ReviewModulation of GH/IGF-1 axis: Potential strategies to counteract sarcopenia in older adults
Introduction
Frailty is a common pathophysiological condition in older adults characterized by diminished reserve capacity and increased risk of disability, institutionalization and mortality. Poor muscle strength is a central feature of frailty, and sarcopenia has been identified as a major modifiable risk factor for this syndrome (Roubenoff, 2000). Multiple factors have been evoked in the etiology of sarcopenia. Among them, atrophy of skeletal muscle fibers secondary to loss of α-motor neurons (Vandervoort, 2002) appears to represent a major causative factor. Other mechanisms are also involved, such as physical inactivity (Szulc et al., 2004), increased levels of pro-inflammatory cytokines (e.g., tumor necrosis factor-α, interleukin-1β, interleukin-6, etc.) (Visser et al., 2002), increased production of free radicals and/or diminished antioxidant defense systems (Fulle et al., 2004), malnutrition (Dreyer and Volpi, 2005), and low anabolic hormone output (e.g., testosterone, growth hormone, etc.) (Szulc et al., 2004). Regarding the latter, attention has been recently focused on the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis, which is regarded as an important regulator of body composition. Notably, local as well as systemic isoforms of IGF-1 have been described. Skeletal muscle expresses at least two distinct splicing variants of IGF-1, namely IGF-1Ea, which is similar to the systemic form, and the mechano growth factor (MGF), which is released in response to physical activity (Yang et al., 1996). These two muscle-derived variants of IGF-1 have different actions, with IGF-1Ea being a potent stimulator of protein synthesis, while MGF promotes satellite cells proliferation.
Serum levels of GH as well as those of its systemic mediators decline with advancing age, and this has been associated with detrimental changes in body composition (i.e., reduction of lean body mass and increased adiposity). Besides the dysfunction of GH/IGF-1 axis, alteration of other humoral factors may be involved in the onset and progression of muscle loss and physical disability at old age. In this regard, angiotensin II has been shown to enhance protein degradation and reduce the autocrine production of IGF-1 in rat muscle (Brink et al., 1996, Brink et al., 2001). In contrast, overexpression of muscle-specific IGF-1 (both splicing variants) almost completely prevented angiotensin II-induced muscle loss in mice (Song et al., 2005). Recent evidence suggests that angiotensin converting enzyme inhibitors (ACEIs) may induce positive changes on body composition and physical function in older populations (Onder et al., 2002). It is also documented that ACEIs increase blood flow to muscles (Frisbee and Lombard, 2000), raise skeletal muscle glucose uptake (Kudoh and Matsuki, 2000), and reduce systemic secretion of inflammatory cytokines (Egido and Ruiz-Ortega, 2007). These effects are attributed primarily, but not exclusively, to the inhibition of the renin–angiotensin–aldosterone system.
Here, we will review the most recent findings regarding the modulation of GH/IGF-1 axis by systemic and/or autocrine up-regulation of IGF-1 and ACEIs as potential strategies to counteract the age-associated muscle loss.
Section snippets
Biological actions of IGF-1 in skeletal muscle
IGF-1 is perhaps the most important mediator of muscle growth and repair (Goldspink, 2007) and is produced in several ways. In response to GH, the liver produces IGF-1 for systemic release. Skeletal muscle also produces and secretes IGF-1 that possesses autocrine and paracrine actions (Daughaday, 2000). Muscle IGF-1 production may occur in response to GH (Sadowski et al., 2001), testosterone (Bhasin et al., 2001), and muscle overload and stretch (Goldspink et al., 2002). DeVol et al. (1990)
Age-related changes in IGF-1 actions
Several studies suggest that IGF-1 is an important modulator of muscle mass, muscle strength and function, not only during development, but also across the entire life span (Ballard and Francis, 1983, Borst and Lowenthal, 1997). In a recent study, Grounds (2002) has concluded that loss of muscle mass occurring with age is mainly a result of atrophy and subsequent reduction in myofiber number (particularly fast-twitch type 2B), whereas impaired muscle regeneration may be only marginally
Effects of GH supplementation on skeletal muscle in the elderly
The effects of GH administration on muscle mass, strength and physical performance are still under debate (Table 1, Table 2). In animal models, GH supplementation appears to be more effective in states of GH deficiency or reduced GH secretion (Table 1) than in normal hormonal state. In fact, in hypophysectomized rats, GH replacement has been shown to restore muscle mass and improve muscle fiber size and/or composition (Grindeland et al., 1994, Roy et al., 1996, Everitt et al., 1996), with an
ACE-inhibitors as a novel strategy to counteract sarcopenia by modulating the GH/IGF-1 axis
Angiotensin II (Ang II), besides its well-known haemodynamic effects, has been shown to produce a marked reduction in body weight in animal models as a result of increased protein degradation (Brink et al., 1996, Brink et al., 2001). This effect has been attributed to a reduction of local production of IGF-1 (Brink et al., 1996, Brink et al., 2001) and impaired insulin signaling at the muscle level (Folli et al., 1997). On the other hand, overexpression of muscle-specific IGF-1 almost
Conclusions
The current literature does not provide uniform evidence on the effectiveness of the modulation of GH/IGF-1 axis as a strategy to improve muscle strength and function in older adults. In particular, the effectiveness of GH supplementation, the most direct approach tested, in ameliorating muscle strength and physical performance at old age is not supported by scientific evidence either in humans or in animal models (Table 1, Table 2). Modulation of the paracrine/autocrine IGF-1 system may be
Acknowledgements
The authors would like to thank Ms. Hazel Lees for the editing of the manuscript. This research was supported by grants to C.L. (NIA R01-AG17994 and AG21042) and S.B. (Department of Veterans Affairs Merit Award). S.G. is partly supported by the Department of Gerontology, Geriatrics and Physiatrics of the Catholic University of the Sacred Heart of Rome, Italy. E.M. is supported by the University of Florida Institute on Aging and Claude D. Pepper Older Americans Independence Center (1 P30
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