The GH/IGF1 axis and signaling pathways in the muscle and bone: mechanisms underlying age-related skeletal muscle wasting and osteoporosis

Abstract

The widespread increase in life expectancy is accompanied by an increased prevalence of features of physical frailty. Signs and symptoms may include sarcopenia and osteopenia, reduced exercise capacity, and diminished sense of wellbeing. The pathogenesis of age-associated sarcopenia and osteopenia is multifactorial, and hormonal decline may be a contributing factor. Aging is associated with a progressive decrease in GH secretion, and more than 30% of elderly people have circulating IGF1 levels below the normal range found in the young. GH acts directly on target tissues, including skeletal muscle and bone among many others, but many effects are mediated indirectly by circulating (liver-derived) or locally produced IGF1. Aging is also associated with reduced insulin sensitivity which, in turn, may contribute to the impairment of IGF1 action. Recent experimental evidence suggests that besides the agedependent decline in GH and IGF1 serum levels, the dysregulation of GH and IGF1 actions due to impairment of the post-receptor signaling machinery may contribute to the loss of muscle mass and osteopenia. This article will focus on the molecular mechanisms of impaired GH and IGF1 signaling and action in aging, and their role in the pathogenesis of sarcopenia and osteoporosis.

Sex-specific differences in risk factors for sarcopenia amongst community-dwelling older adults

“…The growth hormone/IGF-1 axis has been widely examined as a potential mediator of skeletal muscle loss (Perrini et al 2010;Harridge 2003;Scicchitano et al 2009). In a recent application of the EWGSOP criteria for sarcopenia in community-dwelling older people, IGF-1 in the lowest tertile was associated with approximately fourfold higher odds for sarcopenia, a finding that was initially corroborated in our study (Volpato et al 2014).…”

Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue

“…These pathological states share unique features and are all characterized by a loss of collagen type I, dysregulated fibroblast-matrix interactions and impaired fibroblast interactions with organ parenchyma, mainly with organ-specific epithelial cells and muscle (Wenk et al, 1999(Wenk et al, , 2004Krtolica & Campisi, 2002;Campisi, 2005;Labat-Robert & Robert, 2007;Treiber et al, 2009). A variety of genetic and environmental factors including increased concentration of ROS, mitochondrial dysfunction (Hiona & Leeuwenburgh, 2008), changes in autocrine, paracrine and endocrine release of hormones, growth factors (Perrini et al, 2010) and cytokines (Coppe et al, 2008) have been identified to contribute to skin aging, sarcopenia and osteoporosis in humans and rodents (Zofkova, 2003;Raisz, 2005;Ralston & de Crombrugghe, 2006;Hiona & Leeuwenburgh, 2008;Marzetti et al, 2009). Research on the regulation of connective tissue organization by enhanced release of ROS from mitochondria during fibroblast aging is a matter of increasing interest and relevance as it may provide ultimate clues for mechanisms underlying disruption of connective tissue homoeostasis in aging-related skin atrophy, sarcopenia and osteoporosis.…”

Nutritional influences on age-related skeletal muscle loss

“…Metabolic acidosis potentially accelerates proteolysis and amino acid catabolism, probably through activation of caspase-3 and the ubiquitin proteasome system or via effects on the growth hormone/IGF-1 axis (97,(182)(183)(184)(185)(186) .…”