Systemic Myostatin Inhibition via Liver-Targeted Gene Transfer in Normal and Dystrophic Mice

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dc.contributor.authorBish, Lawrence T
dc.contributor.authorSleeper, Margaret M
dc.contributor.authorBarton, Elisabeth R
dc.contributor.authorSweeney, H. Lee
dc.contributor.authorPendrak, Klara
dc.contributor.authorSleeper, Margaret M
dc.contributor.authorBarton, Elisabeth R
dc.contributor.authorSweeney, H. Lee
dc.date2023-05-17T07:54:49.000
dc.date.accessioned2023-05-23T04:44:31Z
dc.date.available2023-05-23T04:44:31Z
dc.date.issued2010-02-11
dc.date.submitted2013-07-24T13:55:12-07:00
dc.description.abstractBackground: Myostatin 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 Findings: Here 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/Significance: Liver-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.
dc.identifier.urihttps://repository.upenn.edu/handle/20.500.14332/48879
dc.legacy.articleid1011
dc.legacy.fieldstrue
dc.legacy.fields10.1371/journal.pone.0009176
dc.legacy.fulltexturlhttps://repository.upenn.edu/cgi/viewcontent.cgi?article=1011&context=vet_papers&unstamped=1
dc.rights© 2010 Morine et al. This is an open-access article distributed under the terms of the <a href="http://creativecommons.org/licenses/by/3.0/">Creative Commons Attribution License</a>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.source.beginpagee9176
dc.source.issue12
dc.source.issue2
dc.source.journalDepartmental Papers (Vet)
dc.source.journaltitlePLoS One
dc.source.peerreviewedtrue
dc.source.statuspublished
dc.source.volume5
dc.subject.otherComparative and Laboratory Animal Medicine
dc.subject.otherDiseases
dc.subject.otherMedicine and Health Sciences
dc.subject.otherMusculoskeletal Diseases
dc.subject.otherVeterinary Medicine
dc.titleSystemic Myostatin Inhibition via Liver-Targeted Gene Transfer in Normal and Dystrophic Mice
dc.typeArticle
digcom.contributor.authorMorine, Kevin J
digcom.contributor.authorisAuthorOfPublication|email:bish@mail.med.upenn.edu|institution:University of Pennsylvania|Bish, Lawrence T
digcom.contributor.authorPendrak, Klara
digcom.contributor.authorisAuthorOfPublication|email:sleeper@vet.upenn.edu|institution:University of Pennsylvania|Sleeper, Margaret M
digcom.contributor.authorisAuthorOfPublication|email:erbarton@biochem.dental.upenn.edu|institution:University of Pennsylvania|Barton, Elisabeth R
digcom.contributor.authorisAuthorOfPublication|email:lsweeney@mail.med.upenn.edu|institution:University of Pennsylvania|Sweeney, H. Lee
digcom.identifiervet_papers/12
digcom.identifier.contextkey4343806
digcom.identifier.submissionpathvet_papers/12
digcom.typearticle
dspace.entity.typePublication
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upenn.schoolDepartmentCenterDepartmental Papers (Vet)
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