Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice

The Journal of clinical investigation (Impact Factor: 13.22). 01/2013; 123(2). DOI: 10.1172/JCI39920
Source: PubMed


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.

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Available from: Sharmila Fagoonee, Oct 08, 2014
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    • "It has been reported that both AG and UnAG activate PI3Kβ‐mTORC2 pathways in C2C12 cell line and protect myotubes from dexamethazone‐induced atrophy.27 In our in vitro model of ischemia, we were unable to demonstrate the activation of these signaling pathways (data not shown). "
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    ABSTRACT: Surgical treatment of peripheral artery disease, even if successful, does not prevent reoccurrence. Under these conditions, increased oxidative stress is a crucial determinant of tissue damage. Given its reported antioxidant effects, we investigated the potential of unacylated-ghrelin (UnAG) to reduce ischemia-induced tissue damage in a mouse model of peripheral artery disease. We show that UnAG but not acylated ghrelin (AG) induces skeletal muscle regeneration in response to ischemia via canonical p38/mitogen-actived protein kinase signaling UnAG protected against reactive oxygen species-induced cell injuries by inducing the expression of superoxide dismutase-2 (SOD-2) in satellite cells. This led to a reduced number of infiltrating CD68(+) cells and was followed by induction of the myogenic process and a reduction in functional impairment. Moreover, we found that miR-221/222, previously linked to muscle regeneration processes, was up-regulated and negatively correlated with p57(Kip2) expression in UnAG-treated mice. UnAG, unlike AG, promoted cell-cycle entry in satellite cells of mice lacking the genes for ghrelin and its receptor (GHSR1a). UnAG-induced p38/mitogen-actived protein kinase phosphorylation, leading to activation of the myogenic process, was prevented in SOD-2-depleted SCs. By siRNA technology, we also demonstrated that SOD-2 is the antioxidant enzyme involved in the control of miR-221/222-driven posttranscriptional p57(Kip2) regulation. Loss-of-function experiments targeting miR-221/222 and local pre-miR-221/222 injection in vivo confirmed a role for miR-221/222 in driving skeletal muscle regeneration after ischemia. These results indicate that UnAG-induced skeletal muscle regeneration after ischemia depends on SOD-2-induced miR-221/222 expression and highlight its clinical potential for the treatment of reactive oxygen species-mediated skeletal muscle damage.
    Journal of the American Heart Association 10/2013; 2(6):e000376. DOI:10.1161/JAHA.113.000376 · 4.31 Impact Factor
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    • "Recently the hormone ghrelin was found to prevent muscle wasting (Porporato et al., 2013). Ghrelin is a peptide hormone that stimulates growth hormone (GH) release and positive energy balance through binding to the receptor GHSR-1a. "
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    ABSTRACT: Skeletal muscle adapts its mass as consequence of physical activity, metabolism and hormones. Catabolic conditions or inactivity induce signaling pathways that regulate the process of muscle loss. Muscle atrophy in adult tissue occurs when protein degradation rates exceed protein synthesis. Two major protein degradation pathways, the ubiquitin-proteasome and the autophagy-lysosome systems, are activated during muscle atrophy and variably contribute to the loss of muscle mass. These degradation systems are controlled by a transcription dependent program that modulate the expression of rate-limiting enzymes of these proteolytic systems. The transcription factors FoxO3, which is negatively regulated by Insulin-Akt pathway, and NF-κB, which is activated by inflammatory cytokines, were the first to be indentified as critical for the atrophy process. In the last years a variety of pathways and transcription factors have been found to be involved in regulation of atrophy. This review will focus on the last progress in ubiquitin-proteasome and autophagy-lysosome systems and their involvement in muscle atrophy.
    The international journal of biochemistry & cell biology 05/2013; 45(10). DOI:10.1016/j.biocel.2013.04.023 · 4.05 Impact Factor
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    ABSTRACT: Ghrelin circulates into two different forms: (1) acylated ghrelin (AG) which holds an n-octanoic acid at its third serine residue, and (2) des-acyl ghrelin (DAG). AG, but not DAG, binds the GH secretagogue type 1a receptor (GHS-R1a) and stimulates secretion of GH and other pituitary hormones. Accumulating evidence indicate that both AG and DAG have non-GHS-R1a-mediated biological activities and particularly exert a significant role in the fine-tuning of insulin secretion and glucose metabolism, sometimes acting as agonists others as antagonists. DAG promotes insulin secretion from β-cell lines and enhances the portal insulin response following an intravenous glucose tolerance test in rats. In addition, DAG has been shown to inhibit in vitro hepatic glucose output, suggesting that at least part of the beneficial effect on glucose could also be secondary to an insulin-independent mechanism. Finally, recent results suggest that DAG has also proliferative and protective effects on β-cells. Transgenic mice over-expressing DAG display reduced fat mass and blood triglycerides. Also, the coadministration of AG and DAG reduces plasma FFA in GHD patients. Finally, results of recent preliminary experiments on circulating angiogenic cells (CAC) suggest that DAG may beneficially impact the vascular remodeling process, which is known to be impaired in type 2 diabetes patients. In this chapter, we summarize the data that indicate that DAG exerts several important (metabolic) actions that should separate DAG from AG and make DAG a signaling factor with its own intrinsic role in many metabolic processes.
    Ghrelin in Health and Disease, 01/2012: pages 267-275; , ISBN: 978-1-61779-902-0
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