386 J.A. Faulkner et al.
Fig. 7 (a) Model of the sarcolemmal membrane skeleton and its relationship to desmin and
cytokeratin. This figure depicts a model of the organization of the muscle cell surface, from the
extracellular space to the contractile apparatus. The membrane skeletal and intermediate filament
proteins that we have studied at costameres are emphasized, whereas many proteins known to be
at or near the sarcolemma or in the contractile structures have been omitted for clarity. Longitudinal
domains, which are similar in composition to M line domains, and intercostameric regions are not
illustrated. The only extracellular protein depicted is a-dystroglycan (a-DG). Integral proteins of
the sarcolemma shown are the a and b chains of the Na,K-ATPase, b-dystropglycan (b-DG),
sarcoglycans (SG), and sarcospan (SP). The membrane skeletal proteins illustrated are ankyrin 3
(Ank), dystrophin, aII-spectrin (a-fodrin), bIS2-spectrin (b-spectrin). Sarcomeric proteins shown
are actin, myosin and a-actinin. Our results suggest that two sets of intermediate filaments
connect the contractile apparatus to the costameres at the sarcolemma: desmin, which links the Z
disks to the Z line domains of costameres, and cytokeratin, which links the contractile apparatus
to all three costameric domains. Cytokeratin filaments were referred to as “connectors” in an earlier
version of this cartoon (Williams et al. 2001). Not drawn to scale (Reprinted with permission)
(b) Cellular location of costameres in striated muscle. Shown is a schematic diagram illustrating
costameres as circumferential elements that physically couple peripheral myofibrils to the
sarcolemma in periodic register with the Z-disk (Reprinted with permission Ervasti 2003. The
American Society for Biochemistry and Molecular Biology)
387Role of Contraction-Induced Injury in Age-Related Muscle Wasting and Weakness
frog semitendinous muscle to the epimysium of the muscle (Street 1983). The
assumption is that the same process functions effectively in mammalian skeletal
muscles (Patel and Lieber 1997; Monti et al. 1999).
The lateral transmission of force is absolutely vital to the stability of myofibers
within a maximally-activated skeletal muscle, even during isometric contractions
(Claflin and Brooks 2008), or of myofibrils within muscle fibers (Panchangam
et al. 2008). The necessity for the lateral transmission of force within a maximally
activated muscle fiber is that all the sarcomeres do not generate the same force
while contracting (Panchangam et al. 2008). Stronger sarcomeres surrounding
weaker sarcomeres laterally are able to provide some support by the balancing out

of force through lateral transmission of force around the weaker sarcomeres during
isometric or shortening contractions and even during short stretches of activated
muscles. As with the myofibrils within a single fiber, when a whole skeletal muscle
is activated maximally and fibers contract, all the fibers in the skeletal muscle do
not generate exactly the same forces, because fibers vary in cross-sectional area and
sarcomeres within the fibers vary in their intrinsic maximum strengths. Throughout
a skeletal muscle, any given fiber has five to eight adjacent fibers around it, and
each myofibril has about the same variability in lateral contacts with other myofi-
brils. This structure provides lateral stability for the sarcomeres throughout the
myofibrils within a single muscle fiber, as well as for single fibers throughout the
whole muscle. Consequently, for most people contraction-induced injuries to skel-
etal muscle fibers are not a frequent occurrence, but with maximum activation and
a large strain, or even with smaller strains during repeated lengthening contractions,
the lateral support system may break down. The result is that weaker sarcomeres
are stretched excessively, and contraction induced injury occurs. The magnitudes of
the force deficits attest to the severity of some contraction-induced injuries, but the
magnitude and extent of the contraction-induced injury would be even greater were
it not for the highly sophisticated system that has evolved for the lateral transmis-
sion of force in skeletal muscles. The extensive contraction-induced injury observed
in the lumbrical muscles of dystrophin deficient mdx mice during isometric con-
tractions compared with the lack of any sign of injury in the muscles of wild-type
mice attests to the effectiveness of the system for the lateral transmission of force
in control muscles (Claflin and Brooks 2008).
8 Role of Contraction-Induced Injury in Wasting
and Weakness
For young, healthy men and women, even severe contraction-induced injuries
are well-tolerated and recovery is fairly rapid and complete. Most athletes with
well-defined competitive seasons expect to encounter some degree of discomfort
as they transition into a period of more demanding training as their competitive
season approaches. The already conditioned athlete is accustomed to regular, heavy

