Muscle growth after postdevelopmental myostatin gene knockout.
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 mo 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 mo of age), muscle mass had not changed from the pretreatment level in Mstn[w/w]/Cre+ control mice. Tamoxifen administration to 4-mo-old Mstn[f/f]/Cre+ mice reduced myostatin mRNA expression to less than 1% of normal, which increased muscle mass approximately 25% over the following 3 mo 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 postdevelopmental myostatin knockout. We conclude that, even after developmental muscle growth has ceased, knockout of the myostatin gene induces a significant increase in muscle mass.
Welle
Stephen
S
Department of Medicine, University of Rochester, Rochester, NY, USA. stephen_welle@urmc.rochester.edu
Bhatt
Kirti
K
Pinkert
Carl A
CA
Tawil
Rabi
R
Thornton
Charles A
CA
D000818:Animals; D005260:Female; D005355:Fibrosis; D006984:Hypertrophy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D055435:Myostatin; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000172:deficiency* / Q000235:genetics
C525912:Mstn protein, mouse; D055435:Myostatin; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D013629:Tamoxifen