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Molecular and Cellular Biology, April 2008, p. 2637-2647, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.01601-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Mice Lacking Homer 1 Exhibit a Skeletal Myopathy Characterized by Abnormal Transient Receptor Potential Channel Activity{triangledown} ,{dagger}

Jonathan A. Stiber,1 Zhu-Shan Zhang,1 Jarrett Burch,1 Jerry P. Eu,1 Sarah Zhang,2 George A. Truskey,2 Malini Seth,1 Naohiro Yamaguchi,3 Gerhard Meissner,3 Ripal Shah,1 Paul F. Worley,4 R. Sanders Williams,1 and Paul B. Rosenberg1*

Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710,1 Department of Biomedical Engineering, Duke University, Durham, North Carolina 27710,2 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,3 Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland 212054

Received 30 August 2007/ Returned for modification 1 October 2007/ Accepted 19 January 2008

Transient receptor potential (TRP) channels are nonselective 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 reexpression 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.

* Corresponding author. Mailing address: Department of Medicine, Duke University Medical Center, 4321 Medical Park Drive, Suite 200, Durham, NC 27704. Phone: (919) 479-2315. Fax: (919) 477-0632. E-mail: rosen029{at}mc.duke.edu

{triangledown} Published ahead of print on 11 February 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, April 2008, p. 2637-2647, Vol. 28, No. 8
0270-7306/08/$08.00+0     doi:10.1128/MCB.01601-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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