CATTLE CONGENITAL PSEUDOMYOTONIA AS ANIMAL MODEL: WHEN DIAPHRAGM MUSCLE CAN MAKE THE DIFFERENCE

Cattle “congenital pseudomyotonia” (PMT) is a muscular disorder described for the first time in Chianina cattle breed [1] and subsequently in Romagnola breed, characterized by an impairment of muscle relaxation induced by exercise. By DNA sequencing, we provided evidence of missense mutations in ATP2A1 gene, coding for SERCA1 isoform. Pathological muscles of PMT affected animals are characterized by a striking, selective reduction in the expression level of SERCA1 protein. Although present at low levels, the SERCA1 variants maintained the basic intrinsic properties of wild-type (WT) SERCA1, notably the Ca2+ dependent ATPase activity [2,3]. On the bases of clinical, genetic and biochemical analyses, our group has demonstrated that PMT is the true counterpart of human Brody myopathy, a rare and orphan disease for which an appropriate pharmacological treatment is now not available. Our results showing that in bovine PMT, SERCA1 mutations do not abolish SERCA1 activity, prompted us to hypothesize that the retention of functional properties of mutated SERCA pump represents the requisite for the efficacy of a potential innovative therapy. We have recently designed a novel pharmacological approach based on the employment of protein folding CFTR correctors, specifically developed for rescuing type II Cystic Fibrosis Transmembrane Regulator (CFTR) mutants [4]. Our preliminary results show that CFTR correctors successfully rescued in vitro SERCA1 mutants, causing bovine PMT. In vitro studies are fundamental for experimental settings and permit tight control of fundamental principles and the testing of therapeutic hypotheses. They represent the first step toward a cure, being the second step of preclinical research in drug development, represented by in vivo animal studies which are essential and necessary before clinical trial can be pursued. Mouse is undoubtedly the preferred model for preclinical therapeutic trials, nevertheless sometimes this model fails to mirror the disease phenotype and therefore is unsuitable to study certain human pathologies. This is the case of human Brody disease. Due to the wide difference in fiber type composition of diaphragm muscle between mice and large mammals, including humans, mouse is not appropriate as animal model for this pathology. To solve this problem, we treated locally bovine PMT affected muscle with CFTR correctors, resulted from the most promising in vitro studies.