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    Six homeoproteins and Wnt-beta-catenin pathway in muscle development and disease

    Topic leaders : Pascal MAIRE and Isabelle GUILLET-DENIAU

    Six homeoproteins. We have shown that the SIX homeoproteins family was expressed throughout muscle development in mammals, controlling bHLH MRF4 myogenin and MyoD determination genes in the embryo, as well as the aldolase A gene, which is specifically expressed in adult fast IIB fibers. We aim to determine the functions of SIX proteins and their EYA cofactors in the control of muscle morphogenesis in the mouse, their involvement in muscle myofiber specification, and to define the genetic targets of the SIX-EYA complex. To allow this study we generated a Six1 as well as a double Six1-Six4 invalidation models, and obtained Eya1 and Eya2 deficient animals from P-X. Xu (USA) Six2 deficient mice from G.Oliver (USA) and Six5 deficient mice from S. Tapscott (USA). These different mouse models have allowed us to begin to characterize the functions of SIX and EYA proteins during mouse embryogenesis. The second aspect of our work, is to characterize the contribution to muscle diversity of the Six-Eya complex. The transcription factors and signalling pathways participating in the fast-glycolytic fiber type phenotype specification have not yet been characterized. We proposed that the homeoprotein Six1 associated with its Eya1 cofactor could be one of the main actor controlling the fast-type fibre program in muscles, and we aimed to understand how this is achieved. We presently analyse several models of KO mice to get insight on the role of Six and Eya genes in muscle fibre diversity, and characterize new partners of Six 1 that could be involved in the control of Six transcriptional activity.

    Intramyocellular lipid accumulation is related to the down-regulation of Wnt-beta-catenin pathway. Metabolic Syndrome is a collection of health risks that increase the chance of developing heart disease, stroke, obesity and diabetes. It is characterized by an ectopic lipid deposition in muscle, heart, and pancreas leading to insulin resistance. As muscle tissue normally contains adipocytes, the potential contribution of myoblast conversion to an adipogenic cell type that would increase fat content in muscle is not well established. We have recently reported that de novo lipogenesis occured in rat contracting myotubes deriving from muscle satellite cells through a SREBP-1c dependent pathway, whereas overexpression of Wnt-10b, a member of a family of secreted proteins that regulate developmental processes, was shown to inhibit adipogenic differentiation. As Wnt-10b and SREBP-1c proteins showed an inverse expression profile throughout differentiation in cultured satellite cells, we plan to determine whether activation of the Wnt-beta-catenin pathway could maintain muscle satellite cells in the myoblastic lineage, preventing them from expressing adipogenic factors that induce lipid synthesis in skeletal muscle. Investigation of SREBP-1c regulation by the Wnt-catenin pathway should provide new insights into muscle insulin resistance and open perspectives for the unravelling of cellular mechanisms involved in ectopic lipid deposition in skeletal muscle during obesity and type 2 diabetes.