Sarcopenia Age-Related Muscle Wasting and Weakness: Mechanisms and Treatments P35 potx

326 A. McArdle and M.J. Jackson
8 Future Directions
In the light of these data we hypothesise that attenuation of the adaptive responses
to contractions is a key factor leading to age-related loss of muscle mass and func-
tion; ROS generated during contractions are important stimulators of adaptive
responses and they originate from a source associated with the cytosol; Mitochondria
release increased amounts of hydrogen peroxide and the resulting chronic oxidation
blocks the normal adaptations to contractile activity through either: (1) inducing
upregulation of ROS defence systems (SODs, catalase and HSPs) that suppress the
cytosolic ROS signal that normally stimulates adaptive responses to contractions or
(2) preventing activation of the cytosol-associated ROS generating system that are
activated by contractions.
Targeted interventions to suppress mitochondrial H2O2 generation are necessary
to restore adaptive responses to contractions in old mice since interventions based
on antioxidant supplementation will suppress ROS signals in both mitochondrial
and cytosolic compartments and hence be ineffective at prevention of age-related
changes.
Acknowledgements The authors would like to thank The Biotechnology and Biological
Sciences Research Council, The Medical Research Council, The Wellcome Trust, Research into
Ageing, The United States National Institutes on Aging (PO1, AG20591) and The Dowager
Countess Eleanor Peel Trust for financial support and current and past collaborators.
References
Ammirante, M., Rosati, A., Gentilella, A., Festa, M., Petrella, A., Marzullo, L., Pascale, M.,
Belisario, M. A., Leone, A., Turco, M. C. (2008). The activity of hsp90 alpha promoter is regu-
lated by NF-kappa B transcription factors. Oncogene, 27, 1175–1178.
Bakkar, N., Wang, J., Ladner, K. J., Wang, H., Dahlman, J. M., Carathers, M., Acharyya, S.,
Rudnicki, M. A., Hollenbach, A. D., Guttridge, D. C. (2008). IKK/NF-kappaB regulates skel-
etal myogenesis via a signaling switch to inhibit differentiation and promote mitochondrial
biogenesis. The Journal of Cell Biology, 180, 787–802.
Balon, T. W. & Nadler, J. L. (1994). Nitric oxide release is present from incubated skeletal muscle
preparations. Journal of Applied Physiology, 77(6), 2519–2521.

Bar-Shai, M., Carmeli, E., Reznick, A. Z. (2005). The role of NF-kappaB in protein breakdown
in immobilization, aging, and exercise: from basic processes to promotion of health. Annals of
the New York Academy of Sciences, 1057, 431–447.
Broome, C. S., Kayani, A. C., Palomero, J., Dillmann, W. H., Mestril, R., Jackson, M. J., McArdle, A.
(2006). Effect of lifelong overexpression of HSP70 in skeletal muscle on age-related oxidative
stress and adaptation after nondamaging contractile activity. The FASEB Journal, 20, 1549–1551.
Chen, Y. & Currie, R. W. (2006). Small interfering RNA knocks down heat shock factor-1 (HSF-
1) and exacerbates pro-inflammatory activation of NF- B and AP-1 in vascular smooth muscle
cells. Cardiovascular Research, 69, 66–75.
Chen, Y., Arrigo, A. P., Currie, R. W. (2004). Heat shock treatment suppresses Angiotensin
II-induced activation of NF- B pathway and heart inflammation: a role for IKK depletion by
heat shock? The American Journal of Physiology, 287, H1104–H1114.
327Reactive Oxygen Species Generation and Skeletal Muscle Wasting – Implications
Cotto, J. J. & Morimoto, R. I. (1999). Stress-induced activation of the heat-shock response: cell
and molecular biology of heat-shock factors. Biochemical Society Symposia, 64, 105–118.
Cuthbertson, D., Smith, K., Babraj, J., Leese, G., Waddell, T., Atherton, P., Wackerhage, H.,
Taylor, P. M., Rennie, M. J. (2005). Anabolic signaling deficits underlie amino acid resistance
of wasting, aging muscle. The FASEB Journal, 19, 422–424.
Dahlman, J. M., Wang, J., Bakkar, N., Guttridge, D. C. (2009). The RelA/p65 subunit of
NF-kappaB specifically regulates cyclin D1 protein stability: implications for cell cycle with-
drawal and skeletal myogenesis. Journal of Cellular Biochemistry, 106, 42–51.
Davies, K. J., Quintanilha, A. T., Brooks, G. A., Packer, L. (1982). Free radicals and tissue damage
produced by exercise. Biochemical and Biophysical Research Communications, 107,
1198–1205.
Demirel, H. A., Hamilton, K. L., Shanely, R. A., Tümer, N., Koroly, M. J., Powers, S. K. (2003).
Age and attenuation of exercise-induced myocardial HSP72 accumulation. American Journal
of Physiology. Heart and Circulatory Physiology, 285, H1609–H1615.
Drew, B., Phaneuf, S., Dirks, A., Selman, C., Gredilla, R., Lezza, A., Barja, G., Leeuwenburgh, C.
(2003). Effects of aging and caloric restriction on mitochondrial energy production in gastroc-
nemius muscle and heart. The American Journal of Physiology, 284, R474–R480.

