Alterations in myostatin expression are associated with changes in cardiac left ventricular mass but not ejection fraction in the mouse.
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.
Artaza
Jorge N
JN
Division of Endocrinology Metabolism and Molecular Medicine, Charles R Drew University of Medicine and Science, Los Angeles, CA 90059, USA.
Reisz-Porszasz
Suzanne
S
Dow
Joan S
JS
Kloner
Robert A
RA
Tsao
James
J
Bhasin
Shalender
S
Gonzalez-Cadavid
Nestor F
NF
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D015870:Gene Expression; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D055435:Myostatin; D009929:Organ Size; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013318:Stroke Volume; D014162:Transfection / Q000379:methods; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014741:Video Recording
D018797:Cell Cycle Proteins; C525911:MSTN protein, human; C525912:Mstn protein, mouse; C525913:Mstn protein, rat; D055435:Myostatin; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta