Jaka, O. 1, 2 , Casas-Fraile, L. . 1, 2 , Azpitarte, M. 1, 2 , Aiastui, A. 1, 2 , López de Munain, A. 1, 2, 3, 4 & Sáenz, A. 1, 2
1 Neurosciences Area, Biodonostia Institute
2 Department of Neurology, Hospital Universitario Donostia
3 Department of Neurosciences, University of the Basque Country
4 CIBERNED, Centro de Investigaciones Biomédicas en Red sobre Enfermedades Neurodegenerativas, Institute Carlos III, Spanish Ministry of Economy and Competitiveness
Background: Limb girdle muscular dystrophy type 2A (LGMD2A) due to mutations in CAPN3 is one of the most common autosomal recessive limb girdle muscular dystrophies. Microarray analysis showed that several genes are deregulated in muscle of LGMD2A patients, but it remains unclear which changes are relevant to the muscle degeneration process. Objective: To unveil whether the altered expression pattern in muscle of LGMD2A patients is replicated in other tissues (blood, skin fibroblasts and myoblasts/myotubes), and to analyze the implication of commonly regulated genes in the pathophysiology of LGMD2A. Results: As reported for muscle, melusin, CD9 and FRZB were upregulated in fibroblasts of LGMD2A patients. Melusin and CD9 are known to interact with B1 integrins, and LGMD2A myotubes showed altered B1 integrin isoform replacement. Although melusin, CD9 and FRZB have not been described to directly interact, our results indicate that in vitro they are related at expression control level. Furthermore, melusin and FRZB also controlled integrin B1 isoform replacement. Conclusion: The derregulation of melusin and FRZB could modify the integrin B1D recruitment in LGMD2A, thereby perturbing the interaction of premyofibrils with the extracellular matrix and signal generation. Moreover, since the upregulation of FRZB inhibits the Wnt pathway, its deregulation could trigger the failed myogenesis in LGMD2A. Therefore, the regulation of these genes might constitute a therapeutic alternative in the treatment of muscular dystrophies.