Pharmacological TRPC6 inhibition improves survival and muscle function in mice with Duchenne muscular dystrophy

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 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.

Comparative DNA methylation reveals epigenetic adaptation to high altitude in snub-nosed monkeys

“…TRPC6, found hypermethylated in the Yunnan snub-nosed monkey, encodes a non-selective calcium channel important for cellular functions including gene transcription, cell proliferation, and death (Liao et al, 2008;Wang & Zheng, 2010). In the absence of dystrophin, TRPC6 deletion reduced cell damage in mice (Lin et al, 2022), with knockdown also prevented apoptosis of renal tubular epithelial cells upon oxidative stress (Hou et al, 2018), possibly by lowering Ca 2+ overload through PI3K/AKT and ERK pathways (Hou et al, 2021). In hypoxia, the increased mitochondrial ROS may directly cause extracellular Ca 2+ influx by opening of store-operated Ca 2+ (SOC) channels (Wang & Zheng, 2010).…”

Exploring the Gut Microbiota–Muscle Axis in Duchenne Muscular Dystrophy

“…In mdx mice and DMD patients, TRPC6 levels are increased both in the cardiac and skeletal muscles [ 64 ]. A recent study demonstrated that the gene deletion or the pharmacological inhibition of TRPC6 ameliorated skeletal and cardiac muscle defects and bone deformities in double knockout mice for both dystrophin and utrophin (mdx/utrn−/−), constituting a severe DMD model [ 73 ]. In addition to canonical TRPCs, another channel belonging to the TRPC family, the transient receptor potential vanilloid type 2 (TRPV2), may contribute to increase the intracellular Ca 2+ concentration in DMD.…”

Ion Channels of the Sarcolemma and Intracellular Organelles in Duchenne Muscular Dystrophy: A Role in the Dysregulation of Ion Homeostasis and a Possible Target for Therapy

“…TRPC6 levels are known to be elevated in cardiac and skeletal muscle in mice [41,46,47], and humans in DMD [48,49]. It has recently been shown that genetic or pharmacological inactivation of TRPC6 with the small molecule BI 749327 results in improving skeletal and cardiac morphology and dysfunction, and reducing skeletal and bone deformities in mice lacking both dystrophin and utrophin (mdx/utrn -/double knockout (dko) mice) representing a severe DMD model [50]. This confirms the involvement of TRPC6 in the development of striated muscle pathology.…”