Sarcopenia Age-Related Muscle Wasting and Weakness: Mechanisms and Treatments P2 ppt

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

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

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

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

Miranda D. Grounds
School of Anatomy & Human Biology, the University of Western Australia,
Nedlands Western Australia, 6009, Australia

Russell T. Hepple
Faculty of Kinesiology and Faculty of Medicine,
University of Calgary, Calgary, Canada

Malcolm J. Jackson
School of Clinical Sciences, University of Liverpool, UK

xiContributors
Ravi Kambadur
School of Biological Sciences, Nanyang Technological University,
60 Nanyang Drive, Singapore

René Koopman
Basic and Clinical Myology Laboratory, Department of Physiology,
The University of Melbourne, Australia

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

Bertrand Lèger
Basic and Clinical Myology Laboratory, Department of Physiology,
The University of Melbourne, Parkville, 3010, Australia

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

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

Anne McArdle
School of Clinical Sciences, University of Liverpool, UK

Craig McFarlane
Singapore Institute for Clinical Sciences, Singapore
Chris D. McMahon
AgResearch Limited, Ruakura Research Centre, Hamilton, New Zealand

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

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

Aaron P. Russell
Centre for Physical Activity and Nutrition, School of Exercise
and Nutrition Sciences, Deakin University, Burwood 3125, Australia

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

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

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

xiiiContributors
Parco M. Siu
Department of Health Technology and Informatics,
The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China

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

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

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:
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.
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