Faulkner, J. A., Larkin, L. M., Claflin, D. R., Brooks, S. V. (2007). Age-related changes in the
structure and function of skeletal muscles. Clinical and Experimental Pharmacology and
Physiology, 34, 1091–1096.
Febbraio, M. A. & Pedersen, B. K. (2005). Contraction-induced myokine production and release:
is skeletal muscle an endocrine organ? Exercise and Sport Sciences Reviews, 33, 114–119.
Gomez-Cabrera, M. C., Domenech, E., Romagnoli, M., Arduini, A., Borras, C., Pallardo, F. V.,
Sastre, J. Viña-Ribes, J. (2008). Oral administration of vitamin C decreases muscle mitochon-
drial biogenesis and hampers training-induced adaptations in endurance performance.
American Journal of Clinical and Nutrition, 87, 142–149.
Grimby, G. & Saltin, B. (1983). The ageing muscle. Clinical Physiology, 3, 209–218.
Guzhova, I. V., Darieva, Z. A., Melo, A. R., Margulis, B. A. (1997). Major stress protein Hsp70
interacts with NF- B regulatory complex in human T-lymphoma cells. Cell Stress and
Chaperones, 2, 132–139.
Hadley, E. C., Ory, M. G., Suzman, R., Weindruch, R., Fried, L. (1993). Physical frailty: A treat-
able cause of dependence in old age. Journal of Gerontology, 48, 1–88.
Hansen, J. M., Zhang, H., Jones, D. P. (2006). Mitochondrial thioredoxin-2 has a key role in
determining tumor necrosis factor-alpha-induced reactive oxygen species generation,
NF-kappaB activation, and apoptosis. Toxicological Sciences, 91, 643–650.
Harman, D. (1956). Aging: a theory based on free radical and radiation chemistry. Journal of
Gerontology, 11, 298–300.
Harman, D. (2003). The free radical theory of aging. Antioxidants Redox Signaling, 5, 557–561.
Hayden, M. S. & Ghosh, S. (2008). Shared principles in NF-kappaB signalling. Cell, 132, 344–362.
Heinzel, B., John, M., Klatt, P., Bohme, E., Mayer, B. (1992). Ca2+/calmodulin-dependent forma-
tion of hydrogen peroxide by brain nitric oxide synthase. The Biochemical Journal, 281,
627–630.
Heydari, A. R., You, S., Takahashi, R., Gutsmann-Conrad, A., Sarge, K. D., Richardson, A.
(2000). Age-related alterations in the activation of heat shock transcription factor 1 in rat
hepatocytes. Experimental Cell Research, 256, 83–93.
Hollander, J. M., Lin, K. M., Scott, B. T., Dillmann, W. H. (2003). Overexpression of PHGPx and
HSP60/10 protects against ischemia/reoxygenation injury. Free Radical Biology and Medicine,

