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 References Abbott, B. C., Aubert, X. M., Hill, A. V. (1951). The absorption of work by a muscle stretched during a single twitch or a short tetanus. Proceedings of the Royal Society of London. Series B: Biological Sciences, 139, 86–104. Abbott, B. C., Bigland, B., Ritchie, J. M. (1952). The physiological cost of negative work. Journal de Physiologie, 117, 380–390. Armstrong, R. B. (1990). Initial events in exercise-induced muscular injury. Medicine and Science in Sports and Exercise, 22, 429–435. Armstrong, R. B., Ogilvie, R. W., Schwane, J. A. (1983). Eccentric exercise-induced injury to rat skeletal muscle. Journal of Applied Physiology, 54, 80–93. Bischoff, R. (1994). The satellite cell and muscle regeneration. In Myology (eds) Engel, A.G., and Franzini-Armstrong, C. pp. 97-118. McGraw-Hill, New York. Bortz, W. M. (2002). A conceptual framework of frailty: A review. The Journals of Gerontology. Series A: Biological Sciences and Medical Sciences, 57, M283–M288. Brack, A. S., Conboy, M. J., Roy, S., Lee, M., Kuo, C. J., Keller, C., Rando, T. A. (2007). Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science, 317, 807–810. Brooks, S. V. & Faulkner, J. A. (1990). Contraction-induced injury: Recovery of skeletal muscles in young and old mice. American Journal of Physiology (Cell), 258, C436–C442. Brooks, S. V. & Faulkner, J. A. (1996). The magnitude of the initial injury induced by stretches of maximally activated muscle fibres of mice and rats increases in old age. Journal of Physiology (London), 497(Pt 2), 573–580. Brooks, S. V., Zerba, E., Faulkner, J. A. (1995). Injury to muscle fibres after single stretches of passive and maximally stimulated muscles in mice. Journal of Physiology (London), 488(Pt 2), 459–469. Campbell, M. J., McComas, A. J., Petito, F. (1973). Physiological changes in ageing muscles. Journal of Neurology, Neurosurgery and Psychiatry, 36, 174–182. Carlson, M. E., Conboy, M. J., Hsu, M., Barchas, L., Jeong, J., Agrawal, A., Mikels, A. J., Agrawal, S., Schaffer, D. V., Conboy, I. M. (2009). Relative roles of TGF-beta1 and Wnt in the systemic regulation and aging of satellite cell responses. Aging Cell, 8, 676–689. Cheung, K., Hume, P., Maxwell, L. (2003). Delayed onset muscle soreness: Treatment strategies and performance factors. Sports Medicine, 33, 145–164. Claflin, D. R. & Brooks, S. V. (2008). Direct observation of failing fibers in muscles of dystrophic mice provides mechanistic insight into muscular dystrophy. American Journal of Physiology (Cell), 294, C651–C658. Conboy, I. M., Conboy, M. J., Smythe, G. M., Rando, T. A. (2003). Notch-mediated restoration of regenerative potential to aged muscle. Science, 302, 1575–1577. Ervasti, J. M. (2003). Costameres: the Achilles’ heel of Herculean muscle. J Biol Chem, 278, 13591-13594. Doherty, T. J. & Brown, W. F. (1993). The estimated numbers and relative sizes of thenar motor units as selected by multiple point stimulation in young and older adults. Muscle & Nerve, 16, 355–366. Faulkner, J. A., Jones, D. A., Round, J. M. (1989). Injury to skeletal muscles of mice by forced lengthen- ing during contractions. Quarterly Journal of Experimental Physiology, 74, 661–670. Faulkner, J. A , Brooks, S. V, Opiteck, J. A. (1993). Injury to skeletal muscle fibers during contractions: conditions of occurrence and prevention. Phys Ther, 73, 911–921. Faulkner, J. A., Brooks, S. V., Zerba, E. (1995). Muscle atrophy and weakness with aging: contraction-induced injury as an underlying mechanism. J Gerontol A Biol Sci Med Sci, 50 Spec No:124–129. Faulkner, J. A., Larkin, L. M., Claflin, D. R., Brooks, S. V. (2007). Age-related changes in the structure and function of skeletal muscles. Clin Exp Pharmacol Physiol, 34:1091–1096. Feinstein, B., Lindegard, B., Nyman, E., Wohlfart, G. (1955). Morphologic studies of motor units in normal human muscles. Acta Anatomica Scandinavica (Basel), 23, 127–142. 