Human Molecular Genetics Advance Access published online on August 27, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn264
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Akt activation prevents the force drop induced by eccentric contractions in dystrophin-deficient skeletal muscle
1 Department of Biomedical Sciences, CNR Institute of Neurosciences, University of Padova, Padova, Italy 2 Venetian Institute of Molecular Medicine (VIMM), Padova, Italy 3 Dulbecco Telethon Institute 4 Department of Human Anatomy and Physiology, University of Padova, Padova, Italy
* To whom correspondence should be addressed at: Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35126 Padova, Italy. Tel: +39-0497923232; Fax: +39-0497923250; Email: stefano.schiaffino{at}unipd.it
Received July 16, 2008; Revised August 24, 2008; Accepted August 24, 2008
Skeletal muscles of the mdx mouse, a model of Duchenne Muscular Dystrophy, show an excessive reduction in the maximal tetanic force following eccentric contractions. This specific sign of the susceptibility of dystrophin-deficient muscles to mechanical stress can be used as a quantitative test to measure the efficacy of therapeutic interventions. Using inducible transgenesis in mice, we show that when Akt activity is increased the force drop induced by eccentric contractions in mdx mice becomes similar to that of wild type mice. This effect is not correlated with muscle hypertrophy and is not blocked by rapamycin treatment. The force drop induced by eccentric contractions is similar in skinned muscle fibers from mdx and Akt-mdx mice when stretch is applied directly to skinned fibers. However, skinned fibers isolated from mdx muscles exposed to eccentric contractions in vivo develop less isometric force than wild type fibers and this force depression is completely prevented by Akt activation. These experiments indicate that the myofibrillar-cytoskeletal system of dystrophin-deficient muscle is highly susceptible to a damage caused by eccentric contraction when elongation is applied in vivo, and this damage can be prevented by Akt activation. Microarray and PCR analyses indicate that Akt activation induces up-regulation of genes coding for proteins associated with Z-disks and costameres, and for proteins with anti-oxidant or chaperone function. The protein levels of utrophin and dysferlin are also increased by Akt activation.
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