Vitamin D binding protein induces skeletal muscle atrophy and contributes to cancer-associated muscle wasting independently of vitamin D status in preclinical models

: The maintenance of skeletal muscle is of pivotal importance, as its loss is often associated with progressive pathologies, generally worsening the prognosis. Increased levels of vitamin D binding protein (VDBP) were reported in diseases susceptible to muscle wasting, including several tumors. We hypothesized that VDBP might participate in muscle wasting and investigated its direct effects on skeletal muscle homeostasis. Here, we demonstrate that VDBP induces atrophy independently of vitamin D. In C2C12 myotubes, we identified intracellular actin dynamics perturbation and subsequent mitochondrial fragmentation as the main molecular mechanisms of VDBP-induced atrophy. Coherently, the ectopic introduction of VDBP in mice lacking the protein (Gc-knockout mice) induced muscle atrophy and decreased strength. Finally, we present proof-of-concept evidence that VDBP contributes to cancer-associated muscle wasting in Lewis lung carcinoma (LLC)-bearing male mice. Altogether, these findings provide novel insights into the biological function of VDBP as a pro-atrophic hormone with potential implications for the treatment of muscle wasting.