x Contributors Osvaldo Delbono Departments of Internal Medicine, Section on Gerontology and Geriatric Medicine, Department of Physiology and Pharmacology, Molecular Medicine and Neuroscience Programs, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA odelbono@wfubmc.edu Pamela Donoghue Conway Institute, University College Dublin, Belfield, Ireland Philip Doran Department of Biological Chemistry, University of California, Los Angeles, CA, USA John A. Faulkner Departments of Biomedical Engineering and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109-2200, USA jafaulk@umich.edu Roger 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 roger.fielding@tufts.edu Joan Gannon Department of Biology, National University of Ireland, Maynooth, Co. Kildare, Ireland Luc E. Gosselin Department of Exercise and Nutrition Sciences, University at Buffalo, 211 Kimball Tower, Buffalo, NY 14214-8028, USA gosselin@buffalo.edu Miranda D. Grounds School of Anatomy & Human Biology, the University of Western Australia, Nedlands Western Australia, 6009, Australia mgrounds@anhb.uwa.edu.au Russell T. Hepple Faculty of Kinesiology and Faculty of Medicine, University of Calgary, Calgary, Canada hepple@ucalgary.ca Malcolm J. Jackson School of Clinical Sciences, University of Liverpool, UK m.j.jackson@liverpool.ac.uk xiContributors Ravi Kambadur School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore Kravi@ntu.edu.sg René Koopman Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Australia rkoopman@unimelb.edu.au Lars Larsson Department of Clinical Neurophysiology, Uppsala University Hospital, Entrance 85, 3rd Floor, 751 85 Uppsala, Sweden and Department of Biobehavioral Health, the Pennsylvania State University, PA, USA lars.larsson@neurofys.uu.se Bertrand Lèger Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Parkville, 3010, Australia Bertrand.Leger@crr-suva.ch Francisco J. López-Soriano Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona Gordon S. Lynch Department of Physiology, Basic and Clinical Myology Laboratory, The University of Melbourne, Victoria, Australia gsl@unimelb.edu.au Carlos B. Mantilla Departments of Physiology & Biomedical Engineering and Anesthesiology, College of Medicine, Mayo Clinic, Joseph 4W-184, St. Marys Hospital, 200 First Street SW, Rochester, MN 55905, USA mantilla.carlos@mayo.edu Anne McArdle School of Clinical Sciences, University of Liverpool, UK mdcr02@liverpool.ac.uk Craig McFarlane Singapore Institute for Clinical Sciences, Singapore Chris D. McMahon AgResearch Limited, Ruakura Research Centre, Hamilton, New Zealand chris.mcmahon@agresearch.co.nz xii Contributors Christopher L. Mendias Departments of Orthopaedic Surgery and School of Kinesiology, University of Michigan, Ann Arbor, MI 48109-2200, USA Kay Ohlendieck Department of Biology, National University of Ireland, Maynooth, Co. Kildare, Ireland kay.ohlendieck@nuim.ie Marcel Orpi Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona Donato A. Rivas Nutrition Exercise Physiology and Sarcopenia Laboratory Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, MA 02111, USA Stephen M. Roth Department of Kinesiology, School of Public Health, University of Maryland, College Park, MD 20742, USA sroth1@umd.edu Aaron P. Russell Centre for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Burwood 3125, Australia aaron.russell@deakin.edu.au James G. Ryall The Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health (NIH), Bethesda, MD, USA ryallj@mail.nih.gov Roberto Serpe Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona Mridula Sharma Department of Biochemistry, National University of Singapore Thea Shavlakadze School of Anatomy & Human Biology, the University of Western Australia, Nedlands Western Australia, 6009, Australia tshavlakadze@anhb.uwa.edu.au Gary C. Sieck Departments of Physiology & Biomedical Engineering and Anesthesiology, College of Medicine, Mayo Clinic, Joseph 4W-184, St. Marys Hospital, 200 First Street SW, Rochester, MN 55905, USA sieck.gary@mayo.edu xiiiContributors Parco M. Siu Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China htpsiu@inet.polyu.edu.hk Ladora V. Thompson University of Minnesota, Medical School Program in Physical Therapy, Department of Physical Medicine and Rehabilitation, 420 Delaware St, SE, Minneapolis, MN 55455, USA thomp067@umn.edu David E. Vaillancourt Department of Kinesiology and Nutrition and Departments of Bioengineering and Neurology, University of Illinois at Chicago, Chicago, IL, USA Luc J.C. van Loon Department of Human Movement Sciences, Maastricht University Medical Centre, 6200 MD, Maastricht, The Netherlands L.vanLoon@HB.unimaas.nl Lex B. Verdijk Department of Human Movement Sciences, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University Medical Centre, Maastricht, The Netherlands 1 G.S. Lynch (ed.), Sarcopenia – Age-Related Muscle Wasting and Weakness, DOI 10.1007/978-90-481-9713-2_1, © Springer Science+Business Media B.V. 2011 Abstract Some of the most serious consequences of ageing are its effects on skeletal muscle. ‘Sarcopenia’ involves a progressive age-related loss of muscle mass and associated muscle weakness that renders frail elders susceptible to serious injury from sudden falls and fractures and losing their functional independence. Not surprisingly, sarcopenia is a significant global public health problem, especially in the developed world. There is an urgent need to better understand the mechanisms underlying age-related muscle wasting and to develop therapeutic strategies that can attenuate, prevent, or ultimately reverse skeletal muscle wasting and weakness. Research and development in academic and research institutions and in large and small pharma is being directed to sarcopenia and related issues to develop and evaluate novel therapies. This book provides the latest information on sarcopenia from leading international researchers studying the cellular and molecular mechanisms underlying age-related changes in skeletal muscle and identifying strategies to combat sarcopenia and related muscle wasting conditions and neuromuscular disorders. The range of interventions for sarcopenia is extensive and not all can be covered in this first volume. While not covering every possible theme, the selected topics provide important insights into the some of the mechanisms underlying sarcopenia and serve as the basis for subsequent complementary volumes that will eventually provide a definitive resource for understanding age-related muscle wasting and weakness and therapeutic approaches to combat sarcopenia. Keywords Ageing • Aging, cancer cachexia • Cytokine • Geriatrics • Gerontology • Growth factors • Hormones • Inflammation • Muscle injury and repair • Muscle wasting • Muscle weakness • Neuromuscular • Sarcopenia • Senescence • Skeletal muscle G.S. Lynch (*) Department of Physiology, Basic and Clinical Myology Laboratory, The University of Melbourne, Victoria, Australia e-mail: gsl@unimelb.edu.au Overview of Sarcopenia Gordon S. Lynch 2 G.S. Lynch 1 Defining Sarcopenia Some of the most serious consequences of ageing are its effects on skeletal muscle particularly the progressive loss of mass and function which impacts on quality of life, and ultimately on survival. Although the term ‘sarcopenia’ was originally coined to describe the progressive loss of muscle mass with advancing age (Rosenberg 1989; Evans and Campbell 1993; Evans 1995), only recently have consensus definitions of ‘sarcopenia’ been established. Updated definitions of sarcopenia were published in 2010 by the European Working Group on Sarcopenia in Older People (Cruz-Jentoft et al. 2010), by the Special Interest Group on cachexia-anorexia in chronic wasting diseases within The European Society for Clinical Nutrition and Metabolism (ESPEN, Muscaritoli et al. 2010), and by Evans (2010) who all proposed that the accompanying deterioration of muscle function or muscle weakness should be included in the defini- tion of sarcopenia. A slightly different view was proposed by Narici and Maffulli (2010) who suggested that although muscle weakness was an inevitable consequence of sarcopenia, the two terms should not be used interchangeably because of the impli- cation that they were proportional. Instead, they proposed that sarcopenia should be used uniquely to describe age-related loss of muscle mass and that its relation to the loss of muscle strength be discussed separately (Narici and Maffulli 2010). Regardless of these slight variations in definition, most groups agree that there are several criteria for the clinical diagnosis of sarcopenia, such as the presence of low muscle mass accompanied by low muscle strength and/or low physical performance (Janssen et al. 2002; Cruz-Jentoft et al. 2010). The definition of sarcopenia provided by Evans (2010) describes these structural and functional criteria comprehensively; i.e. Sarcopenia is the age-associated loss of skeletal muscle mass and function. The causes of sarcopenia are multifactorial and can include disuse, changing endocrine function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. Whereas cachexia may be a component of sarcopenia, the two conditions are not the same. The diagnosis of sarcopenia should be considered in all older patients who present with observed declines in physical function, strength, or overall health. Sarcopenia should specifically be considered in patients who are bedridden, cannot independently rise from a chair, or who have a mea- sured gait speed <1.0 m/s. Patients who meet these initial criteria should further undergo body composition assessment using dual-energy X-ray absorptiometry with sarcopenia being defined as an appendicular lean/fat mass 2 SD less than that of young adult. A diag- nosis of sarcopenia is consistent with a gait speed of <1 m/s and an appendicular lean/fat ratio <2 SD of the average of a young adult (Evans 2010). This definition serves as an appropriate starting point for understanding the underlying mechanisms of sarcopenia and for developing safe and effective interventions. 