S. E. (2003). Skeletal muscle function and hypertrophy are diminished in
old age. Muscle & Nerve, 27, 339–347.
Degens, H., Swisher, A. K., Heijdra, Y. F., Siu, P. M., Dekhuijzen, P. N., Alway, S. E. (2007).
Apoptosis and Id2 expression in diaphragm and soleus muscle from the emphysematous ham-
ster. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology,
293, R135–R144.
Degterev, A., Boyce, M., Yuan, J. (2003). A decade of caspases. Oncogene, 22, 8543–8567.
Dejean, L. M., Martinez-Caballero, S., Guo, L., Hughes, C., Teijido, O., Ducret, T., Ichas, F.,
Korsmeyer, S. J., Antonsson, B., Jonas, E. A., Kinnally, K. W. (2005). Oligomeric Bax is a
component of the putative cytochrome c release channel MAC, mitochondrial apoptosis-
induced channel. Molecular Biology of the Cell, 16, 2424–2432.
Dejean, L. M., Martinez-Caballero, S., Kinnally, K. W. (2006a). Is MAC the knife that cuts cyto-
chrome c from mitochondria during apoptosis? Cell Death and Differentiation, 13,
1387–1395.
Dejean, L. M., Martinez-Caballero, S., Manon, S., Kinnally, K. W. (2006b). Regulation of the
mitochondrial apoptosis-induced channel, MAC, by BCL-2 family proteins. Biochimica et
Biophysica Acta, 1762, 191–201.
Desagher, S. & Martinou, J. C. (2000). Mitochondria as the central control point of apoptosis.
Trends in Cell Biology, 10, 369–377.
Deschenes, M. R. & Kraemer, W. J. (2002). Performance and physiologic adaptations to resistance
training. American Journal of Physical Medicine & Rehabilitation, 81, S3–16.
197Nuclear Apoptosis and Sarcopenia
Deveraux, Q. L. & Reed, J. C. (1999). IAP family proteins–suppressors of apoptosis. Genes
Development, 13, 239–252.
Deveraux, Q. L., Roy, N., Stennicke, H. R., Van, A. T., Zhou, Q., Srinivasula, S. M., Alnemri, E. S.,
Salvesen, G. S., Reed, J. C. (1998). IAPs block apoptotic events induced by caspase 8 and
cytochrome c by direct inhibition of distinct caspases. The EMBO Journal, 17, 2215–2223.

Deveraux, Q. L., Stennicke, H. R., Salvesen, G. S., Reed, J. C. (1999). Endogenous inhibitors of
caspases. Journal of Clinical Immunology, 19, 388–398.
Dirks, A. J. & Jones, K. M. (2006). Statin-induced apoptosis and skeletal myopathy. American
Journal of Physiology. Cell Physiology, 291, C1208–C1212.
Dirks, A. & Leeuwenburgh, C. (2002). Apoptosis in skeletal muscle with aging. American Journal
of Physiology: Regulatory, Integrative and Comparative Physiology, 282, R519–R527.
Dirks, A. J. & Leeuwenburgh, C. (2004). Aging and lifelong calorie restriction result in adapta-
tions of skeletal muscle apoptosis repressor, apoptosis-inducing factor, X-linked inhibitor of
apoptosis, caspase 3, and caspase-12. Free Radical Biology & Medicine, 36, 27–39.
Dirks, A. J. & Leeuwenburgh, C. (2005). The role of apoptosis in age-related skeletal muscle
atrophy. Sports Medicine, 35, 473–483.
Dirks, A. J. & Leeuwenburgh, C. (2006). Tumor necrosis factor alpha signaling in skeletal muscle:
effects of age and caloric restriction. The Journal of Nutritional Biochemistry, 17, 501–508.
Dirks Naylor, A. J. & Leeuwenburgh, C. (2008). Sarcopenia: the role of apoptosis and modulation
by caloric restriction. Exercise and Sport Sciences Reviews, 36, 19–24.
Dirks, A. J., Hofer, T., Marzetti, E., Pahor, M., Leeuwenburgh, C. (2006). Mitochondrial DNA
mutations, energy metabolism and apoptosis in aging muscle. Ageing Research Reviews, 5,
179–195.
Duke, R. C., Ojcius, D. M., Young, J. D. (1996). Cell suicide in health and disease. Scientific
American, 275, 80–87.
Dutta, J., Fan, Y., Gupta, N., Fan, G., Gelinas, C. (2006). Current insights into the regulation of
programmed cell death by NF-kappaB. Oncogene, 25, 6800–6816.
Earnshaw, W. C., Martins, L. M., Kaufmann, S. H. (1999). Mammalian caspases: structure, activa-
tion, substrates, and functions during apoptosis. Annual Review of Biochemistry, 68,
383–424.
Ellis, R. E., Yuan, J. Y., Horvitz, H. R. (1991). Mechanisms and functions of cell death. Annual
Review of Cell Biology, 7, 663–698.
Er, E., Lalier, L., Cartron, P. F., Oliver, L., Vallette, F. M. (2007). Control of Bax homo-dimeriza-
tion by its carboxy-terminal. The Journal of Biological Chemistry, 282(34), 24938–24947.
Fan, Y., Dutta, J., Gupta, N., Fan, G., Gelinas, C. (2008). Regulation of programmed cell death by

