|Ratovitski, Tamara - METAMORPHIX, INC.|
|Brady, James - METAMORPHIX, INC.|
Submitted to: Journal of Molecular Reproduction and Development
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: May 15, 2001
Publication Date: N/A
Interpretive Summary: The double muscling observed in Belgian Blue and Piedmontese cattle is a consequence of naturally occurring mutations in the myostatin gene. These mutations disrupt myostatin's biological function. The amount of increased muscle mass and increased lean in these cattle is desirable. However, beef producers have not chosen to incorporate these animals in their breeding programs because the double muscling phenotype is often associated with calving difficulties. In an effort to try to circumvent the detrimental aspects of the double muscling phenotype while maintaining the desirable carcass characteristics we have genetically engineered mice with a modified version of the myostatin gene. The MLC-Pro transgene was designed to interfere with myostatin activity and to delay the onset of double muscling until after birth. The carcasses of transgenic mice were 20 to 40% heavier than their littermates controls. The increase in muscle mass was attributable to an increase in the size of muscle fibers rather than a increase in the number of fibers. The transgenic mice also had significantly less body fat. These genetically engineered mice seem otherwise healthy and reproductively normal. These findings suggest livestock species may benefit by the introduction of the transgene used in this project.
Technical Abstract: Myostatin is a member of the TGF-beta family that negatively regulates skeletal muscle development. A 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 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. An expression of the pro domain transgene at 5% actin mRNA 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 non-transgenic littermates (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 over-expression of myostatin pro domain may provide an alternative to myostatin knockout as a means of increasing muscle mass in other mammals.