2 The International Health Problem of Sarcopenia Sarcopenia is a highly significant public health problem affecting the developed world. The true magnitude of the health problems associated with age-related musculoskeletal disability is being realized worldwide as the number and proportion 3Overview of Sarcopenia of older persons in the population continues to escalate. Sarcopenia imposes a significant but modifiable economic burden on healthcare services in most industrial- ized nations (Lynch 2004a). In 2000 it was estimated that healthcare costs in the United States associated with sarcopenia were $18.5 US billion; or ~1.5% of total healthcare expenditure (Janssen et al. 2004). The Centers for Disease Control and Prevention (CDC) later predicted that there were ~34 million people in the United States aged 65 years and older, or ~13% of the total population, and that this would increase to 70 million people by 2030, or ~20% of the total population (Thompson 2007). Furthermore, 1.5 million people in the United States aged 65 years and older were institutionalized and 33% of these people had been admitted to long-term healthcare facilities because of their inability to perform activities of daily living (Thompson 2007). Sarcopenia affects all elderly and does not discriminate based on ethnicity, gender, or wealth. Frail elders who have lost significant muscle mass and strength often require assistance for accomplishing even the most basic tasks of independent living, and they are also at increased risk of serious injury from sudden falls and subsequent fractures. The loss of functional independence is painful not only for the individual but also for family members and carers. Sarcopenia has a dramatic impact on the lives of the elderly and places increasing demands on public health care systems worldwide. Not surprisingly, there is an acute awareness among researchers and clinicians in academic and research institutions and in the pharmaceutical industry about the importance of sarcopenia and the urgent need to develop novel therapies that can attenuate, prevent, and potentially reverse age-related muscle wasting and weakness. 3 Overview of Our Current Understanding of the Cellular and Molecular Mechanisms Underlying Sarcopenia Several reviews have summarized the cellular and molecular mechanisms underlying age-related muscle wasting and weakness (Ryall et al. 2008) and this textbook pro- vides in-depth discussions on some of these different contributing factors. The loss of muscle mass and strength is thought to be attributed to the progressive atrophy and loss of individual muscle fibres associated with some loss of motor units, and a reduc- tion in muscle ‘quality’ due to the infiltration of fat and other non-contractile tissue. Thus, the age-related changes in skeletal muscle are neuromuscular in origin and asso- ciated with a complex interaction of factors affecting neuromuscular transmission, protein synthesis and degradation, muscle architecture, fibre composition, increased generation of reactive oxygen species, myonuclear apoptosis, altered excitation-con- traction coupling, and metabolism (Lynch et al. 2007; Ryall et al. 2008; Arnold et al. 2010; Wenz et al. 2009). Sarcopenia is mechanistically different from the acute muscle atrophies as a consequence of disuse, cachexia, denervation and other conditions (Edström et al. 2006; Combaret et al. 2009). 4 G.S. Lynch Age-related changes in skeletal muscle can be exacerbated by the normally decreasing levels of physical activity with advancing age and also by metabolic changes and oxidative stresses that can result in the accumulation of intracellular damage from free radicals (Meng and Yu 2010). Although physical activity (espe- cially strength training) and good nutrition can help slow the rate of these neuro- muscular impairments (Aagaard et al. 2010), even very active Masters athletes and otherwise healthy older adults also exhibit a progressive loss of muscle mass, strength and (especially) power output (Runge et al. 2004; Yamauchi et al. 2009) that can affect their performance of everyday tasks (Korhonen et al. 2003, 2006; Cristea et al. 2008). Age-related changes in circulating muscle anabolic hormones and growth factors, also contribute to the emergence of the sarcopenic phenotype and the subsequent loss of functional independence and quality of life (Orr and Fiatarone Singh 2004; Bain 2010; Kovacheva et al. 2010; Perrini et al. 2010; Scicchitano et al. 2009). Other conditions can accelerate the progression of muscle atrophy in older adults, including co-morbid diseases such as cancer, kidney dis- ease, diabetes, and peripheral artery disease (Buford et al. 2010). Although age- related changes in skeletal muscle structure and function are inevitable, pharmacological approaches to attenuate, halt or reverse the deleterious effects of advancing age on skeletal muscle are realistic possibilities (Borst 2004; Lynch 2004, 2008; Gullett et al. 2010). Since sarcopenia is considered a neuromuscular syndrome (Tseng et al. 1995; Koopman et al. 2009) drugs for sarcopenia could induce neural and/or muscle-specific effects and I have described these approaches in detail elsewhere (Lynch 2002, 2004b, 2008). The list of different interventions for sarcopenia is extensive and not all can be covered in this first volume. Instead, this text will cover some of the main signalling pathways thought responsible for age-related muscle wasting and weakness and just some of the interventions pro- posed to counteract these effects. This text serves to introduce the reader to some of the significant age-related changes in skeletal muscle and to identify the different factors affecting neuromus- cular transmission, muscle structure and fibre