Pharmacological TRPC6 inhibition improves survival and muscle function in mice with Duchenne muscular dystrophy. JCI Insight 2022 Oct 10;7(19)
Date
09/14/2022Pubmed ID
36099033Pubmed Central ID
PMC9675567DOI
10.1172/jci.insight.158906Scopus ID
2-s2.0-85139571501 (requires institutional sign-in at Scopus site) 10 CitationsAbstract
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.
Author List
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, Kass DAAuthor
Brian L. Lin PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCalcium
Disease Models, Animal
Dystrophin
Humans
Mice
Mice, Inbred mdx
Muscular Dystrophy, Duchenne
Myocardium
TRPC6 Cation Channel
Transforming Growth Factor beta1
Utrophin