35, 742–751.
Hosokawa, N., Takechi, H., Yokota, S., Hirayoshi, K., Nagata, K. (1993). Structure of the gene
encoding the mouse 47-kDa heat-shock protein (HSP47). Gene, 126, 187–193.
Irrcher, I., Ljubicic, V., Hood, D. A. (2009). Interactions between ROS and AMP kinase activity
in the regulation of PGC-1alpha transcription in skeletal muscle cells. American Journal of
Physiology. Cell Physiology, 296, C116–C123.
328 A. McArdle and M.J. Jackson
Jackson, M. J. (2005). Reactive oxygen species and redox-regulation of skeletal muscle adaptations
to exercise. Philosophical Transactions of the Royal Society of London. Series B: Biological
Sciences, 360(1464), 2285–2291.
Jackson, M. J. (2008). Redox regulation of skeletal muscle. IUBMB Life, 60(8), 497–501.
Jackson, M. J., Jones, D. A., Edwards, R. H. (1983). Vitamin E and skeletal muscle. Ciba
Foundation Symposium, 101, 224–239.
Jackson, M. J., Papa, S., Bolaños, J., Bruckdorfer, R., Carlsen, H., Elliott, R. M., Flier, J.,
Griffiths, H. R., Heales, S., Holst, B., Lorusso, M., Lund, E., Øivind Moskaug, J., Moser, U.,
Di Paola, M., Polidori, M. C., Signorile, A., Stahl, W., Viña-Ribes, J., Astley, S. B. (2002).
Antioxidants, reactive oxygen and nitrogen species, gene induction and mitochondrial
function. Molecular Aspects of Medicine, 23, 209–285.
Ji, L. L., Gomez-Cabrera, M. C., Vina, J. (2006). Exercise and hormesis: activation of cellular
antioxidant signaling pathway. Annals of the New York Academy of Sciences, 1067,
425–435.
Kayani, A. C., Close, G. L., Broome, C. S., Jackson, M. J., McArdle, A. (2008). Enhanced recov-
ery from contraction-induced damage in skeletal muscles of old mice following treatment with
the heat shock protein inducer 17-(allylamino)-17-demethoxygeldanamycin. Rejuvenation
Research, 11, 1021–1030.
Kayani, A. C., Close, G. L., Jackson, M. J., McArdle, A. (2008). Prolonged treadmill training
increases HSP70 in skeletal muscle but does not affect age-related functional deficits. American
Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 294, R568–R576.
Khassaf, M., Child, R. B., McArdle, A., Brodie, D. A., Esanu, C., Jackson, M. J. (2001). Time
course of responses of human skeletal muscle to oxidative stress induced by nondamaging

exercise. Journal of Applied Physiology, 90, 1031–1035.
Kobzik, L., Reid, M. B., Bredt, D. S., Stamler, J. S. (1994). Nitric oxide in skeletal muscle. Nature,
372(6506), 546–548.
Lass, A., Sohal, B. H., Weindruch, R., Forster, M. J., Sohal, R. S. (1998). Caloric restriction pre-
vents age-associated accrual of oxidative damage to mouse skeletal muscle mitochondria. Free
Radical Biology and Medicine, 25, 1089–1097.
Lee, S., Shin, H. S., Shireman, P. K., Vasilaki, A., Van Remmen, H., Csete, M. E. (2006).
Glutathione-peroxidase-1 null muscle progenitor cells are globally defective. Free Radical
Biology and Medicine, 41(7), 1174–1184.
Lee, C. E., McArdle, A., Griffiths, R. D. (2007). The role of hormones, cytokines and heat shock
proteins during age-related muscle loss. Clinical Nutrition, 26, 524–534.
Ljubicic, V. & Hood, D. A. (2008). Kinase-specific responsiveness to incremental contractile
activity in skeletal muscle with low and high mitochondrial content. American Journal of
Physiology. Endocrinology and Metabolism, 295, E195–E204.
Locke, M. & Tanguay, R. M. (1996). Diminished heat shock response in the aged myocardium.
Cell Stress and Chaperones, 1(4), 251–260.
Mansouri, A., Muller, F. L., Liu, Y., Ng, R., Faulkner, J., Hamilton, M., Richardson, A., Huang,
T. T., Epstein, C. J., Van Remmen, H. (2006). Alterations in mitochondrial function, hydro-
gen peroxide release and oxidative damage in mouse hind-limb skeletal muscle during
aging. Mechanisms of Ageing and Development, 127, 298–306.
Marcell, T. J. (2003). Sarcopenia: causes, consequences, and preventions. The Journals of
Gerontology. Series A: Biological Sciences and Medical Sciences, 58, M911–M916.
McArdle, A., Pattwell, D., Vasilaki, A., Griffiths, R. D., Jackson, M. J. (2001). Contractile activ-
ity-induced oxidative stress: cellular origin and adaptive responses. American Journal of
Physiology (Cell), 280, C621–C627.
McArdle, F., Spiers, S., Aldemir, H., Vasilaki, A., Beaver, A., Iwanejko, L., McArdle, A., Jackson, M. J.
(2004a). Preconditioning of skeletal muscle against contraction-induced damage: the role of
adaptations to oxidants in mice. Journal de Physiologie, 561, 233–244.
McArdle, A., Dillmann, W. H., Mestril, R., Faulkner, J. A., Jackson, M. J. (2004b). Overexpression
of HSP70 in mouse skeletal muscle protects against muscle damage and age-related muscle

