Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice

Abstract

Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghrelin is a peptide hormone that stimulates growth hormone (GH) release and positive energy balance through binding to the receptor GHSR-1a. Only acylated ghrelin (AG), but not the unacylated form (UnAG), can bind GHSR-1a; however, UnAG and AG share several GHSR-1a-independent biological activities. Here we investigated whether UnAG and AG could protect against skeletal muscle atrophy in a GHSR-1a-independent manner. We found that both AG and UnAG inhibited dexamethasone-induced skeletal muscle atrophy and atrogene expression through PI3Kβ-, mTORC2-, and p38-mediated pathways in myotubes. Upregulation of circulating UnAG in mice impaired skeletal muscle atrophy induced by either fasting or denervation without stimulating muscle hypertrophy and GHSR-1a-mediated activation of the GH/IGF-1 axis. In Ghsr-deficient mice, both AG and UnAG induced phosphorylation of Akt in skeletal muscle and impaired fasting-induced atrophy. These results demonstrate that AG and UnAG act on a common, unidentified receptor to block skeletal muscle atrophy in a GH-independent manner.

Ghrelin Gene Products in Acute and Chronic Inflammation

“…Although ghrelin may undeniably inhibit cachexia through the GHS-R1a-mediated anti-inflammatory and orexigenic activities, some evidences prove that both acylated and unacylated ghrelin have a direct anti-atrophic activity in skeletal muscles: unacylated ghrelin, which does not bind GHS-R1a and does not activate the GH/IGF-1 axis, reduces burn-induced skeletal muscle proteolysis and TNF-a up-regulation in rats (Sheriff et al 2012), counteracts muscle atrophy induced by either fasting or denervation, and, as a final point, both acylated and unacylated peptides impairs fasting-induced atrophy in Ghsr null mice (Porporato et al 2013).…”

“…Since unacylated ghrelin shares with ghrelin common high affinity binding sites in various cell lines, including cells lacking GHS-R1a (Baldanzi et al 2002;Cassoni et al 2001Cassoni et al , 2004Filigheddu et al 2007;Granata et al 2007;Jeffery et al 2002;Muccioli et al 2004), and they share biological activities in vivo, also in Ghsr null mice (Porporato et al 2013), both peptides act in all probability through a common, although yet unidentified, receptor.…”

Ghrelin for the management of cachexia associated with cancer

“…Both acytylated and unacytylated ghrelin blocks skeletal muscle atrophy in a growth hormone-independent manner (Porporato 2013). In vitro studies have demonstrated that ghrelin may regulate mesenchymal cell development by stimulating myogenesis (Zhang 2007).…”

Unacylated Ghrelin Reduces Skeletal Muscle Reactive Oxygen Species Generation and Inflammation and Prevents High-Fat Diet–Induced Hyperglycemia and Whole-Body Insulin Resistance in Rodents

“…We therefore studied lean rats and a transgenic mouse model of systemic UnAG overproduction (19) to test the hypothesis that UnAG 1) lowers mitochondrial ROS production and inflammation and enhances insulin action in lean rodent muscle and 2) normalizes high-fat diet (HFD)-induced muscle metabolic alterations, whole-body insulin resistance, and hyperglycemia. In addition, effects of UnAG were verified in vitro in myotubes, where we also mechanistically tested the hypothesis that UnAG activities are at least partly mediated by positive modulation of autophagy.…”