Expression of myostatin pro domain results in muscular transgenic mice

Myostatin, a member of the TGF-beta family, negatively regulates skeletal m uscle development. Depression of myostatin activity leads to increased musc le growth and carcass lean yield, In an attempt to down-regulate myostatin, transgenic mice were produced with a ribozyme-based construct or a myostat in pro domain construct. Though the expression of the ribozyme was detected , muscle development was not altered by the ribozyme transgene. However, a dramatic muscling phenotype was observed in transgenic mice carrying the my ostatin pro domain gene. Expression of the pro domain transgene at 5% of be ta -actin mRNA levels resulted in a 17-30% increase in body weight (P <0.00 1). The carcass weight of the transgenic mice showed a 22-44% increase comp ared with nontransgenic littermates at 9 weeks of age (16.05 +/- 0.67 vs. 1 1.16 +/- 0.28 g in males; 9.99 +/- 0.38 vs. 8.19 +/- 0.19 g in females, P < 0.001). Extreme muscling was present throughout the whole carcass of trans genic mice as hind and fore limbs and trunk weights, all increased signific antly (P < 0.001). Epididymal fat pad weight, an indicator of body fat, was significantly decreased in pro domain transgenic mice (P <0.001), Analysis of muscle morphology indicated that cross-sectional areas of fast-glycolyt ic fibers (gastrocnemius) and fast-oxidative glycolytic fibers (tibialis) w ere larger in pro domain transgenic mice than in their controls (P <0.01), whereas fiber number (gastrocnemius) was not different (P >0.05). Thus, the muscular phenotype is attributable to myofiber hypertrophy rather than hyp erplasia. The results of this study suggest that the overexpression of myos tatin pro domain may provide an alternative to myostatin knockouts as a mea ns of increasing muscle mass in other mammals. (C) 2001 Wiley-Liss, Inc.