Human Brody disease and its animal model cattle pseudomyotonia: from understanding the pathogenetic mechanism to the identification of novel therapeutic approaches

Human Brody myopathy is a rare skeletal muscle disorder due to SERCA1 deficiency, resulting from mutations of ATP2A1 gene. The main clinical signs are exercise-induced stiffness and delayed muscular relaxation after physical exercises even mild, and muscles involved are prevalently voluntary muscles used for movement as legs, arms but also eyelids. SERCA1 isoform is responsible for transporting Ca2+ from cytosol to the lumen of sarcoplasmic reticulum (SR) and controlling intracellular Ca2+ concentration. SERCA1 deficiency is responsible for impairment of muscle relaxation, after contraction, due to prolonged increase of calcium concentration in skeletal muscle fibers cytoplasm. Our research group has demonstrated that Chianina cattle congenital pseudomyotonia represents the true counterpart of Brody myopathy. This is not surprising since, in the last years, the counterparts of human pathologies have been found in many domestic mammalian species. Interestingly, a missense mutation in the ATP2A1 gene is responsible for the pseudomyotonia phenotype and it has been clarified that the pathogenic mechanism underling pseudomyotonia involves ubiquitin-proteasome system degradation of the mutated bovine SERCA1. At present, neither specific therapy nor mouse model for Brody myopathy exists. However, we have recently designed and proven in vitro a novel pharmacological approach based on the employment of protein folding correctors named CFTR (Cystic Fibrosis Transmembrane Regulator) exploited in Cystic Fibrosis, which help SERCA1 mutants to properly fold. These data have been confirmed by those obtained ex vivo on adult skeletal muscle fibres from a biopsy from a pseudomyotonia affected subject. Moreover, local treatments of bovine pseudomyotonia muscle with the most effective in vitro CFTR corrector, although not easy, but show quite promising results.