388 J.A. Faulkner et al.
training and they handle the transition into an increased training load with a minimum
of discomfort. Under these circumstances, a severe contraction-induced injury is
not likely to occur and moderate injuries are well-tolerated and rarely even disrupt
the training schedule. For the elderly, the musculoskeletal system has been
described as the entry pathway for the development of frailty (Bortz 2002). The
timing of the onset and the rate of progression of frailty in the elderly is governed
by both heredity and the degree of habitual physical activity in the life style (Bortz
2002). Immutable changes occur in skeletal muscles of humans that begin at about
50 years of age and initiate linear decreases in both the number of motor units
(Campbell et al. 1973; Doherty and Brown 1993) and the number of fibers (Lexell
et al. 1988) in skeletal muscles of humans. By age 80, these losses result in
decreases of 75% in the number of motor units and 50% in the number of fibers.
Due to these immutable changes, the skeletal muscles of the frail elderly are
intrinsically weak and consequently highly susceptible to contraction-induced
injury. Moreover, the frail elderly are neither accustomed to the rigors of training
nor the inconvenience and discomfort that contraction-induced injuries may cause
as a conditioning program is introduced into their daily schedule. Even more
distressing is the inadvertent and often unexpected, slip, fall, or awkward movement
that loads an unused muscle heavily and without preparation. The occurrence of
severe injuries, from which the muscles of the elderly person may not recover, can
further accelerate the rate of progression of worsening frailty.
9 Measures to Prevent Contraction-Induced Injury
Accepting that the musculoskeletal system constitutes a major/entry pathway/ for
the development of frailty (Bortz 2002), it also qualifies as a potential/exit pathway/
to cure the elderly from the condition of frailty. An increase in daily physical activ-
ity that is carefully graded in intensity and highly selective as to the types of exer-
cise can likely induce protective adaptations even in the frail elderly. Although
protection from contraction-induced injury is achieved most effectively by training
programs that include lengthening contractions through a full-range of motion and

with at least a moderate load, contraction-induced injury and regeneration of a
muscle are not required to increase resistance to subsequent injuries (Koh and Brooks
2001). Conditioning protocols that involved isometric contractions or even stretch-
ing of relaxed muscles provide some degree of protection for subsequent exposures
to lengthening contractions protocols that have the potential to induce injuries to
muscles in both young (Koh and Brooks 2001) and old (Koh et al. 2003) animals.
Lengthening contraction exercises, although of considerable value for the elderly
must be implemented with great care and with the involvement of a highly trained
exercise leader well-versed in the physical training of frail elderly. Under these
circumstances and with great attention to the details as to the intensity and types of
physical activities involved, the benefits of exercise programs that involve lengthening
contractions can be substantial.
389Role of Contraction-Induced Injury in Age-Related Muscle Wasting and Weakness
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393
G.S. Lynch (ed.), Sarcopenia – Age-Related Muscle Wasting and Weakness,
DOI 10.1007/978-90-481-9713-2_17, © Springer Science+Business Media B.V. 2011
Abstract While insulin-like growth factor-1 (IGF-1) is closely involved in the
growth, hypertrophy and maintenance of skeletal muscle mass, the role of IGF-1
in age-related muscle wasting (sarcopenia) is unclear: this is the focus of the pres-
ent discussion. The complexity of the IGF-1 system that involves different IGF-1
isoforms, binding proteins and receptors, with modulation of systemic IGF-1 levels
by growth hormone (GH) is first outlined. The classic IGF-1 signalling pathways
in skeletal muscle with a focus on the central role of Akt in protein synthesis and
degradation are presented and various conditions that can impair IGF-1 signalling
are discussed with respect to inflammation (TNF), oxidative stress (ROS) and
lipids. Complex interactions between other factors that influence the age-related
decrease in IGF-1 activity are addressed, including GH, nutrition, caloric restric-
tion, Klotho and Vitamin D. Finally, the potential for therapeutic interventions for
sarcopenia related to IGF-1 signalling is considered. The big questions are ‘to what
extent does IGF-1 contribute to sarcopenia’ and ‘can elevated IGF-1 prevent or
reverse sarcopenia?
Keywords Insulin like growth factor-1 (IGF-1) • Growth hormone • Skeletal
muscle wasting • Muscle atrophy • Sarcopenia
M.D. Grounds (*) and T. Shavlakadze
School of Anatomy & Human Biology, The University of Western Australia,
Nedlands, WA, Australia 6009
e-mail: ;
C.D. McMahon
AgResearch Limited, Ruakura Research Centre, Hamilton, New Zealand

