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Pharmacological TRPC6 inhibition improves survival and muscle function in mice with Duchenne muscular dystrophy.
- Source :
-
JCI insight [JCI Insight] 2022 Oct 10; Vol. 7 (19). Date of Electronic Publication: 2022 Oct 10. - Publication Year :
- 2022
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 7
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 36099033
- Full Text :
- https://doi.org/10.1172/jci.insight.158906