Simone Spuler

Summary

Muscular dystrophies are devastating diseases for which there is no treatment. Limb-girdle muscular dystrophy 2B is caused by mutations in the gene encoding dysferlin, a disorder investigated in detail by our group. We showed earlier that dysferlin deficiency is associated with downregulation of complement-inhibitory factor, CD55. We have preliminary evidence that the link between dysferlin and CD55 occurs via myostatin. Myostatin, a cytokine belonging to the transforming growth factor (TGF) superfamily, plays a key role in muscle development; its absence is associated with massive hypertrophy. Myostatin signals via SMAD phosphorylation. The CD55 gene promoter harbors a SMAD-binding element. We will now test the global hypothesis that myostatin influences dysferlin-deficient muscular dystophy. The effect of myostatin will be investigated in vivo in A/J mice carrying a dysferlin-mutation as well as in vitro in well-characterized human dysferlin-deficient myoblasts. In our first aim, we will pharmacologically inhibit myostatin in the A/J mouse model with follistatin. Furthermore, we will cross dysferlin gene-deficient mice with myostatin gene-deficient mice (A/J/Mstn^-/- mouse) and subject the double knockout mice to provocative maneuvers. In our second aim, we will use human dysferlin-deficient myoblasts featuring all five novel mutations that we recently identified. In these cells, myostatin will be both overexpressed and inhibited.