dysfunction. The FASEB Journal, 18, 355–357.
329Reactive Oxygen Species Generation and Skeletal Muscle Wasting – Implications
McArdle, A., Broome, C. S., Kayani, A. C., Tully, M. D., Close, G. L., Vasilaki, A., Jackson, M. J.
(2006). HSF expression in skeletal muscle during myogenesis: implications for failed
regeneration in old mice. Experimental Gerontology, 41, 497–500.
McArdle, F., Pattwell, D. M., Vasilaki, A., McArdle, A., Jackson, M. J. (2005).Intracellular generation
of reactive oxygen species by contracting muscle cells. Free Radial Biology and Medicine, 39,
651–657.
Moran, L. K., Gutteridge, J. M., Quinlan, G. J. (2001). Thiols in cellular redox signalling and
control. Current Medicinal Chemistry, 8(7), 763–772.
Morton, J. P., Maclaren, D. P., Cable, N. T., Campbell, I. T., Evans, L., Bongers, T., Griffiths, R. D.,
Kayani, A. C., McArdle, A., Drust, B. (2007). Elevated core and muscle temperature to levels
comparable to exercise do not increase heat shock protein content of skeletal muscle of physi-
cally active men. Acta Physiologica (Oxford), 190(4), 319–327.
Morton, J. P., Maclaren, D. P., Cable, N. T., Campbell, I. T., Evans, L., Kayani, A. C., McArdle, A.,
Drust, B. (2008). Trained men display increased Basal heat shock protein content of skeletal
muscle. Medicine and Science in Sports and Exercise, 40(7), 1255–1262.
Morse, C. I., Thom, J. M., Reeves, N. D., Birch, K. M., Narici, M. V. (2005). In vivo physiological
cross-sectional area and specific force are reduced in the gastrocnemius of elderly men.
Journal of Applied Physiology, 99, 1050–1055.
Muller, F. L., Song, W., Jang, Y. C., Liu, Y., Sabia, M., Richardson, A., Van Remmen, H. (2007).
Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS
production. American Journal of Physiology: Regulatory, Integrative and Comparative
Physiology, 293, R1159–R1168.
Muramatsu, T., Hatoko, M., Tada, H., Shirai, T., Ohnishi, T. (1996). Age-related decrease in the
inductability of heat shock protein 72 in normal human skin. The British Journal of
Dermatology, 134, 1035–1038.
O’Neill, C. A., Stebbins, C. L., Bonigut, S., Halliwell, B., Longhurst, J. C. (1996). Production of
hydroxyl radicals in contracting skeletal muscle of cats. Journal of Applied Physiology, 81(3),
1197–1206.

