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

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.

Fig. 1

Synoptic view of the GH/IGF-1 axis. GH is released from the anterior pituitary gland in response to hypothalamus stimulus. Growth hormone releasing hormone (GHRH) initiates the pulse, which is self-limiting. IGF-1 circulates in both a “free” and “bound” state. The main circulating form of IGF-1 is IGF-1 + IGFBP-3 + ALS (acid labile subunit). Both bound and free circulating IGF-1 is represented by the IGF-1Ea form. There are also GH-independent, autocrine/paracrine isoforms of IGF-1 produced by skeletal muscle: IGF-1Ea and MGF or IGF-1Ec in humans; IGF-1Ea and IGF-1Eb in rodents. Dashed lines indicate age-related changes.

Fig. 2

Actions of IGF-1 and angiotensin II in skeletal muscle. Binding of muscle IGF-1 to IGF-1 receptors via intracellular signaling pathways involving tyrosine kinase (TK) activity may exert antiapoptotic effect and reduce muscle atrophy via phosphatidylinositol 3-kinase (PI3K)-dependent Akt Kinase (Akt)-dependent phosphorylation. On the other hand, Ang II down-regulates IGF-1, IGFBP-3 and IGFBP-5 genes, thus negatively affecting the autocrine IGF-1 system. Moreover, Ang II can also stimulate the ubiquitin-proteasome pathway as a result of increased expression of atrophy-related ubiquitin ligases (atrogin-1 and MuRF-1).