Understanding skeletal muscle fiber-type differentiation
One focus of our lab is understanding the mechanisms behind how skeletal muscle cells differentiate into a specific muscle fiber type, either fast twitch or slow twitch. We are using zebrafish and mouse models to study the functions of new factors, such as Pbx homeodomain transcription factors, and how they control muscle fiber-type development.
Certain muscular dystrophies preferentially affect either fast or slow twitch muscle fibers. In human and mouse models of Duchenne Muscular Dystrophy (DMD), fast muscle fibers are more susceptible to damage than slow fibers. It is not clear how fiber-type identity confers susceptibility or resistance to muscular dystrophy. A goal of this project is to test a fundamental hypothesis: that factors that promote slow muscle differentiation will ameliorate the effects of DMD. Recent studies, including work from our lab, now create an opportunity to directly test whether fiber-type modulation is a viable therapeutic approach for muscular dystrophies. We take advantage of zebrafish models to address whether factors that regulate fiber-type differentiation enhance or suppress the zebrafish dmd muscle degeneration phenotype. Our approach is to manipulate fiber-type regulators that function early in development in dmd zebrafish embryos. We are also working to identify new epigenetic factors that regulate muscle fiber type. We are screening epigenetic chemicals for their abilities to enhance or suppress the zebrafish dmd phenotype. We expect that this project will identify genetic and epigenetic regulators of muscle fiber-type identities that confer susceptibility or resistance to muscular dystrophy. This project is aimed at an ultimate goal of manipulating skeletal muscle fiber type as a treatment for muscular dystrophy.