Palomero, J., Pye, D., Kabayo, T., Spiller, D. G., Jackson, M. J. (2008a). In situ detection and
measurement of intracellular reactive oxygen species in single isolated mature skeletal mus-
cle fibers by real time fluorescence microscopy. Antioxidants Redox Signaling, 10,
1463–1474.
Palomero, J., Broome, C. S., Rasmussen, P., Mohr, M., Nielsen, B., Nybo, L., McArdle, A., Drust, B.
(2008b). Heat shock factor activation in human muscles following a demanding intermittent
exercise protocol is attenuated with hyperthermia. Acta Physiologica (Oxford), 193(1),
79–88.
Palomero, J., Jackson, M.J. (2010). Redox regulation in skeletal muscle during contractile activity
and aging. Journal of Animal Science, 88, 1307–1313.
Park, K. J., Gaynor, R. B., Kwak, Y. T. (2003). Heat shock protein 27 association with the I kappa
B kinase complex regulates tumor necrosis factor alpha-induced NF-kappa B activation. The
Journal of Biological Chemistry, 278, 35272–35278.
Pattwell, D. M., McArdle, A., Morgan, J. E., Patridge, T. A., Jackson, M. J. (2004). Release of
reactive oxygen and nitrogen species from contracting skeletal muscle cells. Free Radical
Biology and Medicine, 37, 1064–1072.
Pérez, V. I., Bokov, A., Van Remmen, H., Mele, J., Ran, Q., Ikeno, Y., Richardson, A. (2009).
Is the oxidative stress theory of aging dead? Biochimica et Biophysica Acta, 1790(10),
1005–1014.
Peterson, J. M. & Guttridge, D. C. (2008). Skeletal muscle diseases, inflammation, and NF-kappaB
signaling: insights and opportunities for therapeutic intervention. International Reviews of
Immunology, 27, 375–387.
Pirkkala, L., Nykanen, P., Sistonen, L. (2001). Roles of the heat shock transcription factors in
regulation of the heat shock response and beyond. The FASEB Journal, 15, 1118–1131.
Porter, M. M., Vandervoort, A. A., Lexell, J. (1995). Aging of human muscle: structure, function
and adaptability. Scandinavian Journal of Medicine and Science in Sports, 5, 129–142.
330 A. McArdle and M.J. Jackson
Pou, S., Pou, W. S., Bredt, D. S., Snyder, S. H., Rosen, G. M. (1992). Generation of superoxide
by purified brain nitric oxide synthase. The Journal of Biological Chemistry, 267,
24173–24176.

Powers, S. K. & Jackson, M. J. (2008). Exercise-induced oxidative stress: cellular mechanisms
and impact on muscle force production. Physiological Reviews, 88, 1243–1276.
Pritts, T. A., Wang, Q., Sun, X., Moon, M. R., Fischer, D. R., Fischer, J. E., Wong, H. R.,
Hasselgren, P. O. (2000). Induction of the stress response in vivo decreases nuclear factor-
kappa B activity in jejunal mucosa of endotoxemic mice. Archives of Surgery, 135, 860–866.
Prudham, D. & Evans, J. G. (1981). Factors associated with falls in the elderly: a community
study. Age and Ageing, 10, 141–146.
Rao, D. V., Watson, K., Jones, G. L. (1999). Age-related attenuation in the expression of the major
heat shock proteins in human peripheral lymphocytes. Mechanisms of Ageing and Development,
107, 105–118.
Reid, M. B., Haack, K. E., Franchek, K. M., Valberg, P. A., Kobzik, L., West, M. S. (1992).
Reactive oxygen in skeletal muscle. I. Intracellular oxidant kinetics and fatigue in vitro.
Journal of Applied Physiology, 73(5), 1797–1804.
Reid, M. B., Shoji, T., Moody, M. R., Entman, M. L. (1992). Reactive oxygen in skeletal muscle.
II. Extracellular release of free radicals. Journal of Applied Physiology, 73(5), 1805–1809.
Ristow, M., Zarse, K., Oberbach, A., Klöting, N., Birringer, M., Kiehntopf, M., Stumvoll, M.,
Kahn, C. R., Blüher, M. (2009). Antioxidants prevent health-promoting effects of physical
exercise in humans. Proceedings of the National Academy of Sciences of the United States of
America, 106, 8665–8670.
Sanz, A., Pamplona, R., Barja, G. (2006). Is the mitochondrial free radical theory of aging intact?
Antioxidants and Redox Signaling, 8, 582–599.
Sastre, J., Pallardo, F. V., Vina, J. (2003). The role of mitochondrial oxidative stress in aging. Free
Radical Biology and Medicine, 35, 1–8.
Shah, V. O., Scariano, J., Waters, D., Qualls, C., Morgan, M., Pickett, G., Gasparovic, C.,
Dokladny, K., Moseley, P., Raj, D. S. (2009). Mitochondrial DNA deletion and sarcopenia.
Genetics in Medicine, 11(3), 147–152.
Shimizu, M., Tamamori-Adachi, M., Arai, H., Tabuchi, N., Tanaka, H., Sunamori, M. (2002).
Lipopolysaccharide pretreatment attenuates myocardial infarct size: A possible mechanism
involving heat shock protein 70-inhibitory kappaBalpha complex and attenuation of nuclear
factor kappaB. The Journal of Thoracic and Cardiovascular Surgery, 124, 933–941.