NF-kappaB and its role in tumorigenesis and therapy. Advances in Experimental Medicine and
Biology, 615, 223–250.
Ferketich, A. K., Kirby, T. E., Alway, S. E. (1998). Cardiovascular and muscular adaptations to
combined endurance and strength training in elderly women. Acta Physiologica Scandinavica,
164, 259–267.
Figueras, M., Busquets, S., Carbo, N., Almendro, V., Argiles, J. M., Lopez-Soriano, F. J. (2005).
Cancer cachexia results in an increase in TNF-alpha receptor gene expression in both skeletal
muscle and adipose tissue. International Journal of Oncology, 27, 855–860.
Forsey, R. J., Thompson, J. M., Ernerudh, J., Hurst, T. L., Strindhall, J., Johansson, B., Nilsson, B. O.,
Wikby, A. (2003). Plasma cytokine profiles in elderly humans. Mechanisms of Ageing and
Development, 124, 487–493.
Forte, M. & Bernardi, P. (2006). The permeability transition and BCL-2 family proteins in apopto-
sis: co-conspirators or independent agents? Cell Death and Differentiation, 13, 1287–1290.
Foulstone, E. J., Meadows, K. A., Holly, J. M., Stewart, C. E. (2001). Insulin-like growth factors
(IGF-I and IGF-II) inhibit C2 skeletal myoblast differentiation and enhance TNF alpha-
induced apoptosis. Journal of Cellular Physiology, 189, 207–215.
Garcia-Martinez, C., Agell, N., Llovera, M., Lopez-Soriano, F. J., Argiles, J. M. (1993a). Tumour
necrosis factor-alpha increases the ubiquitinization of rat skeletal muscle proteins. FEBS
Letters, 323, 211–214.
198 S.E. Alway and P.M. Siu
Garcia-Martinez, C., Lopez-Soriano, F. J., Argiles, J. M. (1993b). Acute treatment with tumour
necrosis factor-alpha induces changes in protein metabolism in rat skeletal muscle. Molecular
and Cellular Biochemistry, 125, 11–18.
Garcia-Martinez, C., Llovera, M., Agell, N., Lopez-Soriano, F. J., Argiles, J. M. (1995).
Ubiquitin gene expression in skeletal muscle is increased during sepsis: involvement of
TNF-alpha but not IL-1. Biochemical and Biophysical Research Communications, 217,
839–844.
Ghosh, A. P., Walls, K. C., Klocke, B. J., Toms, R., Strasser, A., Roth, K. A. (2009). The proapop-
totic BH3-only, Bcl-2 family member, Puma is critical for acute ethanol-induced neuronal
apoptosis. Journal of Neuropathology and Experimental Neurology, 68, 747–756.

Gorman, A. M., Ceccatelli, S., Orrenius, S. (2000). Role of mitochondria in neuronal apoptosis.
Developmental Neuroscience, 22, 348–358.
Green, D. R., Kroemer, G. (2004). The pathophysiology of mitochondrial cell death. Science, 305,
626–629.
Grinberg, M., Schwarz, M., Zaltsman, Y., Eini, T., Niv, H., Pietrokovski, S., Gross, A. (2005).
Mitochondrial carrier homolog 2 is a target of tBID in cells signaled to die by tumor necrosis
factor alpha. Molecular and Cellular Biology, 25, 4579–4590.
Grutter, M. G. (2000). Caspases: key players in programmed cell death. Current Opinion in
Structural Biology, 10, 649–655.
Gustafsson, A. B., Tsai, J. G., Logue, S. E., Crow, M. T., Gottlieb, R. A. (2004). Apoptosis repres-
sor with caspase recruitment domain protects against cell death by interfering with Bax activa-
tion. The Journal of Biological Chemistry, 279, 21233–21238.
Hagen, J. L., Krause, D. J., Baker, D. J., Fu, M. H., Tarnopolsky, M. A., Hepple, R. T. (2004).
Skeletal muscle aging in F344BN F1-hybrid rats: I. Mitochondrial dysfunction contributes to
the age-associated reduction in VO2max. The Journals of Gerontology. Series A: Biological
Sciences and Medical Sciences, 59, 1099–1110.
Harman, D. (1956). Aging: a theory based on free radical and radiation chemistry. Journal of
Gerontology, 11, 298–300.
Harman, D. (1992). Role of free radicals in aging and disease. Annals of the New York Academy
of Sciences, 673, 126–141.
Harman, D. (2003). The free radical theory of aging. Antioxidants Redox Signaling, 5, 557–561.
Harman, D. (2006). Free radical theory of aging: an update: increasing the functional life span.
Annals of the New York Academy of Sciences, 1067, 10–21.
Harman, D. (2009). Origin and evolution of the free radical theory of aging: a brief personal
history, 1954–2009. Biogerontology, 10, 773–781.
Hawke, T. J. & Garry, D. J. (2001). Myogenic satellite cells: physiology to molecular biology.
Journal of Applied Physiology, 91, 534–551.
Hegde, R., Srinivasula, S. M., Zhang, Z., Wassell, R., Mukattash, R., Cilenti, L., DuBois, G.,
Lazebnik, Y., Zervos, A. S., Fernandes-Alnemri, T., Alnemri, E. S. (2002). Identification of
Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis

