MEK-inhibitors decrease Nfix in muscular dystrophy but induce unexpected calcifications, partially rescued with Cyanidin diet

Giuseppe Angelini; Emanuele Capra; Francesca Rossi; Giada Mura; Marielle Saclier; Valentina Taglietti; Gabriele Rovetta; Raffaele Epis; Giorgia Careccia; Chiara Bonfanti; Graziella Messina

doi:10.1016/j.isci.2023.108696

MEK-inhibitors decrease Nfix in muscular dystrophy but induce unexpected calcifications, partially rescued with Cyanidin diet

iScience. 2023 Dec 10;27(1):108696. doi: 10.1016/j.isci.2023.108696. eCollection 2024 Jan 19.

Affiliation

¹ Department of Biosciences, University of Milan, 20133 Milan, Italy.

Abstract

Muscular dystrophies (MDs) are incurable genetic myopathies characterized by progressive degeneration of skeletal muscles. Dystrophic mice lacking the transcription factor Nfix display morphological and functional improvements of the disease. Recently, we demonstrated that MAPK signaling pathway positively regulates Nfix in muscle development and that Cyanidin, a natural antioxidant molecule, strongly ameliorates the pathology. To explore a synergistic approach aimed at treating MDs, we administered Trametinib, a clinically approved MEK inhibitor, alone or combined with Cyanidin to adult Sgca null mice. We observed that chronic treatment with Trametinib and Cyanidin reduced Nfix in myogenic cells but, unexpectedly, caused ectopic calcifications exclusively in dystrophic muscles. The combined treatment with Cyanidin resulted in histological improvements by preventing Trametinib-induced calcifications in Diaphragm and Soleus. Collectively, this first pilot study revealed that Nfix is modulated by the MAPK pathway in MDs, and that Cyanidin partly rescued the unexpected ectopic calcifications caused by MEK inhibition.

Keywords: Cancer; Drugs; Pathophysiology.