composition, excitation-contraction coupling, and skeletal muscle metabolism. Contributions have been sought from leading researchers in the field to describe these different factors and mechanisms responsible for the deleterious changes to skeletal muscle as a consequence of advancing age. While there sometimes may be conflicting views among research- ers about the relative importance of these different contributing mechanisms, each chapter provides a concise and timely update about the age-associated changes in the structural, functional and biochemical properties of skeletal muscle and taken together they provide a basis for identifying novel approaches to tackle sarcopenia. The chapters cover diverse topics ranging from insights into the mechanisms of the neuromuscular deficit, including age-related changes in the neuromuscular junction and neurotransmission, alterations in motor unit properties, actomyosin structure and interaction, and excitation-contraction coupling; alterations in meta- bolic properties including mitochondrial function and some of the factors regulat- ing fibrosis and nuclear apoptosis. The book discusses the mechanisms regulating 5Overview of Sarcopenia the balance between protein synthesis and protein degradation and how these processes are affected during aging as well as understanding genetic variation and proteomic profiling of skeletal muscles during aging. Other topics describe the role of exercise in counteracting some of the effects of aging on skeletal muscle, how contraction-mediated injury contributes to age-related muscle wasting and weak- ness, and the role of different signaling pathways in regulating skeletal muscle mass and how these pathways can be modified during aging. While not covering every possible theme, the selected topics provide important insights into the some of the mechanisms underlying sarcopenia and generous reference lists for pursuing topics further. It is expected that the introductory themes provided in this text will serve as the basis for subsequent volumes that will eventually provide the definitive resource for understanding all of the signalling pathways implicated in age-related muscle wasting and weakness and describing the comprehensive list of drugs and approaches to combat sarcopenia. References Aagaard, P., Suetta, C., Caserotti, P., Magnusson, S. P., Kjær, M. (2010). Role of the nervous system in sarcopenia and muscle atrophy with aging: strength training as a countermeasure. Scandinavian Journal of Medicine & Science in Sports, 20, 49–64. Arnold, A. S., Egger, A., Handschin, C. (2010). PGC-1alpha and myokines in the aging muscle – a mini-review. Gerontology (in press) DOI: 10.1159/000281883. Bain, J. (2010). Testosterone and the aging male: to treat or not to treat? Maturitas, 66, 16–22. Borst, S. E. (2004). Interventions for sarcopenia and muscle weakness in older people. Age and Ageing, 33, 548–555. Buford, T. W., Anton, S. D., Judge, A. R., Marzetti, E., Wohlgemuth, S. E., Carter, C. S., Leeuwenburgh, C., Pahor, M., Manini, T. M. (2010). Models of accelerated sarcopenia: critical pieces for solving the puzzle of age-related muscle atrophy. Ageing Research Reviews, 9, 369–383. Combaret, L., Dardevet, D., Béchet, D., Taillandier, D., Mosoni, L., Attaix, D. (2009). Skeletal muscle proteolysis in aging. Current Opinion in Clinical Nutrition and Metabolic Care, 12, 37–41. Cristea, A., Korhonen, M. T., Häkkinen, K., Mero, A., Alén, M., Sipilä, S., Viitasalo, J. T., Koljonen, M. J., Suominen, H., Larsson, L. (2008). Effects of combined strength and sprint training on regulation of muscle contraction at the whole-muscle and single-fibre levels in elite master sprinters. Acta Physiologica, 193, 275–289. Cruz-Jentoft, A. J., Baeyens, J. P., Bauer, J. M., Boirie, Y., Cederholm, T., Landi, F., Martin, F. C., Michel, J. P., Rolland, Y., Schneider, S. M., Topinková, E., Vandewoude, M., Zamboni, M. (2010). Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing, April 13, 1–12. Edström, E., Altun, M., Hägglund, M., Ulfhake, B. (2006). Atrogin-1/MAFbx and MuRF1 are downregulated in aging-related loss of skeletal muscle. The Journals of Gerontology. Series A: Biological Sciences and Medical Sciences, 61, 663–674. Evans, W. J. (1995). What is sarcopenia? The Journals of Gerontology. Series A: Biological Sciences and Medical Sciences, 50A, 5–8. Evans, W. J. (2010). Skeletal muscle loss: cachexia, sarcopenia, and inactivity. The American Journal of Clinical Nutrition, 91, 1123S–1127S. Evans, W. J. & Campbell, W. W. (1993). Sarcopenia and age-related changes in body composition and functional capacity. Journal of Nutrition 123(2 Suppl), 465–468. . better understand the mechanisms underlying age-related muscle wasting and to develop therapeutic strategies that can attenuate, prevent, or ultimately reverse skeletal muscle wasting and weakness attenuate, prevent, and potentially reverse age-related muscle wasting and weakness. 3 Overview of Our Current Understanding of the Cellular and Molecular Mechanisms Underlying Sarcopenia Several. resource for understanding all of the signalling pathways implicated in age-related muscle wasting and weakness and describing the comprehensive list of drugs and approaches to combat sarcopenia. References Aagaard,