Review
Modulation of GH/IGF-1 axis: Potential strategies to counteract sarcopenia in older adults

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Abstract

Aging is associated with progressive decline of skeletal muscle mass and function. This condition, termed sarcopenia, is associated with several adverse outcomes, including loss of autonomy and mortality. Due to the high prevalence of sarcopenia, a deeper understanding of its pathophysiology and possible remedies represents a high public health priority. Evidence suggests the existence of a relationship between declining growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels and age-related changes in body composition and physical function. Therefore, the age-dependent decline of GH and IGF-1 serum levels may promote frailty by contributing to the loss of muscle mass and strength. Preclinical studies showed that infusion of angiotensin II produced a marked reduction in body weight, accompanied by decreased serum and muscle levels of IGF-1. Conversely, overexpression of muscle-specific isoform of IGF-1 mitigates angiotensin II-induced muscle loss. Moreover, IGF-1 serum levels have been shown to increase following angiotensin converting enzyme inhibitors (ACEIs) treatment. Here we will review the most recent evidence regarding age-related changes of the GH/IGF-1 axis and its modulation by several interventions, including ACEIs which might represent a potential novel strategy to delay the onset and impede the progression of sarcopenia.

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

References (129)

  • T.B. Harris et al.

    Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly

    Am. J. Med.

    (1999)
  • J.O. Jorgensen et al.

    Beneficial effects of growth hormone treatment in GH-deficient adults

    Lancet

    (1989)
  • M.E. Lewis et al.

    Insulin-like growth factor-I: potential for treatment of motor neuronal disorders

    Exp. Neurol.

    (1993)
  • G.S. Lynch et al.

    IGF-I treatment improves the functional properties of fast- and slow-twitch skeletal muscles from dystrophic mice

    Neuromuscul. Disord.

    (2001)
  • M. Maggio et al.

    Relation of angiotensin-converting enzyme inhibitor treatment to insulin-like growth factor-1 serum levels in subjects >65 years of age (the InCHIANTI study)

    Am. J. Cardiol.

    (2006)
  • L.C. Martineau et al.

    Age-associated alterations in cardiac and skeletal muscle glucose transporters, insulin and IGF-1 receptors, and PI3-kinase protein contents in the C57BL/6 mouse

    Mech. Ageing Dev.

    (1999)
  • J. Niebauer et al.

    Deficient insulin-like growth factor I in chronic heart failure predicts altered body composition, anabolic deficiency, cytokine and neurohormonal activation

    J. Am. Coll. Cardiol.

    (1998)
  • G. Onder et al.

    Relation between use of angiotensin-converting enzyme inhibitors and muscle strength and physical function in older women: an observational study

    Lancet

    (2002)
  • V. Owino et al.

    Age-related loss of skeletal muscle function and the inability to express the autocrine form of insulin-like growth factor-1 (MGF) in response to mechanical overload

    FEBS Lett.

    (2001)
  • D.R. Powell et al.

    Insulin inhibits transcription of the human gene for insulin-like growth factor-binding protein-1

    J. Biol. Chem.

    (1991)
  • X. Qin et al.

    Structure-function analysis of the human insulin-like growth factor binding protein-4

    J. Biol. Chem.

    (1998)
  • D.L. Allen et al.

    Growth hormone/IGF-I and/or resistive exercise maintains myonuclear number in hindlimb unweighted muscles

    J. Appl. Physiol.

    (1997)
  • N.B. Andersen et al.

    Growth hormone and mild exercise in combination increases markedly muscle mass and tetanic tension in old rats

    Eur. J. Endocrinol.

    (2000)
  • E. Arvat et al.

    Insulin-Like growth factor I: implications in aging

    Drugs Aging

    (2000)
  • F.J. Ballard et al.

    Effects of anabolic agents on protein breakdown in L6 myoblasts

    Biochem. J.

    (1983)
  • M. Barbieri et al.

    Chronic inflammation and the effect of IGF-I on muscle strength and power in older persons

    Am. J. Physiol. Endocrinol. Metab.

