THU515 Vitamin D Binding Protein Induces Skeletal Muscle Atrophy And Contributes To Cancer-associated Muscle Wasting

Abstract

Abstract Disclosure: T. Raiteri: None. S. Reano: None. A. Scircoli: None. I. Zaggia: None. F. Prodam: None. N. Filigheddu: None. Vitamin D binding protein (VDBP), encoded by the Gc gene, is a multifunctional serum glycoprotein synthesized by hepatocytes, whose primary function is the transport of vitamin D metabolites in the bloodstream. In addition, VDBP enhances the chemotactic activity of neutrophil chemoattractants and takes part in the actin-scavenger system by acting as a monomeric G-actin-binding protein. Several studies have reported a correlation between increased levels of VDBP and various pathologies often associated with muscle wasting, including different types of tumors. Given these findings, we hypothesized that VDBP may play a role in muscle atrophy and cancer-associated muscle wasting and investigated its direct effects on skeletal muscle homeostasis in vitro and in vivo. We showed that, in C2C12 myotubes, VDBP uptake through megalin-mediated endocytosis induced mitochondrial dysfunction and exacerbation of mitophagy that resulted in atrophy. Furthermore, VDBP treatment impaired myoblast differentiation and the formation and stability of acetylcholine receptor (AChR) clusters, an in vitro model of neuromuscular junctions (NMJ). The main molecular mechanism behind the atrophic effect of VDBP is the perturbation of intracellular actin dynamics due to VDBP's ability to bind G-actin. To assess if VDBP has a causative role in muscle homeostasis also in vivo, we experimentally induced the expression of VDBP in Gc knock-out mice (VDBP KO) by adeno-associated virus (AAV)-mediated gene delivery, and we observed that a relatively small amount of circulating VDBP was sufficient to affect muscle performances and reduce muscle mass. Moreover, coherently with the in vitro data, VDBP induced morphological abnormalities in the NMJ. Coherently with the upregulation of VDBP observed in cancer patients, we detected an increase of VDBP in two commonly used models of cancer cachexia, C26 colon carcinoma and Lewis Lung Carcinoma (LLC) tumor-bearing mice. To test the hypothesis that VDBP could play a role in cancer-associated muscle wasting, we induced cancer cachexia in VDBP KO mice by inoculating LLC cells. Tumor-bearing VDBP KO mice preserved their body weight and performances, and the muscle loss and NMJ dismantling were minimal compared to cachectic WT mice. Although the primary function of VDBP is the transport of vitamin D metabolites, we demonstrated that VDBP acts as a hormone per se, having a direct pro-atrophic activity on skeletal muscle. Altogether, our data suggest that VDBP is a new player in the onset of cancer-associated muscle wasting, thus representing a potential therapeutic target to treat cancer cachexia. Presentation: Thursday, June 15, 2023