Gene mutations causing loss of dystrophin result in the severe muscle disease known as Duchenne muscular dystrophy (DMD). Despite efforts at genetic repair, DMD therapy remains largely palliative. Loss of dystrophin destabilizes the sarcolemmal membrane impacting mechanosensitive cation channels to increase calcium entry, promoting cell damage, and eventually muscle dysfunction. One putative channel is transient receptor potential canonical 6 (TRPC6) that we showed contributes to abnormal force and calcium stress-responses in mouse cardiomyocytes lacking dystrophin and haplodeficient in utrophin mdx/utrn+/- (HET). Here, we show in both HET and the far more severe homozygous mdx/utrn-/- (DKO) mouse that TRPC6 gene deletion or its selective pharmacologic inhibition (BI 749327) prolongs survival 2-3-fold, improving skeletal and cardiac muscle and bone defects. Gene pathways reduced by BI 749327 treatment most prominently regulate fat metabolism and TGFβ1 signaling. These results support the testing of TRPC6 inhibitors in human trials for other diseases as a novel DMD therapy.
Brian L. Lin, Joseph Y. Shin, William P.D. Jeffreys, Nadan Wang, Clarisse A. Lukban, Megan C. Moorer, Esteban Velarde, Olivia A. Hanselman, Seoyoung Kwon, Suraj Kannan, Ryan C. Riddle, Christopher W. Ward, Steven S. Pullen, Antonio Filareto, David A. Kass