Systemic Myostatin Inhibition via Liver-Targeted Gene Transfer in Normal and Dystrophic Mice |
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Authors: | Kevin J. Morine Lawrence T. Bish Klara Pendrak Meg M. Sleeper Elisabeth R. Barton H. Lee Sweeney |
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Affiliation: | 1. Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.; 2. Section of Cardiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of America.; 3. Department of Anatomy and Cell Biology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, United States of America.;University of Florida, United States of America |
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Abstract: | BackgroundMyostatin inhibition is a promising therapeutic strategy to maintain muscle mass in a variety of disorders, including the muscular dystrophies, cachexia, and sarcopenia. Previously described approaches to blocking myostatin signaling include injection delivery of inhibitory propeptide domain or neutralizing antibodies.Methodology/Principal FindingsHere we describe a unique method of myostatin inhibition utilizing recombinant adeno-associated virus to overexpress a secretable dominant negative myostatin exclusively in the liver of mice. Systemic myostatin inhibition led to increased skeletal muscle mass and strength in control C57 Bl/6 mice and in the dystrophin-deficient mdx model of Duchenne muscular dystrophy. The mdx soleus, a mouse muscle more representative of human fiber type composition, demonstrated the most profound improvement in force production and a shift toward faster myosin-heavy chain isoforms. Unexpectedly, the 11-month-old mdx diaphragm was not rescued by long-term myostatin inhibition. Further, mdx mice treated for 11 months exhibited cardiac hypertrophy and impaired function in an inhibitor dose–dependent manner.Conclusions/SignificanceLiver-targeted gene transfer of a myostatin inhibitor is a valuable tool for preclinical investigation of myostatin blockade and provides novel insights into the long-term effects and shortcomings of myostatin inhibition on striated muscle. |
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