CFTR corrector C17 rescues defective SERCA1 in bovine pseudomyotonia: a potential therapy for Brody myopathy.

Brody myopathy is an ultra-rare autosomal recessive inherited disorder that impairs skeletal muscle function in humans. It is caused by deficiency of the Sarco(Endo)plasmic reticulum Ca2+-ATPase isoform1 (SERCA1), arising from defects, mainly missense mutations, in the ATP2A1 gene. At present, neither specific therapy, nor mouse model exists for Brody myopathy. Bovine pseudomyotonia (PMT) is a very rare skeletal muscle disorder. As Brody myopathy, it is an autosomal recessive inherited disorder caused by missense variants in the atp2a1 gene. Most mutations generate proteins corrupted in proper folding that although catalytically active, were ubiquitinated and prematurely degraded by the ubiquitin-proteasome system, thus sharing with Cystic Fibrosis the same pathogenetic mechanism. Bovine PMT, despite unconventional, is currently the unique mammalian model of Brody disease. In this study, we show that CFTR correctors, particularly C17, successfully rescue SERCA1 mutants both in vitro and in vivo models. Our findings suggest that CFTR correctors may be a potential innovative pharmacological approach addressing Brody patients in which mutated SERCA1 retains its activity.