Sies, H. & Jones, D. P. (2007). In G. Fink (Ed.), Oxidative stress in Encyclopedia of stress (pp.
45–48). San Diego, CA: Elsevier.
Skelton, D. A., Greig, C. A., Davies, J. M., Young, A. (1994). Strength, power and related func-
tional ability of healthy people aged 65-89 years. Age and Ageing, 23, 371–377.
Song, Y., Cardounel, A. J., Zweier, J. L., Xia, Y. (2002). Inhibition of superoxide generation from
neuronal nitric oxide synthase by heat shock protein 90: implications in NOS regulation.
Biochemistry, 41(34), 10616–10622.
Taylor, R. W., Barron, M. J., Borthwick, G. M., Gospel, A., Chinnery, P. F., Samuels, D. C.,
Taylor, G. A., Plusa, S. M., Needham, S. J., Greaves, L. C., Kirkwood, T. B., Turnbull, D. M.
(2003). Mitochondrial DNA mutations in human colonic crypt stem cells. Journal of Clinical
Investigation, 112, 1351–1360.
Van Gammeren, D., Damrauer, J. S., Jackman, R. W., Kandarian, S. C. (2009). The IkappaB
kinases IKKalpha and IKKbeta are necessary and sufficient for skeletal muscle atrophy. The
FASEB Journal, 23, 362–370.
Vasilaki, A., Jackson, M, J., McArdle, A. (2002). Attenuated HSP70 response in skeletal Muscle
of aged rats following contractile activity. Muscle Nerve, 25, 902–905.
Vasilaki, A., Csete, M., Pye, D., Lee, S., Palomero, J., McArdle, F., Van Remmen, H., Richardson, A.,
McArdle, A., Faulkner, J. A., Jackson, M. J. (2006a). Genetic modification of the manganese
superoxide dismutase/glutathione peroxidase 1 pathway influences intracellular ROS genera-
tion in quiescent, but not contracting, skeletal muscle cells. Free Radical Biology and
Medicine, 41, 1719–1725.
331Reactive Oxygen Species Generation and Skeletal Muscle Wasting – Implications
Vasilaki, A., McArdle, F., Iwanejko, L. M., McArdle, A. (2006b). Adaptive responses of mouse
skeletal muscle to contractile activity: the effect of age. Mechanisms of Ageing and
Development, 127, 830–839.
Vasilaki, A., Mansouri, A., Remmen, H., van der Meulen, J. H., Larkin, L., Richardson, A. G.,
McArdle, A., Faulkner, J. A., Jackson, M. J. (2006c). Free radical generation by skeletal
muscle of adult and old mice: effect of contractile activity. Aging Cell, 5, 109–117.
Vasilaki, A., McArdle, F., McLean, L., Simpson, D., Beynon, R. J., Van Remmen, H., Richardson, A. G.,
McArdle, A., Faulkner, J. A., Jackson, M. J. (2007). Formation of 3-nitrotyrosines in carbonic

anhydrase III is a sensitive marker of oxidative stress in skeletal muscle. Proteomics (Clinical
Applications), 1, 362–372.
Vranić, T. S., Bobinac, D., Jurisić-Erzen, D., Muhvić, D., Sandri, M., Jerković, R. (2002).
Expression of neuronal nitric oxide synthase in fast rat skeletal muscle. Collegium
Antropologicum, 26(Suppl), 183–188.
Wiswell, R. A., Hawkins, S. A., Jaque, S. V., Hyslop, D., Constantino, N., Tarpenning, K.,
Marcell, T., Schroeder, E. T. (2001). Relationship between physiological loss, performance
decrement, and age in master athletes. The Journals of Gerontology. Series A: Biological
Sciences and Medical Sciences, 56, M618–M626.
Yoo, C. G., Lee, S., Lee, C. T., Kim, Y. W., Han, S. K., Shim, Y. S. (2000). Anti-inflammatory
effect of heat shock protein induction is related to stabilization of I kappa B alpha through
preventing I kappa B kinase activation in respiratory epithelial cells. Journal of Immunology,
164, 5416–5423.
Young, A. & Skelton, D. A. (1994). Applied physiology of strength and power in old age.
International Journal of Sports Medicine, 15, 149–151.