protein-caspase interaction. The Journal of Biological Chemistry, 277, 432–438.
Heikaus, S., Kempf, T., Mahotka, C., Gabbert, H. E., Ramp, U. (2008). Caspase 8 and its inhibi-
tors in RCCs in vivo: the prominent role of ARC. Apoptosis, 13, 938–949.
Hsu, Y. T., Wolter, K. G., Youle, R. J. (1997). Cytosol-to-membrane redistribution of Bax and
Bcl-X(L) during apoptosis. Proceedings of the National Academy of Sciences of the United
States of America, 94, 3668–3672.
Hu, A., Jiao, X., Gao, E., Li, Y., Sharifi-Azad, S., Grunwald, Z., Ma, X. L., Sun, J. Z. (2008). Tonic
beta-adrenergic drive provokes proinflammatory and proapoptotic changes in aging mouse
heart. Rejuvenation Research, 11, 215–226.
Huang, Z., Jiang, J., Tyurin, V. A., Zhao, Q., Mnuskin, A., Ren, J., Belikova, N. A., Feng, W.,
Kurnikov, I. V., Kagan, V. E. (2008). Cardiolipin deficiency leads to decreased cardiolipin
peroxidation and increased resistance of cells to apoptosis. Free Radical Biology Medicine, 44,
1935–1944.
199Nuclear Apoptosis and Sarcopenia
Irmler, M., Thome, M., Hahne, M., Schneider, P., Hofmann, K., Steiner, V., Bodmer, J. L.,
Schroter, M., Burns, K., Mattmann, C., Rimoldi, D., French, L. E., Tschopp, J. (1997).
Inhibition of death receptor signals by cellular FLIP. Nature, 388, 190–195.
Jejurikar, S. S., Marcelo, C. L., Kuzon, W. M., Jr. (2002). Skeletal muscle denervation increases
satellite cell susceptibility to apoptosis. Plastic and Reconstructive Surgery, 110, 160–168.
Jin, H., Wu, Z., Tian, T., Gu, Y. (2001). Apoptosis in atrophic skeletal muscle induced by brachial
plexus injury in rats. The Journal of Trauma, 50, 31–35.
Johnson, C. R. & Jarvis, W. D. (2004). Caspase-9 regulation: an update. Apoptosis, 9, 423–427.
Johnston, A. P., De, L. M., Parise, G. (2008). Resistance training, sarcopenia, and the mitochon-
drial theory of aging. Applied Physiology, Nutrition, and Metabolism, 33, 191–199.
Joza, N., Susin, S. A., Daugas, E., Stanford, W. L., Cho, S. K., Li, C. Y., Sasaki, T., Elia, A. J.,
Cheng, H. Y., Ravagnan, L., Ferri, K. F., Zamzami, N., Wakeham, A., Hakem, R., Yoshida, H.,
Kong, Y. Y., Mak, T. W., Zuniga-Pflucker, J. C., Kroemer, G., Penninger, J. M. (2001).
Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death.
Nature, 410, 549–554.
Joza, N., Oudit, G. Y., Brown, D., Benit, P., Kassiri, Z., Vahsen, N., Benoit, L., Patel, M. M.,

Nowikovsky, K., Vassault, A., Backx, P. H., Wada, T., Kroemer, G., Rustin, P., Penninger, J. M.
(2005). Muscle-specific loss of apoptosis-inducing factor leads to mitochondrial dysfunction,
skeletal muscle atrophy, and dilated cardiomyopathy. Molecular and Cellular Biology, 25,
10261–10272.
Jubrias, S. A., Esselman, P. C., Price, L. B., Cress, M. E., Conley, K. E. (2001). Large energetic
adaptations of elderly muscle to resistance and endurance training. Journal of Applied
Physiology, 90, 1663–1670.
Kadenbach, B., Ramzan, R., Vogt, S. (2009). Degenerative diseases, oxidative stress and cyto-
chrome c oxidase function. Trends in Molecular Medicine, 15, 139–147.
Kearns, J. D. & Hoffmann, A. (2009). Integrating computational and biochemical studies to
explore mechanisms in NF-{kappa}B signaling. The Journal of Biological Chemistry, 284,
5439–5443.
Kerr, J. F., Wyllie, A. H., Currie, A. R. (1972). Apoptosis: a basic biological phenomenon with
wide-ranging implications in tissue kinetics. British Journal of Cancer, 26, 239–257.
Knudson, C. M. & Brown, N. M. (2008). Mitochondria potential, bax “activation”, and pro-
grammed cell death. Methods in Molecular Biology, 414, 95–108.
Korolchuk, V. I., Mansilla, A., Menzies, F. M., Rubinsztein, D. C. (2009). Autophagy inhibition
compromises degradation of ubiquitin-proteasome pathway substrates. Molecular Cell, 33,
517–527.
Korsmeyer, S. J. (1995). Regulators of cell death. Trends in Genetics, 11, 101–105.
Korsmeyer, S. J. (1999). BCL-2 gene family and the regulation of programmed cell death. Cancer
Research, 59, 1693s–1700s.
Korsmeyer, S. J., Yin, X. M., Oltvai, Z. N., Veis-Novack, D. J., Linette, G. P. (1995). Reactive
oxygen species and the regulation of cell death by the Bcl-2 gene family. Biochimica et
Biophysica Acta, 1271, 63–66.
Koseki, T., Inohara, N., Chen, S., Nunez, G. (1998). ARC, an inhibitor of apoptosis expressed in
skeletal muscle and heart that interacts selectively with caspases. Proceedings of the National
Academy of Sciences of the United States of America, 95, 5156–5160.
Krajnak, K., Waugh, S., Miller, R., Baker, B., Geronilla, K., Alway, S. E., Cutlip, R. G. (2006).
Proapoptotic factor Bax is increased in satellite cells in the tibialis anterior muscles of old rats.