e-mail:
Role of IGF-1 in Age-Related Loss of Skeletal
Muscle Mass and Function
Chris D. McMahon, Thea Shavlakadze, and Miranda D. Grounds
394 C.D. McMahon et al.
1 Introduction
Insulin-like growth factor -1 (IGF-1) is, as the name implies, similar to insulin in
its structure and some of its functions. For example, both IGF-1 and insulin can
bind with different affinities to their respective receptors, and both similarly acti-
vate signalling pathways such as that mediated by Akt/mTOR. A key difference
appears to be the distinct roles that insulin and IGF-1 play at different stages of life.
IGF-1 is crucial for muscle formation and growth during embryogenesis and post-
natal development, whereas insulin is more important for metabolism in the post-
natal and adult states. In skeletal muscle, IGF-1 is closely involved in muscle
growth, hypertrophy and maintenance of muscle mass (Fig. 1); however, the role of
IGF-1 in age-related muscle wasting is unclear and is the focus of the present dis-
cussion. There are two isoforms of the insulin receptor A and B which vary by
tissue and stage of development. Type A is more prevalent in developing tissue, and
has a high affinity for IGF-2 as well as insulin. Activation of insulin receptor A by
insulin leads primarily to metabolic effects, whereas its activation by IGF-2 leads
primarily to mitogenic effects (Frasca et al. 1999). IGF-2 is expressed at high levels
during fetal development in all species and is an important factor in overall growth
regulation, acting through the type 1 IGF-1R and insulin receptor A. Indeed, the
birth phenotype of IGF-2 knockout mice is more severe than for IGF-1R knockout
mice (Accili et al. 1999; Dikkes et al. 2007). In rodents, IGF-2 is down-regulated
at birth and has a small post-natal role; however, in humans IGF-2 expression is
sustained throughout life and is believed to have important metabolic and anabolic
functions. It is important to consider such species differences when extrapolating
Fig. 1 Simplistic representation to indicate the relative importance of IGF-1 and growth hormone
(GH) for maintenance of skeletal muscle mass throughout life. It is considered that IGF-1 is

essential for normal skeletal muscle development and growth during embryogenesis and in post-
natal life. When muscle mass reaches homeostasis in adults the role of IGF-1 decreases, although
it is required for muscle maintenance and is important for increasing muscle mass and protein
content during hypertrophy in response to loading/exercise. Growth hormone is especially impor-
tant for postnatal growth and also regulates IGF-1 levels. The roles of IGF-1 and GH during
muscle wasting with ageing (sarcopenia) remain to be fully defined. Dark bars indicate the rela-
tively high importance for regulating muscle mass and the light bars indicate relatively low impor-
tance (Adapted from Shavlakadze and Grounds 2006)
395Role of IGF-1 in Age-Related Loss of Skeletal Muscle Mass and Function
rodent and other experimental data to the human condition. This review will focus
on IGF-1.
The Chapter starts by introducing IGF-1, its isoforms, receptors and binding
proteins, importance during growth and regulation by growth. The classic IGF-1
signalling is outlined and consequences of impaired IGF-1/insulin signalling
related to diabetes, obesity and ageing are discussed. The focus then shifts to age-
related muscle wasting (sarcopenia) and factors that may contribute to this. A
wealth of information from animal studies related to modulation of levels of IGF-1
and related moleculesis presented. The impact of exercise and various therapies and
molecular interventions (often involving IGF-1) that have been shown in animal
models to slow sarcopenia are then critically discussed with respect to realistic
applications to the human condition.
2 Complexity of the IGF-1 System and Importance
in Skeletal Muscle
2.1 IGF-1 Isoforms and IGF-1 Availability in Muscle and Blood
IGF-1 plays a central role in skeletal muscle hypertrophy and atrophy (Grounds
2002) via promotion of protein synthesis and inhibition of protein degradation
(Shavlakadze and Grounds 2006) and this protein balance is of critical importance
for muscle wasting in ageing (sarcopenia), in inflammatory disorders (cachexia),
denervation, disuse atrophy and also in the metabolic syndrome (Shavlakadze and
Grounds 2006). The IGF-1 gene can be spliced in different ways to produce at least

six mRNA isoforms although the specific biological function of these different
isoforms of IGF-1 are still unknown (Winn et al. 2002; Shavlakadze et al. 2005b).
The mechanisms by which these transcripts might exert different effects are unclear,
since ultimately all are processed to produce the same 70 amino acid mature IGF-1
peptide (Fig. 2). While these various isoforms may exert distinct functions, another
possibility is that transcription of these various isoforms may instead present the
possibility for tissue specific regulation of IGF-1 expression. Available data from
transgenic mice over-expressing the various isoforms only in skeletal muscle, indi-
cate that the Ea isoforms (both Class 1 or Class 2) have hypertrophic effects in situ-
ations of growth (Shavlakadze et al., unpublished data), whereas the Eb isoform (in
rodents and termed Ec in humans), also known as mechano-growth factor (MGF)
may instead have early mitogenic and protective effects because mRNA is acutely
increased and precedes an increase of IGF-IEa mRNA after injury to skeletal
muscle (Yang and Goldspink 2002; Hill and Goldspink 2003). While transgenic
studies are a powerful tool, it should be emphasised that this forced artificial over-
expression may not accurately reflect the native in vivo situation, since different
isoforms may instead normally be transcribed by tissues other than skeletal muscle.
For example the Class 2 isoforms are expressed mainly by liver, whereas skeletal