Expression of myostatin pro domain results in muscular transgenic mice

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Abstract
Myostatin, a member of the TGF‐β family, negatively regulates skeletal muscle development. Depression of myostatin activity leads to increased muscle growth and carcass lean yield. In an attempt to down‐regulate myostatin, transgenic mice were produced with a ribozyme‐based construct or a myostatin 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 myostatin pro domain gene. Expression of the pro domain transgene at 5% of β‐actin mRNA levels resulted in a 17–30% increase in body weight (P < 0.001). The carcass weight of the transgenic mice showed a 22–44% increase compared with nontransgenic littermates at 9 weeks of age (16.05 ± 0.67 vs. 11.16 ± 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 transgenic mice as hind and fore limbs and trunk weights, all increased significantly (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‐glycolytic fibers (gastrocnemius) and fast‐oxidative glycolytic fibers (tibialis) were 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 hyperplasia. The results of this study suggest that the over‐expression of myostatin pro domain may provide an alternative to myostatin knockouts as a means of increasing muscle mass in other mammals. Mol. Reprod. Dev. 60: 351–361, 2001.