Muscle & Nerve, 34, 720–730.
Kroemer, G. & Reed, J. C. (2000). Mitochondrial control of cell death. Natural Medicines, 6,
513–519.
Kroemer, G., Galluzzi, L., Brenner, C. (2007). Mitochondrial membrane permeabilization in cell
death. Physiological Reviews, 87, 99–163.
Kujoth, G. C., Hiona, A., Pugh, T. D., Someya, S., Panzer, K., Wohlgemuth, S. E., Hofer, T.,
Seo, A.Y., Sullivan, R., Jobling, W. A., Morrow, J. D., Van, R. H., Sedivy, J. M., Yamasoba, T.,
200 S.E. Alway and P.M. Siu
Tanokura, M., Weindruch, R., Leeuwenburgh, C., Prolla, T. A. (2005). Mitochondrial DNA
mutations, oxidative stress, and apoptosis in mammalian aging. Science, 309, 481–484.
Kujoth, G. C., Leeuwenburgh, C., Prolla, T. A. (2006). Mitochondrial DNA mutations and apop-
tosis in mammalian aging. Cancer Research, 66, 7386–7389.
Kwak, H. B., Song, W., Lawler, J. M. (2006). Exercise training attenuates age-induced elevation
in Bax/Bcl-2 ratio, apoptosis, and remodeling in the rat heart. The FASEB Journal, 20,
791–793.
Lalier, L., Cartron, P. F., Juin, P., Nedelkina, S., Manon, S., Bechinger, B., Vallette, F. M. (2007).
Bax activation and mitochondrial insertion during apoptosis. Apoptosis, 12, 887–896.
Lanza, I. R., Short, D. K., Short, K. R., Raghavakaimal, S., Basu, R., Joyner, M. J., McConnell, J. P.,
Nair, K. S. (2008). Endurance exercise as a countermeasure for aging. Diabetes, 57(11),
2933–42.
Lee, S. C. & Pervaiz, S. (2007). Apoptosis in the pathophysiology of diabetes mellitus. The
International Journal of Biochemistry & Cell Biology, 39, 497–504.
Lee, H. C. & Wei, Y. H. (2007). Oxidative stress, mitochondrial DNA mutation, and apoptosis in
aging. Experimental Biology and Medicine (Maywood), 232, 592–606.
Lee, D. H., Rhee, J. G., Lee, Y. J. (2009). Reactive oxygen species up-regulate p53 and Puma; a
possible mechanism for apoptosis during combined treatment with TRAIL and wogonin.
British Journal of Pharmacology, 157, 1189–1202.
Lees, S. J., Zwetsloot, K. A., Booth, F. W. (2009). Muscle precursor cells isolated from aged rats
exhibit an increased tumor necrosis factor- alpha response. Aging Cell, 8, 26–35.
Leeuwenburgh, C. (2003). Role of apoptosis in sarcopenia. The Journals of Gerontology. Series

A: Biological Sciences and Medical Sciences, 58, 999–1001.
Leeuwenburgh, C., Gurley, C. M., Strotman, B. A., Dupont-Versteegden, E. E. (2005). Age-
related differences in apoptosis with disuse atrophy in soleus muscle. American Journal of
Physiology: Regulatory, Integrative and Comparative Physiology, 288, R1288–R1296.
Li, H., Zhu, H., Xu, C. J., Yuan, J. (1998). Cleavage of BID by caspase 8 mediates the mitochon-
drial damage in the Fas pathway of apoptosis. Cell, 94, 491–501.
Li, L. Y., Luo, X., Wang, X. (2001). Endonuclease G is an apoptotic DNase when released from
mitochondria. Nature, 412, 95–99.
Linke, A., Adams, V., Schulze, P. C., Erbs, S., Gielen, S., Fiehn, E., Mobius-Winkler, S., Schubert, A.,
Schuler, G., Hambrecht, R. (2005). Antioxidative effects of exercise training in patients with
chronic heart failure: increase in radical scavenger enzyme activity in skeletal muscle.
Circulation, 111, 1763–1770.
Lipton, S. A. & Bossy-Wetzel, E. (2002). Dueling activities of AIF in cell death versus survival:
DNA binding and redox activity. Cell, 111, 147–150.
li-Youcef, N., Lagouge, M., Froelich, S., Koehl, C., Schoonjans, K., Auwerx, J. (2007). Sirtuins: the
‘magnificent seven’, function, metabolism and longevity. Annali Medici, 39, 335–345.
Llovera, M., Garcia-Martinez, C., Agell, N., Lopez-Soriano, F. J., Argiles, J. M. (1997). TNF can
directly induce the expression of ubiquitin-dependent proteolytic system in rat soleus muscles.
Biochemical and Biophysical Research Communications, 230, 238–241.
Llovera, M., Garcia-Martinez, C., Agell, N., Lopez-Soriano, F. J., Authier, F. J., Gherardi, R. K.,
Argiles, J. M. (1998). Ubiquitin and proteasome gene expression is increased in skeletal
muscle of slim AIDS patients. International Journal of Molecular Medicine, 2, 69–73.
Ma, Y. S., Wu, S. B., Lee, W. Y., Cheng, J. S., Wei, Y. H. (2009). Response to the increase of
oxidative stress and mutation of mitochondrial DNA in aging. Biochimica et Biophysica Acta,
1790(10), 1021–9.
Malinska, D., Kudin, A. P., bska-Vielhaber, G., Vielhaber, S., Kunz, W. S. (2009). Chapter 23
Quantification of superoxide production by mouse brain and skeletal muscle mitochondria.
Methods in Enzymology, 456, 419–437.
Martin, C., Dubouchaud, H., Mosoni, L., Chardigny, J. M., Oudot, A., Fontaine, E., Vergely, C.,
Keriel, C., Rochette, L., Leverve, X., Demaison, L. (2007). Abnormalities of mitochondrial

functioning can partly explain the metabolic disorders encountered in sarcopenic gastrocne-
mius. Aging Cell, 6, 165–177.
201Nuclear Apoptosis and Sarcopenia
Marzetti, E., Groban, L., Wohlgemuth, S. E., Lees, H. A., Lin, M., Jobe, H., Giovannini, S.,
Leeuwenburgh, C., Carter, C. S. (2008a). Effects of short-term GH supplementation and tread-
mill exercise training on physical performance and skeletal muscle apoptosis in old rats.
American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 294,
R558–R567.
Marzetti, E., Lawler, J. M., Hiona, A., Manini, T., Seo, A. Y., Leeuwenburgh, C. (2008b).
Modulation of age-induced apoptotic signaling and cellular remodeling by exercise and calorie
restriction in skeletal muscle. Free Radical Biology & Medicine, 44, 160–168.
Marzetti, E., Wohlgemuth, S. E., Lees, H. A., Chung, H. Y., Giovannini, S., Leeuwenburgh, C.
(2008c). Age-related activation of mitochondrial caspase-independent apoptotic signaling in
rat gastrocnemius muscle. Mechanisms of Ageing and Development, 129, 542–549.
Marzetti, E., Carter, C. S., Wohlgemuth, S. E., Lees, H. A., Giovannini, S., Anderson, B., Quinn, L. S.,
Leeuwenburgh, C. (2009a). Changes in IL-15 expression and death-receptor apoptotic
signaling in rat gastrocnemius muscle with aging and life-long calorie restriction. Mechanisms
of Ageing and Development, 130, 272–280.
Marzetti, E., Hwang, J. C., Lees, H. A., Wohlgemuth, S. E., Dupont-Versteegden, E. E., Carter, C. S.,
Bernabei, R., Leeuwenburgh, C. (2009b). Mitochondrial death effectors: relevance to sarcope-
nia and disuse muscle atrophy. Biochimimica et Biophysica Acta, 1800(3), 235–244.
Mayhew, D. L., Kim, J. S., Cross, J. M., Ferrando, A. A., Bamman, M. M. (2009). Translational
signaling responses preceding resistance training-mediated myofiber hypertrophy in young
and old humans. Journal of Applied Physiology, In Press.
McCall, G. E., Allen, D. L., Linderman, J. K., Grindeland, R. E., Roy, R. R., Mukku, V. R.,
Edgerton, V. R. (1998). Maintenance of myonuclear domain size in rat soleus after overload
and growth hormone/IGF-I treatment. Journal of Applied Physiology, 84, 1407–1412.
McMullen, C. A., Ferry, A. L., Gamboa, J. L., Andrade, F. H., Dupont-Versteegden, E. E. (2009).
Age-related changes of cell death pathways in rat extraocular muscle. Experimental
Gerontology, 44(6–7), 420–425.

