Previous results showed that our physical rehabilitation program could induce weight loss in a group of adult PWS patients, but failed to improve their muscular mass (Grolla et al.2010). The loss of muscle mass affects elderly, obese and PWS patients leading to frailty and impaired quality of life. It is becoming apparent, using animal models, that the consequences of high fat diet is not just an increase in fat mass but also a decrease in the skeletal muscle mass (Sitnick et al, 2009, Pedersen BK, 2010). The mechanism responsible of muscle mass growth is the rate of protein synthesis controlled by an enzyme called mTOR (Pende M, 2006). This enzyme allows cells to modify the rate of protein synthesis in response to extracellular signals, such nutrients hormones and training. In high fat diet the rate of protein synthesis is unbalanced and is caused by mTOR malfunction. A consequence of that is a decrease in muscle mass as observed in animal experiments. There are data in the literature showing the efficacy of physical training in regaining muscle mass in obese adults (Frimel T. et al 2008). The key question is why resistance training had no effect on adult PWS muscular mass. Our hypothesis is the existence in PWS cells of dysfunctions in the integration of nutrients and energy balance signals which results in persistent alteration of protein synthesis rate. Our proposal is to obtain PWS muscle cells and to verify the existence of such defects. We will investigate the details of such impairment at molecular levels. Our study, if successfully, will provide an in vitro muscle model for PWS that is actually still missing. In addition it will shed light on key regulatory mechanisms implicated in the regulation of the muscular mass in PWS. Furthermore, it will help in elucidating possible therapeutic interventions in order to contrast frailty of PWS patients.
The main purpose of our research is to shed light on molecular mechanisms that cause muscle wasting in Prader Willi (PW). A key condition of our approach was the generation of an in vitro model that reproduces the muscle condition observed in patients. To this end, we reprogrammed PW fibroblasts from skin biopsies and differentiated them into muscle cells. Thanks to the financial support from the FPWR foundation, we generated induced pluripotent stem cells (iPS) from two patients by an innovative technology based on synthetic mRNA. This nonintegrating strategy is actually being tested for its ability to drive muscle cell differentiation. The full evaluation of iPS pluripotency and their capacity of myogenic differentiation will support their use for modelling in vitro PW muscle atrophy. This is a unique opportunity to understand developmental and regulatory mechanisms underlying muscle atrophy, and to identify novel drugs and therapeutic interventions to contrast frailty of PW patients.
Insulin-driven translational capacity is impaired in primary fibroblasts of Prader Willi. Meneghello C, Segat D, Fortunati E. Intractable & Rare Diseases Research. 2016 Feb;5(1):17-24.
Elisabetta Fortunati, PhD
Baschirotto Institute for Rare Diseases, Italy