Human Molecular Genetics Advance Access originally published online on November 4, 2008
Human Molecular Genetics 2009 18(2):318-327; doi:10.1093/hmg/ddn358
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Myogenic Akt signaling upregulates the utrophin–glycoprotein complex and promotes sarcolemma stability in muscular dystrophy
1 Department of Physiological Science 2 Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA 3 Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA
* To whom correspondence should be addressed at: Department of Physiological Science, University of California Los Angeles, 621 Charles E. Young Drive South, Life Sciences Building Room 5804, Los Angeles, CA 90025, USA. Tel: +1 3107942103; Fax: +1 3102063987; Email: rcrosbie{at}physci.ucla.edu
Received September 8, 2008; Accepted October 25, 2008
Duchenne muscular dystrophy is caused by dystrophin mutations that lead to structural instability of the sarcolemma membrane, myofiber degeneration/regeneration and progressive muscle wasting. Here we show that myogenic Akt signaling in mouse models of dystrophy promotes increased expression of utrophin, which replaces the function of dystrophin thereby preventing sarcolemma damage and muscle wasting. In contrast to previous suggestions that increased Akt in dystrophy was a secondary consequence of pathology, our findings demonstrate a pivotal role for this signaling pathway such that modulation of Akt can significantly affect disease outcome by amplification of existing, physiological compensatory mechanisms.
These authors contributed equally to this work.