Meadows, K. A., Holly, J. M., Stewart, C. E. (2000). Tumor necrosis factor-alpha-induced apop-
tosis is associated with suppression of insulin-like growth factor binding protein-5 secretion
in differentiating murine skeletal myoblasts. Journal of Cellular Physiology, 183, 330–337.
Meissner, C. (2007). Mutations of mitochondrial. Zeitschrift für Gerontologie und Geriatrie, 40,
325–333.
Meissner, C., Bruse, P., Mohamed, S. A., Schulz, A., Warnk, H., Storm, T., Oehmichen, M. (2008).
The 4977 bp deletion of mitochondrial DNA in human skeletal muscle, heart and different areas
of the brain: a useful biomarker or more? Experimental Gerontology, 43, 645–652.
Melov, S., Tarnopolsky, M. A., Beckman, K., Felkey, K., Hubbard, A. (2007). Resistance exercise
reverses aging in human skeletal muscle. PLoS ONE, 2, e465.
Mikhailov, V., Mikhailova, M., Pulkrabek, D. J., Dong, Z., Venkatachalam, M. A., Saikumar, P.
(2001). Bcl-2 prevents Bax oligomerization in the mitochondrial outer membrane. The Journal
of Biological Chemistry, 276, 18361–18374.
Mikhailov, V., Mikhailova, M., Degenhardt, K., Venkatachalam, M. A., White, E., Saikumar, P.
(2003). Association of Bax and Bak homo-oligomers in mitochondria. Bax requirement for
Bak reorganization and cytochrome c release. The Journal of Biological Chemistry, 278,
5367–5376.
Molina, E. J., Gupta, D., Palma, J., Torres, D., Gaughan, J. P., Houser, S., Macha, M. (2009).
Novel experimental model of pressure overload hypertrophy in rats. The Journal of Surgical
Research, 153, 287–294.
Murray, A. J., Edwards, L. M., Clarke, K. (2007). Mitochondria and heart failure. Current Opinion
in Clinical Nutrition and Metabolic Care, 10, 704–711.
Nakagawa, T. & Yuan, J. (2000). Cross-talk between two cysteine protease families. Activation of
caspase-12 by calpain in apoptosis. The Journal of Cell Biology, 150, 887–894.
Nakagawa, T., Zhu, H., Morishima, N., Li, E., Xu, J., Yankner, B. A., Yuan, J. (2000). Caspase-12
mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature,
403, 98–103.
202 S.E. Alway and P.M. Siu
Narita, M., Shimizu, S., Ito, T., Chittenden, T., Lutz, R. J., Matsuda, H., Tsujimoto, Y. (1998). Bax
interacts with the permeability transition pore to induce permeability transition and cyto-

chrome c release in isolated mitochondria. Proceedings of the National Academy of Sciences
of the United States of America, 95, 14681–14686.
Nickson, P., Toth, A., Erhardt, P. (2007). PUMA is critical for neonatal cardiomyocyte apoptosis
induced by endoplasmic reticulum stress. Cardiovascular Research, 73, 48–56.
Parise, G. & Yarasheski, K. E. (2000). The utility of resistance exercise training and amino acid
supplementation for reversing age-associated decrements in muscle protein mass and function.
Current Opinion in Clinical Nutrition and Metabolic Care, 3, 489–495.
Parise, G., Phillips, S. M., Kaczor, J. J., Tarnopolsky, M. A. (2005). Antioxidant enzyme activity
is up-regulated after unilateral resistance exercise training in older adults. Free Radical
Biology & Medicine, 39, 289–295.
Pedersen, M., Bruunsgaard, H., Weis, N., Hendel, H. W., Andreassen, B. U., Eldrup, E., Dela, F.,
Pedersen, B. K. (2003). Circulating levels of TNF-alpha and IL-6-relation to truncal fat mass
and muscle mass in healthy elderly individuals and in patients with type-2 diabetes.
Mechanisms of Ageing and Development, 124, 495–502.
Peterson, J. M., Bryner, R. W., Sindler, A., Frisbee, J. C., Alway, S. E. (2008). Mitochondrial
apoptotic signaling is elevated in cardiac but not skeletal muscle in the obese Zucker rat and
is reduced with aerobic exercise. Journal of Applied Physiology, 105, 1934–1943.
Phaneuf, S. & Leeuwenburgh, C. (2002). Cytochrome c release from mitochondria in the aging
heart: a possible mechanism for apoptosis with age. American Journal of Physiology:
Regulatory, Integrative and Comparative Physiology, 282, R423–R430.
Phelan, J. N. & Gonyea, W. J. (1997). Effect of radiation on satellite cell activity and protein expres-
sion in overloaded mammalian skeletal muscle. The Anatomical Record, 247, 179–188.
Phillips, T. & Leeuwenburgh, C. (2005). Muscle fiber specific apoptosis and TNF-alpha signaling
in sarcopenia are attenuated by life-long calorie restriction. The FASEB Journal, 19,
668–670.
Pistilli, E. E. & Alway, S. E. (2008). Systemic elevation of interleukin-15 in vivo promotes apop-
tosis in skeletal muscles of young adult and aged rats. Biochemical and Biophysical Research
Communications, 373, 20–24.
Pistilli, E. E., Jackson, J. R., Alway, S. E. (2006a). Death receptor-associated pro-apoptotic signal-
ing in aged skeletal muscle. Apoptosis, 11, 2115–2126.