390 J.A. Faulkner et al. Friden, J., Sjostrom, M., Ekblom, B. (1983). Myofibrillar damage following intense eccentric exercise in man. International Journal of Sports Medicine, 4, 170–176. Friden, J., Sfakianos, P. N., Hargens, A. R. (1986). Muscle soreness and intramuscular fluid pres- sure: Ccomparison between eccentric and concentric load. Journal of Applied Physiology, 61, 2175–2179. Hadley, E. C., Ory, M. G., Suzman, R., Weindruch, R., Fried, L. (1993). Physical frailty: A treatable cause of dependence in old age. Journal of Gerontology, 48, 1–88. Hough, T. (1901). Ergographic studies in neuro-muscular fatigue. The American Journal of Physiology, 5, 240–266. Hough, T. (1902). Ergographic studies in muscular soreness. The American Journal of Physiology, 7, 76–92. Huard, J., Li, Y., Fu, F. H. (2002). Muscle injuries and repair: Current trends in research. The Journal of Bone and Joint Surgery, 84-A, 822–832. Jackman, R. W., Kandarian, S. C. (2004). The molecular basis of skeletal muscle atrophy. American Journal of Physiology (Cell), 287, C834–C843. Järvinen, T. A., Järvinen, T. L., Kääriäinen, M., Kalimo, H., Jarvinen, M. (2005). Muscle inju- ries: Biology and treatment. The American Journal of Sports Medicine, 33, 745–764. Jones, D. A., Newham, D. J., Round, J. M., Tolfree, S. E. (1986). Experimental human muscle damage: Morphological changes in relation to other indices of damage. Journal de Physiologie, 375, 435–448. Knuttgen, H. G. & Saltin, B. (1972). Muscle metabolites and oxygen uptake in short-term sub- maximal exercise in man. Journal of Applied Physiology, 32, 690–694. Knuttgen, H. G., Patton, J. F., Vogel, J. A. (1982). An ergometer for concentric and eccentric muscular exercise. Journal of Applied Physiology, 53, 784–788. Koh, T. J. & Brooks, S. V. (2001). Lengthening contractions are not required to induce protection from contraction-induced muscle injury. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 281, R155–R161. Koh, T. J., Peterson, J. M., Pizza, F. X., Brooks, S. V. (2003). Passive stretches protect skeletal muscle of adult and old mice from lengthening contraction-induced injury. The Journals of Gerontology. Series A: Biological Sciences and Medical Sciences, 58, 592–597. Komi, P. V. (2000). Stretch-shortening cycle: A powerful model to study normal and fatigued muscle. Journal of Biomechanics, 33, 1197–1206. Lexell, J., Taylor, C. C., Sjostrom, M. (1988). What is the cause of the ageing atrophy? Total number, size and proportion of different fiber types studied in whole vastus lateralis muscle from 15- to 83-year-old men. Journal of the Neurological Sciences, 84, 275–294. Li, S., Kimura, E., Ng, R., Fall, B. M., Meuse, L., Reyes, M., Faulkner, J. A., Chamberlain, J. S. (2006). A highly functional mini-dystrophin/GFP fusion gene for cell and gene therapy studies of Duchenne muscular dystrophy. Human Molecular Genetics, 15, 1610–1622. Lynch, G. S., Faulkner, J. A. (1998). Contraction-induced injury to single muscle fibers: velocity of stretch does not influence the force deficit. American Journal of Physiology, 275, C1548-C1554. Lynch, G. S., Faulkner, J. A., Brooks, S. V. (2008). Force deficits and breakage rates after single lengthening contractions of single fast fibers from unconditioned and conditioned muscles of young and old rats. American Journal of Physiology (Cell), 295, C249–C256. Macpherson, P. C., Schork, M. A., Faulkner, J. A. (1996). Contraction-induced injury to single fiber segments from fast and slow muscles of rats by single stretches. American