Systemic myostatin inhibition via liver-targeted gene transfer in normal and dystrophic mice.
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 neut...
Main Authors: | , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2010-02-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC2820101?pdf=render |
id |
doaj-c82d615db8c641b4933c0ebbf297da65 |
---|---|
record_format |
Article |
spelling |
doaj-c82d615db8c641b4933c0ebbf297da652020-11-25T01:21:22ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-02-0152e917610.1371/journal.pone.0009176Systemic myostatin inhibition via liver-targeted gene transfer in normal and dystrophic mice.Kevin J MorineLawrence T BishKlara PendrakMeg M SleeperElisabeth R BartonH Lee SweeneyMyostatin 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.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.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.http://europepmc.org/articles/PMC2820101?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kevin J Morine Lawrence T Bish Klara Pendrak Meg M Sleeper Elisabeth R Barton H Lee Sweeney |
spellingShingle |
Kevin J Morine Lawrence T Bish Klara Pendrak Meg M Sleeper Elisabeth R Barton H Lee Sweeney Systemic myostatin inhibition via liver-targeted gene transfer in normal and dystrophic mice. PLoS ONE |
author_facet |
Kevin J Morine Lawrence T Bish Klara Pendrak Meg M Sleeper Elisabeth R Barton H Lee Sweeney |
author_sort |
Kevin J Morine |
title |
Systemic myostatin inhibition via liver-targeted gene transfer in normal and dystrophic mice. |
title_short |
Systemic myostatin inhibition via liver-targeted gene transfer in normal and dystrophic mice. |
title_full |
Systemic myostatin inhibition via liver-targeted gene transfer in normal and dystrophic mice. |
title_fullStr |
Systemic myostatin inhibition via liver-targeted gene transfer in normal and dystrophic mice. |
title_full_unstemmed |
Systemic myostatin inhibition via liver-targeted gene transfer in normal and dystrophic mice. |
title_sort |
systemic myostatin inhibition via liver-targeted gene transfer in normal and dystrophic mice. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2010-02-01 |
description |
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.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.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. |
url |
http://europepmc.org/articles/PMC2820101?pdf=render |
work_keys_str_mv |
AT kevinjmorine systemicmyostatininhibitionvialivertargetedgenetransferinnormalanddystrophicmice AT lawrencetbish systemicmyostatininhibitionvialivertargetedgenetransferinnormalanddystrophicmice AT klarapendrak systemicmyostatininhibitionvialivertargetedgenetransferinnormalanddystrophicmice AT megmsleeper systemicmyostatininhibitionvialivertargetedgenetransferinnormalanddystrophicmice AT elisabethrbarton systemicmyostatininhibitionvialivertargetedgenetransferinnormalanddystrophicmice AT hleesweeney systemicmyostatininhibitionvialivertargetedgenetransferinnormalanddystrophicmice |
_version_ |
1725130680891867136 |