Deciphering the roles of FXR1 in health and myopathy

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PROJECT SUMMARY/ABSTRACT The mechanism whereby RNA-binding proteins impact muscle function and disease progression is still largely unknown. Fragile X-related protein 1 (FXR1), an RNA-binding protein, is multi-functional and plays a role in regulating the temporal and spatial expression of RNAs in myocytes. It is becoming increasingly evident that FXR1 is essential for normal muscle function and is associated with both human cardiac and skeletal myopathies. Although global knockout of Fxr1 in mice results in perinatal lethality with cardiac and skeletal muscle defects, little is known regarding the fundamental mechanistic role(s) of FXR1. We discovered that FXR1 interacts with, and post-transcriptionally regulates, mRNAs that encode proteins essential for excitation-contraction coupling, including components that regulate phosphorylation of the myosin regulatory light chain (RLC). We also identified an interaction between FXR1 and the mRNA that encodes utrophin, a protein that can functionally substitute for the loss of dystrophin in Duchenne Muscular Dystrophy. Our extensive preliminary data, and data from others, reveal that FXR1 protein levels are significantly reduced in human DMD myocytes as well as in all DMD models tested including those from canine, pig, mouse and rat. Remarkably, restoring FXR1 levels in three different mouse models of DMD attenuates disease progression, resulting in structural and functional improvements in both cardiac and skeletal muscle. Utrophin expression is also enhanced in DMD mice in response to increased FXR1 levels. Thus, we hypothesize that FXR1 specifically regulates cellular components that are critical for proper muscle function and alterations in FXR1 levels/function contribute to disease progression, particularly in DMD. We propose a global, unbiased and multidisciplinary approach from single molecule to in vivo studies, including the use of human tissue, to allow us to accomplish three Specific Aims focused on determining the basic physiological function of a Fragile X protein and the role it plays in muscle pathogenesis. In addition, we will be among the first groups to assess gene-therapy strategies to prevent muscle dysfunction in DMD-rats (a model which closely resembles human DMD). We predict these discoveries will facilitate a unique RNA-level therapeutic approach to ameliorate muscle disease progression.