    (2003)
  • E.R. Barton et al.

    Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice

    J. Cell Biol.

    (2002)
  • E.R. Barton-Davis et al.

    Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function

    Proc. Natl. Acad. Sci. U. S. A.

    (1998)
  • E.R. Barton-Davis et al.

    Contribution of satellite cells to IGF-I induced hypertrophy of skeletal muscle

    Acta Physiol. Scand.

    (1999)
  • S. Bhasin et al.

    Testosterone dose–response relationships in healthy young men

    Am. J. Physiol. Endocrinol. Metab.

    (2001)
  • M.R. Blackman et al.

    Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial

    JAMA

    (2002)
  • M. Boni-Schnetzler et al.

    Insulin regulates insulin-like growth factor I mRNA in rat hepatocytes

    Am. J. Physiol.

    (1991)
  • S. Boonen et al.

    Relationship between age-associated endocrine deficiencies and muscle function in elderly women: a cross-sectional study

    Age Ageing

    (1998)
  • S.E. Borst et al.

    Role of IGF-I in muscular atrophy of aging

    Endocrine

    (1997)
  • K.T. Brill et al.

    Single and combined effects of growth hormone and testosterone administration on measures of body composition, physical performance, mood, sexual function, bone turnover, and muscle gene expression in healthy older men

    J. Clin. Endocrinol. Metab.

    (2002)
  • M. Brink et al.

    Angiotensin II induces skeletal muscle wasting through enhanced protein degradation and down-regulates autocrine insulin-like growth factor I

    Endocrinology

    (2001)
  • M. Brink et al.

    Angiotensin II causes weight loss and decreases circulating insulin-like growth factor I in rats through a pressor-independent mechanism

    J. Clin. Invest.

    (1996)
  • N.J. Brown et al.

    ACE insertion/deletion genotype affects bradykinin metabolism

    J. Cardiovasc. Pharmacol.

    (1998)
  • A.R. Cappola et al.

    Association of IGF-I levels with muscle strength and mobility in older women

    J. Clin. Endocrinol. Metab.

    (2001)
  • E. Carmeli et al.

    Effect of growth hormone on gastrocnemius muscle of aged rats after immobilization: biochemistry and morphology

    J. Appl. Physiol.

    (1993)
  • G.D. Cartee et al.

    Growth hormone supplementation increases skeletal muscle mass of old male Fischer 344/brown Norway rats

    J. Gerontol. A Biol. Sci. Med. Sci.

    (1996)
  • C.M. Cuttica et al.

    Effects of six-month administration of recombinant human growth hormone to healthy elderly subjects

    Aging (Milano.)

    (1997)
  • L. Dalla Libera et al.

    Beneficial effects of GH/IGF-1 on skeletal muscle atrophy and function in experimental heart failure

    Am. J. Physiol. Cell Physiol.

    (2004)
  • W.H. Daughaday

    Growth hormone axis overview—somatomedin hypothesis

    Pediatr. Nephrol.

    (2000)
  • D.L. DeVol et al.

    Activation of insulin-like growth factor gene expression during work-induced skeletal muscle growth

    Am. J. Physiol.

    (1990)
  • R. Deyssig et al.

    Effect of growth hormone treatment on hormonal parameters, body composition and strength in athletes

    Acta Endocrinol. (Copenh)

    (1993)
  • M. Di Bari et al.

    Antihypertensive medications and differences in muscle mass in older persons: the Health, Aging and Body Composition Study

    J. Am. Geriatr. Soc.

    (2004)
  • G.J. Dietze et al.

    Potential role of bradykinin in forearm muscle metabolism in humans

    Diabetes

    (1996)
  • H.C. Dreyer et al.

    Role of protein and amino acids in the pathophysiology and treatment of sarcopenia

    J. Am. Coll. Nutr.

    (2005)
  • J. Egido et al.

    Anti-inflammatory actions of quinapril

    Cardiovasc. Drugs Ther.

    (2007)
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