FSHD myofibers cultured from human xenografts
$100,000 (USD) in total, supported in partnership with Friends of FSH Research (50:50)
FSH Muscular Dystrophy (FSHD) affects 1 in approximately 8,300 individuals worldwide. One of the obstacles in developing treatments for FSHD is the lack of a small animal model of the disease. The genetics of FSHD make it difficult, if not impossible, to make a mouse with muscles that have the same characteristics as the muscles of individuals with FSHD. This in turn has made it difficult to study mature muscle fibers with the characteristics of FSHD muscle in the laboratory, where conditions can be controlled to examine the morphological and physiological changes associated with disease and to test therapeutics that can reverse those changes.
We have taken a novel approach to creating a mouse with FSHD muscles: we are transplanting muscle precursor cells (MPCs) from healthy and FSHD donors into mice and inducing them to form mature muscle tissue. We pretreat the mice to eliminate the major hindlimb muscle, the Tibialis anterior, and to prevent it from regenerating. We then inject MPCs and treat the muscle with an unique set of methods to promote their survival and their ability to form new muscle of human origin. We have had great success using both normal and FSHD MPCs to form human muscle fibers in the mouse hindlimb that are mature and functional. Moreover, the muscles formed from FSHD cells express DUX4, a marker of the disease.
We have recently succeeded in isolating muscle fibers from the muscle grafts and have begun to study them in culture dishes. Here we propose to develop these methods and to use them to study DUX4 in isolated FSHD muscle fibers to learn how DUX4 might lead to FSHD.