Systemic myostatin inhibition via liver-targeted gene transfer in normal and dystrophic mice.
BACKGROUND
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.


RESULTS
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
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.
Morine
Kevin J
KJ
Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America. km446@drexel.edu
Bish
Lawrence T
LT
Pendrak
Klara
K
Sleeper
Meg M
MM
Barton
Elisabeth R
ER
Sweeney
H Lee
HL
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D000229:Dependovirus / Q000235:genetics; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D055435:Myostatin / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors
D050505:Mutant Proteins; D055435:Myostatin