333
G.S. Lynch (ed.), Sarcopenia – Age-Related Muscle Wasting and Weakness,
DOI 10.1007/978-90-481-9713-2_15, © Springer Science+Business Media B.V. 2011
Abstract The aging process is characterized by the gradual decrease in muscle
mass, strength and power leading to a decline in physical functioning, increased
frailty and disability. This age related loss of muscle mass and function has been
termed sarcopenia. The mechanisms that underlie sarcopenia are only beginning
to be elucidated. However, specific modes and intensities of physical activity can
both act to preserve and also increase skeletal muscle mass, strength, power in
healthy and functionally limited older individuals. This effect appears to be per-
vasive throughout the lifespan and there is evidence for similar responses in men
and women. The focus of this chapter is on the role of exercise as a therapeutic
intervention for the prevention and treatment of sarcopenia. This will be accom-
plished by (1) reviewing the epidemiology on physical activity and sarcopenia (2)

summarizing the molecular mechanisms associated with sarcopenia and exercise,
(3) discussing the efficacy of resistance and endurance exercise or multi-modal
exercise, such as the combination of aerobic and resistance exercise for the man-
agement of sarcopenia.
Keywords Sarcopenia • Anabolic stimuli • Molecular signaling • Exercise •
Muscle mass
Exercise as a Countermeasure for Sarcopenia*
Donato A. Rivas and Roger A. Fielding
D.A. Rivas and R.A. Fielding (*)
Nutrition Exercise Physiology and Sarcopenia Laboratory, Jean Mayer USDA
Human Nutrition Research Center on Aging, Tufts University,
711 Washington Street, Boston, MA 02111, USA
e-mail:
*
This chapter is based upon work supported by the U.S. Department of Agriculture, under agree-
ment No. 58-1950-7-707. Any opinions, findings, conclusion, or recommendations expressed in
this publication are those of the author(s) and do not necessarily reflect the view of the U.S.
Department of Agriculture.
334 D.A. Rivas and R.A. Fielding
1 Introduction
The aging process is characterized by the gradual decrease in muscle mass and
strength leading to a decline in physical functioning, increased frailty and disability.
This age related loss of muscle mass and function has been termed sarcopenia
(Rosenberg 1997). The prevalence of sarcopenia between the ages of 60–70 years
is between 5% and 13% and increases to between 11% and 50% at 80 years of age
(Morley 2008). The large variability in the data is the result of how sarcopenia is
defined and measured. Additionally, it has been observed that a loss in muscle mass
is associated with metabolic alterations such as, insulin resistance, type 2 diabetes,
dyslipidaemia, and obesity that are coupled with an increase in mortality (Evans
1997). The total cost of sarcopenia to the American Health System has been

