Frizzled related protein deficiency impairs muscle strength, gait and calpain 3 levels
Leire Casas-Fraile, F.M. Cornelis, Domiziana Costamagna, Anabel Rico, Robin Duelen, Maurilio Sampaolesi, Adolfo López de Munaín, Rik Lories, Amets Sáenz
Abstract
Abstract Background Limb-girdle muscular dystrophy recessive 1 calpain3-related (LGMDR1), previously known as LGMD2A, is a disease caused by mutations in the CAPN3 gene. It is characterized by progressive weakness and muscle degeneration. Frizzled related protein ( FRZB ), upregulated in LGMDR1, was identified as a key regulator of the crosstalk between Wnt and integrin signalling pathways. FRZB gene silencing showed a recovery in the expression of some of the costamere protein levels in myotubes. Results Here, we performed a comprehensive characterization of Frzb −/− mice muscles to study the absence of Frzb in skeletal muscle and eventual links with the molecular characteristics of LGMDR1 patient muscles. Frzb −/− mice showed reduced muscle size and strength. Gait analysis showed that Frzb −/− mice moved more slowly but no impaired regeneration capacity was observed after muscle injury. Additionally, Frzb −/− mice muscle showed an increased number of mesoangioblasts. Lack of Frzb gene in Frzb −/− mice and its increased expression in LGMDR1 patients, showed contrary regulation of Rora , Slc16a1 , Tfrc and Capn3 genes. The reciprocal regulation of Frzb and Capn3 genes further supports this axis as a potential target for LGMDR1 patients. Conclusions Our data confirm a role for Frzb in the regulation of Rora , Slc16a1 , Tfrc , and Capn3 genes in muscle cells. In vivo, reduced muscle strength and gait in the Frzb −/− mice are intriguing features. The reciprocal relationship between FRZB and CAPN3 further supports a key role for this axis in patients with LGMDR1.