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1 Medicine, University of Rochester, Rochester, New York, United States
2 University of Rochester, United States; Medicine, University of Rochester, Rochester, New York, United States
3 Pathology & Laboratory Medicine, University of Rochester, Rochester, New York, United States
4 Neurology, University of Rochester, Rochester, New York, United States
5 Neurology, University of Rochester School of Medicine and Dentistry, United States; Neurology, University of Rochester School of Medicine and Dentistry
* To whom correspondence should be addressed. E-mail: stephen_welle{at}urmc.rochester.edu.
Constitutive myostatin gene knockout in mice causes excessive muscle growth during development. To examine the effect of knocking out the myostatin gene after muscle has matured, we generated mice in which myostatin exon 3 was flanked by loxP sequences (Mstn[f/f]) and crossed them with mice bearing a tamoxifen-inducible, ubiquitously-expressed Cre recombinase transgene. At 4 months of age, Mstn[f/f]/Cre+ mice that had not received tamoxifen had a 50-90% reduction in myostatin expression due to basal Cre activity, but were not hypermuscular relative to Mstn[w/w]/Cre+ mice (homozygous for wild-type myostatin gene). Three months after tamoxifen treatment (initiated at 4 months of age), muscle mass had not changed from the pre-treatment level in Mstn[w/w]/Cre+ control mice. Tamoxifen administration to 4 month old Mstn[f/f]/Cre+ mice reduced myostatin mRNA expression to less than 1% of normal, which increased muscle mass ~25% over the following 3 months in both male and female mice (P < 0.005 vs. control). Fiber hypertrophy appeared to be sufficient to explain the increase in muscle mass. The pattern of expression of genes encoding the various myosin heavy chain isoforms was unaffected by post-developmental myostatin knockout. Conclusion: even after developmental muscle growth has ceased, knockout of the myostatin gene induces a significant increase in muscle mass.
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