reported to be approximately $18.4 billion (Morley 2008; Janssen et al. 2004).
Individuals over the age of 69 years are the largest growing segment of the
American population (Manton and Vaupel 1995). Therefore, therapeutic interven-
tions that treat sarcopenia may have profound effects on the independence and
physical functioning in the elderly.
There is compelling evidence that increased physical activity in older adults is
associated with decreased risk of functional limitation, disability, frailty and meta-
bolic disease states (DiPietro 2001; Fielding 1995; Tanaka and Seals 2008; Kohrt
and Holloszy 1995; Sugawara et al. 2002; Chin et al. 2008). Therefore, exercise
may be a highly effective treatment for preventing the loss of muscle mass associ-
ated with ageing (Chin et al. 2008; Fielding 1995). The focus of this chapter is on
the role of exercise as a therapeutic intervention for the prevention and treatment of
sarcopenia. This will be accomplished by (1) reviewing the epidemiology on physical
activity and sarcopenia (2) summarizing the molecular mechanisms associated with
sarcopenia and exercise, (3) discussing the efficacy of resistance and endurance
exercise or multi-modal exercise, such as the combination of aerobic and resistance
exercise for the management of sarcopenia.
2 Role of Lifelong Habitual Physical Activity
with Changes in Muscle Mass
There are several parallels between the physiological effects of aging and the adap-
tation as a result of disuse and inactivity (Lynch et al. 2007; Bortz 1982; Corcoran
1991; Timiras 1994). For example, aging, disuse and inactivity all have adverse
effects on the cardiovascular system such as, lowering maximal oxygen uptake and
stroke volume and raising blood pressure. Body composition and metabolism are
also similarly affected by aging, disuse and inactivity as seen by decreased lean
body mass, increased fat mass and impaired glucose tolerance. The effects of aging,
disuse and inactivity on the cardiovascular system, body composition and muscle
composition are very difficult to differentiate. For example, it has been reported that
335Exercise as a Countermeasure for Sarcopenia
there are changes in muscle fiber type composition as a result of aging, disuse and

inactivity. However, while disuse is shown to mostly decrease the number of type
1 muscle fibers, studies on aging have revealed a reduction on the number of both
Type 1 and Type 2 fibers and the specific size of type 2 fibers (Lexell et al. 1988;
Larsson 1983; Larsson et al. 1978).
A sedentary lifestyle during aging is associated with decreased lean body mass
and increased fat mass leading to increased mortality and functional limitations
(Baumgartner et al. 1999; Dziura et al. 2004; DiPietro 2001; Fielding 1995; Evans
1997). This is demonstrated in studies showing a decrease in the relative risk of
cardiovascular and all cause mortality in highly active compared to moderately
active and sedentary individuals (Lakatta and Levy 2003; Singh 2004; Chodzko-
Zajko et al. 2009). Declines in exercise capacity throughout an individual’s life
span can affect functional capacity and impinge on the ability to perform activities
of daily living. Recently, Sugawara et al. (2002) observed that appendicular muscle
mass relative to body mass declines with advancing age regardless of physical
activity status, but is significantly higher in endurance-trained men at any age than
their sedentary peers (Sugawara et al. 2002). Both aerobic and resistance exercise
have been shown to increase protein synthesis, while also increasing the cross-
sectional area of both myosin heavy chain (MHC) I and II, respectively (Harber
et al. 2009a, b; Short et al. 2004). The decreased cardiorespiratory function and
reduced muscle mass and strength observed with advancing age and a sedentary
lifestyle resemble the change in these variables which occur with disuse, bedrest or
reduced activity (Saltin and Rowell 1980; Bortz 1982; Chopard et al. 2009a, b).
Despite the evidence demonstrating the benefits of increased physical activity on
healthy aging; the Centers for Disease Control (CDC) reported that three of four
older adults do not meet the minimum recommendation of a brisk walk, or similar
activity, of at least 5 days each week. Studies have reported that increased physical
activity during aging is associated with decreased body fat, increased relative
muscle mass, reduced coronary risk profile (i.e. better insulin sensitivity and glu-
cose homeostasis etc.), slower development of disability in old age, and athletes
that resistance trained (RET) are ~50–60% stronger than their peers (Going et al.

1995; Sugawara et al. 2002; Hagberg et al. 1985; Seals et al. 1984a, b; Hunter et al.
2000, 2002; Klitgaard et al. 1990). The Yale Health and Aging Study, an epidemio-
logical study conducted over 12 years, showed that physical activity had the ability
to attenuate age related weight-loss among the elderly with chronic disease (Dziura
et al. 2004). Furthermore, Baumgartner and colleagues observed that physical
activity was positively correlated with muscle mass and negatively correlated with
body-fat in a cross-sectional study among older men and women (Baumgartner
et al. 1999).
Currently it is projected that the number of elderly will double worldwide from
11% of the population to 22% by 2050 (UN 2007). Because of the rapidly expand-
ing population of older adults and the accumulation of evidence showing the ben-
efits of increased physical activity for healthy older adults and older adults with
chronic disease, a number of guidelines and recommendations on physical activity
have been introduced for this population in the last few years. For the first time, in