Pistilli, E. E., Siu, P. M., Alway, S. E. (2006b). Molecular regulation of apoptosis in fast plantaris
muscles of aged rats. The Journals of Gerontology. Series A: Biological Sciences and Medical
Sciences, 61, 245–255.
Pistilli, E. E., Siu, P. M., Alway, S. E. (2007). Interleukin-15 responses to aging and unloading-
induced skeletal muscle atrophy. American Journal of Physiology. Cell Physiology, 292,
C1298–C1304.
Podhorska-Okolow, M., Sandri, M., Zampieri, S., Brun, B., Rossini, K., Carraro, U. (1998).
Apoptosis of myofibres and satellite cells: exercise-induced damage in skeletal muscle of the
mouse. Neuropathology and Applied Neurobiology, 24, 518–531.
Podhorska-Okolow, M., Krajewska, B., Carraro, U., Zabel, M. (1999). Apoptosis in mouse
skeletal muscles after physical exercise. Folia Histochemica et Cytobiologica, 37,
127–128.
Pollack, M., Phaneuf, S., Dirks, A., Leeuwenburgh, C. (2002). The role of apoptosis in the normal
aging brain, skeletal muscle, and heart. Annals of the New York Academy of Sciences, 959,
93–107.
Precht, T. A., Phelps, R. A., Linseman, D. A., Butts, B. D., Le, S. S., Laessig, T. A., Bouchard, R.J.,
Heidenreich, K. A. (2005). The permeability transition pore triggers Bax translocation to
mitochondria during neuronal apoptosis. Cell Death and Differentiation, 12, 255–265.
Primeau, A. J., Adhihetty, P. J., Hood, D. A. (2002). Apoptosis in heart and skeletal muscle.
Canadian Journal of Applied Physiology, 27, 349–395.
Rasola, A. & Bernardi, P. (2007). The mitochondrial permeability transition pore and its involve-
ment in cell death and in disease pathogenesis. Apoptosis, 12, 815–833.
203Nuclear Apoptosis and Sarcopenia
Reed, J. C. (1997). Double identity for proteins of the Bcl-2 family. Nature, 387, 773–776.
Reed, J. C. (2006). Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiolog-
ical roles, and therapeutic opportunities. Cell Death and Differentiation, 13, 1378–1386.
Reed, J. C., Jurgensmeier, J. M., Matsuyama, S. (1998). Bcl-2 family proteins and mitochondria.
Biochimica et Biophysica Acta, 1366, 127–137.
Renault, V., Thornell, L. E., Butler-Browne, G., Mouly, V. (2002). Human skeletal muscle satellite
cells: aging, oxidative stress and the mitotic clock. Experimental Gerontology, 37, 1229–1236.

Ricci, C., Pastukh, V., Mozaffari, M., Schaffer, S. W. (2007). Insulin withdrawal induces apoptosis
via a free radical-mediated mechanism. Canadian Journal of Physiology and Pharmacology,
85, 455–464.
Roman, W. J., Fleckenstein, J., Stray-Gundersen, J., Alway, S. E., Peshock, R., Gonyea, W. J.
(1993). Adaptations in the elbow flexors of elderly males after heavy- resistance training.
Journal of Applied Physiology, 74, 750–754.
Rosenblatt, J. D., Yong, D., Parry, D. J. (1994). Satellite cell activity is required for hypertrophy
of overloaded adult rat muscle. Muscle & Nerve, 17, 608–613.
Ryan, M. J., Dudash, H. J., Docherty, M., Geronilla, K. B., Baker, B. A., Haff, G. G., Cutlip, R. G.,
Alway, S. E. (2008). Aging-dependent regulation of antioxidant enzymes and redox status in
chronically loaded rat dorsiflexor muscles. The Journals of Gerontology. Series A: Biological
Sciences and Medical Sciences, 63, 1015–1026.
Salvesen, G. S. & Duckett, C. S. (2002). IAP proteins: blocking the road to death’s door. Nature
Reviews. Molecular Cell Biology, 3, 401–410.
Sandmand, M., Bruunsgaard, H., Kemp, K., Andersen-Ranberg, K., Schroll, M., Jeune, B. (2003).
High circulating levels of tumor necrosis factor-alpha in centenarians are not associated with
increased production in T lymphocytes. Gerontology, 49, 155–160.
Sandri, M., Podhorska-Okolow, M., Geromel, V., Rizzi, C., Arslan, P., Franceschi, C., Carraro, U.
(1997). Exercise induces myonuclear ubiquitination and apoptosis in dystrophin- deficient
muscle of mice. Journal of Neuropathology and Experimental Neurology, 56, 45–57.
Sanna, M. G., da Silva, C. J., Ducrey, O., Lee, J., Nomoto, K., Schrantz, N., Deveraux, Q. L.,
Ulevitch, R. J. (2002). IAP suppression of apoptosis involves distinct mechanisms: the TAK1/
JNK1 signaling cascade and caspase inhibition. Molecular and Cellular Biology, 22,
1754–1766.
Schaap, L. A., Pluijm, S. M., Deeg, D. J., Visser, M. (2006). Inflammatory markers and loss of
muscle mass (sarcopenia) and strength. The American Journal of Medicine, 119, 526–17.
Schaap, L. A., Pluijm, S. M., Deeg, D. J., Harris, T. B., Kritchevsky, S. B., Newman, A. B.,
Colbert, L. H., Pahor, M., Rubin, S. M., Tylavsky, F. A., Visser, M. (2009). Higher
Inflammatory Marker Levels in Older Persons: Associations With 5-Year Change in Muscle
Mass and Muscle Strength. The Journals of Gerontology. Series A: Biological Sciences and

