Vitamin D and VDR in cancer cachexia and muscle regeneration

// Andrea Camperi 1, 5, * , Fabrizio Pin 1, 2, * , Domiziana Costamagna 1, 2, 8 , Fabio Penna 1, 2 , Maria Lopez Menduina 1, 3 , Zaira Aversa 4 , Teresa Zimmers 5 , Roberto Verzaro 6 , Raffaella Fittipaldi 7 , Giuseppina Caretti 7 , Francesco Maria Baccino 1 , Maurizio Muscaritoli 4 , Paola Costelli 1, 2 1 Department of Clinical and Biological Sciences, University of Turin, Turin, Italy 2 Interuniversity Institute of Myology, Italy 3 Department of Physiology, Complutense University of Madrid, Madrid, Spain 4 Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy 5 Indiana University School of Medicine - IUPUI, Indianapolis, IN, USA 6 Department of Surgery, M.G. Vannini Hospital, Rome, Italy 7 Department of Biosciences, University of Milan, Milan, Italy 8 Current address: Translational Cardiomyology Laboratory, Stem Cell Biology and Embryology, Department of Development and Regeneration, University Hospital Gasthuisberg, Leuven, Belgium * Andrea Camperi and Fabrizio Pin equally contributed to the present study Correspondence to: Paola Costelli, email: paola.costelli@unito.it Keywords: muscle wasting, regeneration, vitamin D receptor, myogenin, circulating vitamin D Received: July 28, 2016     Accepted: January 27, 2017     Published: February 21, 2017 ABSTRACT Low circulating levels of vitamin D were associated with decreased muscle strength and physical performance. Along this line, the present study was aimed to investigate: i) the therapeutic potential of vitamin D in cancer-induced muscle wasting; ii) the mechanisms by which vitamin D affects muscle phenotype in tumor-bearing animals. Rats bearing the AH130 hepatoma showed decreased circulating vitamin D compared to control rats, while muscle vitamin D receptor (VDR) mRNA was up-regulated. Both circulating vitamin D and muscle VDR expression increased after vitamin D administration, without exerting appreciable effects on body weight and muscle mass. The effects of vitamin D on muscle cells were studied in C2C12 myocytes. Vitamin D-treated myoblasts did not differentiate properly, fusing only partially and forming multinucleated structures with aberrant shape and low myosin heavy chain content. Vitamin D treatment resulted in VDR overexpression and myogenin down-regulation. Silencing VDR expression in C2C12 cultures abrogated the inhibition of differentiation exerted by vitamin D treatment. These data suggest that VDR overexpression in tumor-bearing animals contributes to muscle wasting by impairing muscle regenerative program. In this regard, attention should be paid when considering vitamin D supplementation to patients affected by chronic pathologies where muscle regeneration may be involved.