1. Pharmacological TRPC6 inhibition improves survival and muscle function in mice with Duchenne muscular dystrophy.
- Author
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Lin BL, Shin JY, Jeffreys WP, Wang N, Lukban CA, Moorer MC, Velarde E, Hanselman OA, Kwon S, Kannan S, Riddle RC, Ward CW, Pullen SS, Filareto A, and Kass DA
- Subjects
- Animals, Calcium metabolism, Disease Models, Animal, Humans, Mice, Mice, Inbred mdx, Myocardium metabolism, TRPC6 Cation Channel genetics, TRPC6 Cation Channel metabolism, Transforming Growth Factor beta1 metabolism, Utrophin genetics, Utrophin metabolism, Dystrophin genetics, Dystrophin metabolism, Muscular Dystrophy, Duchenne drug therapy, Muscular Dystrophy, Duchenne genetics, Muscular Dystrophy, Duchenne metabolism
- Abstract
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, inducing mechanosensitive cation channels to increase calcium entry and promote cell damage and, eventually, muscle dysfunction. One putative channel is transient receptor potential canonical 6 (TRPC6); we have shown that TRPC6 contributed to abnormal force and calcium stress-responses in cardiomyocytes from mice lacking dystrophin that were haplodeficient for utrophin (mdx/utrn+/- [HET] mice). Here, we show in both the HET mouse and the far more severe homozygous mdx/utrn-/- mouse that TRPC6 gene deletion or its selective pharmacologic inhibition (by BI 749327) prolonged survival 2- to 3-fold, improving skeletal and cardiac muscle and bone defects. Gene pathways reduced by BI 749327 treatment most prominently regulated fat metabolism and TGF-β1 signaling. These results support the testing of TRPC6 inhibitors in human trials for other diseases as a novel DMD therapy.
- Published
- 2022
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