Mice Lacking Homer 1 Exhibit a Skeletal Myopathy Characterized by Abnormal TRP Channel Activity

Department of Medicine, Duke University Medical Center, Durham, NC 27710; Department of Biomedical Engineering, Duke University, Durham, NC 27710; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205

^* To whom correspondence should be addressed. Email: rosen029{at}mc.duke.edu.

	Abstract

Transient receptor potential (TRP) channels are non-selective cation channels, several of which are expressed in striated muscle. Because the scaffolding protein Homer 1 has been implicated in TRP channel regulation, we hypothesized that Homer proteins play a significant role in skeletal muscle function. Mice lacking Homer 1 exhibited a myopathy characterized by decreased muscle fiber cross-sectional area and decreased skeletal muscle force generation. Homer 1 knockout myotubes displayed increased basal current density and spontaneous cation influx. This spontaneous cation influx in Homer 1 knockout myotubes was blocked by re-expression of Homer 1b, but not Homer 1a, and by gene silencing of TRPC1. Moreover, diminished Homer 1 expression in mouse models of Duchenne's muscular dystrophy suggests that loss of Homer 1 scaffolding of TRP channels may contribute to the increased stretch activated channel activity observed in mdx myofibers. These findings provide direct evidence that Homer 1 functions as an important scaffold for TRP channels and regulates mechanotransduction in skeletal muscle.