Intractable Rare Dis Res. 2016;5(1):17-24. (DOI: 10.5582/irdr.2015.01041)

Insulin-driven translational capacity is impaired in primary fibroblasts of Prader Willi.

Meneghello C, Segat D, Fortunati E

Prader-Willi (PW) syndrome is a rare genetic disorder characterized by hypothalamic-pituitary abnormalities and severe hypotonia, hyperphagia, behavioural and psychiatric problems. Absence of satiety leads to severe obesity and frequently to diabetes. Furthermore, adult patients suffer from a severe loss of muscle mass, which severely impacts their quality of life. The mechanisms underlying alterations in muscle growth in PW remain to be clarified. In this study we explored the hypothesis that, in PW cells, alterations of protein synthesis are determined by dysfunctions in the promotion of cell growth. In order to study the molecular changes leading to dysfunction in protein translation, primary fibroblasts derived from four PW patients and five control subjects were used to study the insulin-mediated signaling pathway implicated in the control of protein synthesis by immunoblotting. Here we present, for the first time, evidences that the protein translation response to insulin is impaired in PW fibroblasts. Insulin alone has a major upregulatory effect on protein kinase B (AKT), glycogen synthase kinase (GSK3beta), while phosphorylation of p70S6K1 protein elongation factor controlled by mammalian target of rapamycin complex I (mTORC1) is reduced. In addition, we provide data that the response to insulin in PW cells can be restored by previous treatment with the amino acid L-Leucine (L-Leu). Our experiments in primary cell cultures demonstrate an impairment of insulin signaling that can be rescued by supplementation with the branched aminoacid L-Leu, indicating a possible therapeutic approach for alleviating muscle mass loss in PW patients.

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