Journal of Physiology (Cell), 271, C1438–C1446. McArdle, A., Dillmann, W. H., Mestril, R., Faulkner, J. A., Jackson, M. J. (2004). Overexpression of HSP70 in mouse skeletal muscle protects against muscle damage and age-related muscle dysfunction. The FASEB Journal, 18, 355–357. McCully, K. K. & Faulkner, J. A. (1985). Injury to skeletal muscle fibers of mice following length- ening contractions. Journal of Applied Physiology, 59, 119–126. McCully, K. K. & Faulkner, J. A. (1986). Characteristics of lengthening contractions associated with injury to skeletal muscle fibers. Journal of Applied Physiology, 61, 293–299. 391Role of Contraction-Induced Injury in Age-Related Muscle Wasting and Weakness Monti, R. J., Roy, R. R., Hodgson, J. A., Edgerton, V. R. (1999). Transmission of forces within mammalian skeletal muscles. Journal of Biomechanics, 32, 371–380. Newham, D. J., Mills, K. R., Quigley, B. M., Edwards, R. H. (1983). Pain and fatigue after con- centric and eccentric muscle contractions. Clinical Science, 64, 55–62. Newham, D. J., McPhail, G., Mills, K. R., Edwards, R. H. (1983). Ultrastructural changes after concentric and eccentric contractions of human muscle. Journal of the Neurological Sciences, 61, 109–122. Newham, D. J., Jones, D. A., Clarkson, P. M. (1987). Repeated high-force eccentric exercise: Effects on muscle pain and damage. Journal of Applied Physiology, 63, 1381–1386. Panchangam, A., Claflin, D. R., Palmer, M. L., Faulkner, J. A. (2008). Magnitude of sarcomere extension correlates with initial sarcomere length during lengthening of activated single fibers from soleus muscle of rats. Biophysical Journal, 95, 1890–1901. Patel, T. J. & Lieber, R. L. (1997). Force transmission in skeletal muscle: From actomyosin to external tendons. Exercise and Sport Sciences Reviews, 25, 321–363. Rader, E. P., Song, W., Van Remmen, H., Richardson, A., Faulkner, J. A. (2006). Raising the antioxidant levels within mouse muscle fibres does not affect contraction-induced injury. Experimental Physiology, 91, 781–789. Schwane, J. A. & Armstrong, R. B. (1983). Effect of training on skeletal muscle injury from downhill running in rats. Journal of Applied Physiology, 55, 969–975. Street, S. F. (1983). Lateral transmission of tension in frog myofibers: A myofibrillar network and transverse cytoskeletal connections are possible transmitters. Journal of Cellular Physiology, 114, 346–364. Tatsumi, R. & Allen, R. E. (2004). Active hepatocyte growth factor is present in skeletal muscle extracellular matrix. Muscle & Nerve, 30, 654–658. Tatsumi, R., Liu, X., Pulido, A., Morales, M., Sakata, T., Dial, S., Hattori, A., Ikeuchi, Y., Allen, R. E. (2006). Satellite cell activation in stretched skeletal muscle and the role of nitric oxide and hepatocyte growth factor. American Journal of Physiology (Cell), 290, C1487–C1494. Tidball, J. G. (1995). Inflammatory cell response to acute muscle injury. Medicine and Science in Sports and Exercise, 27, 1022–1032. Williams, M. W., Resneck, W. G., Kaysser, T., Ursitti, J. A., Birkenmeier, C. S., Barker, J. E., Bloch, R. J. (2001). Na,K-ATPase in skeletal muscle: two populations of beta-spectrin control localization in the sarcolemma but not partitioning between the sarcolemma and the transverse tubules. Journal of Cell Science, 114, 751–762. 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: mgrounds@anhb.uwa.edu.au; tshavlakadze@anhb.uwa.edu.au C.D. McMahon AgResearch Limited, Ruakura Research Centre, Hamilton, New Zealand e-mail: chris.mcmahon@agresearch.co.nz 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 . 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. 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 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).