Mice lacking Homer 1 exhibit a skeletal myopathy characterized by abnormal transient receptor potential channel activity |
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Authors: | Stiber Jonathan A Zhang Zhu-Shan Burch Jarrett Eu Jerry P Zhang Sarah Truskey George A Seth Malini Yamaguchi Naohiro Meissner Gerhard Shah Ripal Worley Paul F Williams R Sanders Rosenberg Paul B |
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Affiliation: | Department of Medicine, Duke University Medical Center, 4321 Medical Park Drive, Suite 200, Durham, NC 27704, USA. |
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Abstract: | 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. |
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