Medical Sciences, 64A(11), 1183–1189.
Schultz, E. (1989). Satellite cell behavior during skeletal muscle growth and regeneration.
Medicine and Science in Sports and Exercise, 21, S181–S186.
Schultz, E. (1996). Satellite cell proliferative compartments in growing skeletal muscles.
Developmental Biology, 175, 84–94.
Schultz, E., McCormick, K. M. (1994). Skeletal muscle satellite cells. Reviews of Physiology
Biochemistry and Pharmacology, 123, 213–257.
Senoo-Matsuda, N., Hartman, P. S., Akatsuka, A., Yoshimura, S., Ishii, N. (2003). A complex II
defect affects mitochondrial structure, leading to ced-3- and ced-4-dependent apoptosis and
aging. The Journal of Biological Chemistry, 278, 22031–22036.
Seo, A. Y., Xu, J., Servais, S., Hofer, T., Marzetti, E., Wohlgemuth, S. E., Knutson, M. D., Chung,
H. Y., Leeuwenburgh, C. (2008). Mitochondrial iron accumulation with age and functional con-
sequences. Aging Cell, 7, 706–716.
Shi, Y. (2002a). Apoptosome: the cellular engine for the activation of caspase-9. Structure, 10,
285–288.
Shi, Y. (2002b). Mechanisms of caspase activation and inhibition during apoptosis. Molecular
Cell, 9, 459–470.
204 S.E. Alway and P.M. Siu
Shi, Y. (2004). Caspase activation, inhibition, and reactivation: a mechanistic view. Protein
Science, 13, 1979–1987.
Shih, V. F., Kearns, J. D., Basak, S., Savinova, O. V., Ghosh, G., Hoffmann, A. (2009). Kinetic
control of negative feedback regulators of NF-kappaB/RelA determines their pathogen- and
cytokine-receptor signaling specificity. Proceedings of the National Academy of Sciences of
the United States of America, 106, 9619–9624.
Shimizu, S., Narita, M., Tsujimoto, Y. (1999). Bcl-2 family proteins regulate the release of
apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature, 399, 483–487.
Shiozaki, E. N., Chai, J., Shi, Y. (2002). Oligomerization and activation of caspase-9, induced by
Apaf-1 CARD. Proceedings of the National Academy of Sciences of the United States of
America, 99, 4197–4202.
Shiozaki, E. N. & Shi, Y. (2004). Caspases, IAPs and Smac/DIABLO: mechanisms from struc-

tural biology. Trends in Biochemical Sciences, 29, 486–494.
Siu, P. M. & Alway, S. E. (2005a). Id2 and p53 participate in apoptosis during unloading-induced
muscle atrophy. American Journal of Physiology. Cell Physiology, 288, C1058–C1073.
Siu, P. M. & Alway, S. E. (2005b). Mitochondria-associated apoptotic signalling in denervated rat
skeletal muscle. Journal de Physiologie, 565, 309–323.
Siu, P. M. & Alway, S. E. (2006a). Aging alters the reduction of pro-apoptotic signaling in
response to loading-induced hypertrophy. Experimental Gerontology, 41, 175–188.
Siu, P. M. & Alway, S. E. (2006b). Deficiency of the Bax gene attenuates denervation-induced
apoptosis. Apoptosis, 11, 967–981.
Siu, P. M. & Alway, S. E. (2009). Response and adaptation of skeletal muscle to denervation
stress: the role of apoptosis in muscle loss. Frontiers in Bioscience, 14, 432–452.
Siu, P. M., Bryner, R. W., Martyn, J. K., Alway, S. E. (2004). Apoptotic adaptations from exercise
training in skeletal and cardiac muscles. The FASEB Journal, 18, 1150–1152.
Siu, P. M., Bryner, R. W., Murlasits, Z., Alway, S. E. (2005a). Response of XIAP, ARC, and FLIP
apoptotic suppressors to 8 wk of treadmill running in rat heart and skeletal muscle. Journal of
Applied Physiology, 99, 204–209.
Siu, P. M., Pistilli, E. E., Alway, S. E. (2005b). Apoptotic responses to hindlimb suspension in
gastrocnemius muscles from young adult and aged rats. American Journal of Physiology:
Regulatory, Integrative and Comparative Physiology, 289, R1015–R1026.
Siu, P. M., Pistilli, E. E., Butler, D. C., Alway, S. E. (2005c). Aging influences cellular and
molecular responses of apoptosis to skeletal muscle unloading. American Journal of
Physiology. Cell Physiology, 288, C338–C349.
Siu, P. M., Pistilli, E. E., Ryan, M. J., Alway, S. E. (2005d). Aging sustains the hypertrophy-
associated elevation of apoptotic suppressor X-linked inhibitor of apoptosis protein (XIAP) in
skeletal muscle during unloading. The Journals of Gerontology. Series A: Biological Sciences
and Medical Sciences, 60, 976–983.
Siu, P. M., Pistilli, E. E., Murlasits, Z., Alway, S. E. (2006). Hindlimb unloading increases muscle
content of cytosolic but not nuclear Id2 and p53 proteins in young adult and aged rats. Journal
of Applied Physiology, 100, 907–916.
Siu, P. M., Bae, S., Bodyak, N., Rigor, D. L., Kang, P. M. (2007). Response of caspase-indepen-

