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1 Division of Endocrinology Metabolism and Molecular Medicine,
2 Department of Biomedical Sciences and
3 RCMI DNA Molecular Core, Charles R Drew University of Medicine and Science, Los Angeles, California 90059, USA
4 The Heart Institute, Good Samaritan Hospital, Division of Cardiovascular Medicine of Keck School of Medicine at University of Southern California, Los Angeles, California 90017, USA
5 Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Boston, Massachusetts 02118, USA
(Requests for offprints should be addressed to N F Gonzalez-Cadavid at Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R Drew University of Medicine and Science, 1731 East 120th Street, Los Angeles, California 90059, USA; Email: ncadavid{at}ucla.edu)
(S Bhasin and N F Gonzalez-Cadavid contributed equally to this work)
* (J N Artaza and S Reisz-Porszasz are joint first authors) Myostatin (Mst) is a negative regulator of skeletal muscle in humans and animals. It is moderately expressed in the heart of sheep and cattle, increasing considerably after infarction. Genetic blockade of Mst expression increases cardiomyocyte growth. We determined whether Mst overexpression in the heart of transgenic mice reduces left ventricular size and function, and inhibits in vitro cardiomyocyte proliferation. Young transgenic mice overexpressing Mst in the heart (Mst transgenic mice (TG) under a muscle creatine kinase (MCK) promoter active in cardiac and skeletal muscle, and Mst knockout (Mst (–/–)) mice were used. Xiscan angiography revealed that the left ventricular ejection fraction did not differ between the Mst TG and the Mst (–/–) mice, when compared with their respective wild-type strains, despite the decrease in whole heart and left ventricular size in Mst TG mice, and their increase in Mst (–/–) animals. The expected changes in cardiac Mst were measured by RT-PCR and western blot. Mst and its receptor (ActRIIb) were detected by RT-PCR in rat H9c2 cardiomyocytes. Transfection of H9c2 with plasmids expressing Mst under muscle-specific creatine kinase promoter, or cytomegalovirus promoter, enhanced p21 and reduced cdk2 expression, when assessed by western blot. A decrease in cell number occurred by incubation with recombinant Mst (formazan assay), without affecting apoptosis or cardiomyocyte size. Anti-Mst antibody increased cardiomyocyte replication, whereas transfection with the Mst-expressing plasmids inhibited it. In conclusion, Mst does not affect cardiac systolic function in mice overexpressing or lacking the active protein, but it reduces cardiac mass and cardiomyocyte proliferation.
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