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1 Division of Endocrinology, Metabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA
2 Transgenic Mouse Facility, University of California at Irvine, Irvine, CA, USA
* To whom correspondence should be addressed. E-mail: ncadavid{at}ucla.edu.
Mutations in the myostatin gene are associated with hypermuscularity, suggesting that myostatin inhibits skeletal muscle growth. We postulated that increased tissue-specific expression of myostatin protein in the skeletal muscle would induce muscle loss. To investigate this hypothesis, we generated transgenic mice that overexpress myostatin protein selectively in the skeletal muscle, with or without ancillary expression in the heart, utilizing cDNA constructs in which wild type (MCK/Mst) or a mutated muscle creatine kinase (MCK-3E/Mst) promoter were placed upstream of mouse myostatin cDNA. Transgenic mice harboring these MCK promoters linked to green fluorescent protein (GFP) expressed the reporter protein only in skeletal and cardiac muscles (MCK), or in skeletal muscle alone (MCK-3E). Seven-week old animals were genotyped by PCR of tail DNA, or by Southern blot analysis of liver DNA. Myostatin mRNA and protein, measured by RT-PCR and western blot, respectively, were significantly higher in the gastrocnemius, quadriceps, and tibialis of MCK/Mst transgenic mice when compared to wild type mice. Male MCK/Mst transgenic mice had 18-24 % lower hind and fore limb muscle weight, and 18 % reduction in quadriceps and gastrocnemius fiber cross-sectional area and myonuclear number (immunohistochemistry), than wild type male mice. Male transgenic mice with the mutated MCK-3E promoter showed similar effects on muscle mass. However, female transgenic mice with either type of MCK promoter did not differ from wild type controls in either body weight or skeletal muscle mass. In conclusion, increased expression of myostatin in the skeletal muscle is associated with lower muscle mass and decreased fiber size and myonuclear number, decreased cardiac muscle mass and increased fat mass in male mice, consistent with its role as an inhibitor of skeletal muscle mass. The mechanism of gender specificity remains to be clarified.
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