dent apoptotic factors to high salt diet-induced heart failure. Journal of Molecular and Cellular
Cardiology, 42, 678–686.
Siu, P. M., Pistilli, E. E., Alway, S. E. (2008). Age-dependent increase in oxidative stress in gas-
trocnemius muscle with unloading. Journal of Applied Physiology, 105, 1695–1705.
Smith, M. I., Huang, Y. Y., Deshmukh, M. (2009). Skeletal muscle differentiation evokes endog-
enous XIAP to restrict the apoptotic pathway. PLoS ONE, 4, e5097.
Song, W., Kwak, H. B., Lawler, J. M. (2006). Exercise training attenuates age-induced changes
in apoptotic signaling in rat skeletal muscle. Antioxidants Redox Signaling, 8, 517–528.
Spierings, D., McStay, G., Saleh, M., Bender, C., Chipuk, J., Maurer, U., Green, D. R. (2005).
Connected to death: the (unexpurgated) mitochondrial pathway of apoptosis. Science, 310, 66–67.
Sprick, M. R. & Walczak, H. (2004). The interplay between the Bcl-2 family and death receptor-
mediated apoptosis. Biochimica et Biophysica Acta, 1644, 125–132.
205Nuclear Apoptosis and Sarcopenia
Stennicke, H. R. & Salvesen, G. S. (1999). Catalytic properties of the caspases. Cell Death and
Differentiation, 6, 1054–1059.
Stennicke, H. R., Deveraux, Q. L., Humke, E. W., Reed, J. C., Dixit, V. M., Salvesen, G. S. (1999).
Caspase-9 can be activated without proteolytic processing. The Journal of Biological
Chemistry, 274, 8359–8362.
Stewart, C. E., Newcomb, P. V., Holly, J. M. (2004). Multifaceted roles of TNF-alpha in myoblast
destruction: a multitude of signal transduction pathways. Journal of Cellular Physiology, 198,
237–247.
Sulston, J. E. & Horvitz, H. R. (1977). Post-embryonic cell lineages of the nematode, Caenorhabditis
elegans. Developmental Biology, 56, 110–156.
Sun, X. M., MacFarlane, M., Zhuang, J., Wolf, B. B., Green, D. R., Cohen, G. M. (1999). Distinct
caspase cascades are initiated in receptor-mediated and chemical-induced apoptosis. The
Journal of Biological Chemistry, 274, 5053–5060.
Suzuki, Y., Takahashi-Niki, K., Akagi, T., Hashikawa, T., Takahashi, R. (2004). Mitochondrial
protease Omi/HtrA2 enhances caspase activation through multiple pathways. Cell Death and
Differentiation, 11, 208–216.
Tamilselvan, J., Jayaraman, G., Sivarajan, K., Panneerselvam, C. (2007). Age-dependent upregu-

lation of p53 and cytochrome c release and susceptibility to apoptosis in skeletal muscle fiber
of aged rats: role of carnitine and lipoic acid. Free Radical Biology & Medicine, 43,
1656–1669.
Tang, D., Lahti, J. M., Kidd, V. J. (2000). Caspase 8 activation and bid cleavage contribute to
MCF7 cellular execution in a caspase 3-dependent manner during staurosporine-mediated
apoptosis. The Journal of Biological Chemistry, 275, 9303–9307.
Tarnopolsky, M. A. (2009). Mitochondrial DNA shifting in older adults following resistance exer-
cise training. Applied Physiology, Nutrition, and Metabolism, 34, 348–354.
Tews, D. S. (2005). Muscle-fiber apoptosis in neuromuscular diseases. Muscle & Nerve, 32,
443–458.
Thompson, C. B. (1995). Apoptosis in the pathogenesis and treatment of disease. Science, 267,
1456–1462.
Tsujimoto, Y. & Shimizu, S. (2000). VDAC regulation by the Bcl-2 family of proteins. Cell Death
and Differentiation, 7, 1174–1181.
Tsujimoto, Y., Nakagawa, T., Shimizu, S. (2006). Mitochondrial membrane permeability transi-
tion and cell death. Biochimica et Biophysica Acta, 1757, 1297–1300.
Vallabhapurapu, S. & Karin, M. (2009). Regulation and function of NF-kappaB transcription fac-
tors in the immune system. Annual Review of Immunology, 27, 693–733.
Vescovo, G. & Dalla, L. L. (2006). Skeletal muscle apoptosis in experimental heart failure: the
only link between inflammation and skeletal muscle wastage? Current Opinion in Clinical
Nutrition and Metabolic Care, 9, 416–422.
Vescovo, G., Volterrani, M., Zennaro, R., Sandri, M., Ceconi, C., Lorusso, R., Ferrari, R.,
Ambrosio, G. B., Dalla, L. L. (2000). Apoptosis in the skeletal muscle of patients with heart
failure: investigation of clinical and biochemical changes. Heart, 84, 431–437.
Visser, M., Pahor, M., Taaffe, D. R., Goodpaster, B. H., Simonsick, E. M., Newman, A. B., Nevitt, M.,
Harris, T. B. (2002). Relationship of interleukin-6 and tumor necrosis factor-alpha with
muscle mass and muscle strength in elderly men and women: the Health ABC Study. The
Journals of Gerontology. Series A: Biological Sciences and Medical Sciences, 57,
M326–M332.
Wajant, H. (2009). The role of TNF in cancer. Results and Problems in Cell Differentiation, 49,

1–15.
Wajant, H., Pfizenmaier, K., Scheurich, P. (2003). Tumor necrosis factor signaling. Cell Death and
Differentiation, 10, 45–65.
Wang, W., Fang, H., Groom, L., Cheng, A., Zhang, W., Liu, J., Wang, X., Li, K., Han, P., Zheng, M.,
Yin, J., Wang, W., Mattson, M. P., Kao, J. P., Lakatta, E. G., Sheu, S. S., Ouyang, K., Chen, J.,
Dirksen, R. T., Cheng, H. (2008). Superoxide flashes in single mitochondria. Cell, 134,
279–290.