Alterations in myostatin expression are associated with changes in cardiac left ventricular mass but not ejection fraction in the mouse

Abstract

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 (K/K)) mice were used. Xiscan angiography revealed that the left ventricular ejection fraction did not differ between the Mst TG and the Mst (K/K) 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 (K/K) 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.

Myostatin promotes a fibrotic phenotypic switch in multipotent C3H 10T1/2 cells without affecting their differentiation into myofibroblasts

“…This is likely to be mediated by the ActIIb receptor that binds myostatin and mediates its signaling, and which was detected in C3H10T1/2 cells (Artaza et al 2007). The increase in the mRNA expression of other minor isoforms of collagen, particularly II and IV, and, to a lesser extent, collagen IX, by myostatin, agrees with what occurs in fibrotic conditions (Bhogal et al 2005, Attallah et al 2007).…”

Angiotensin II activates myostatin expression in cultured rat neonatal cardiomyocytes via p38 MAP kinase and myocyte enhance factor 2 pathway

“…Myostatin has been shown to regulate cardiomyocyte growth through the modulation of Akt signaling (Morissette et al 2006). More recently, two studies reported that myostatin is an inhibitor of cardiomyocyte proliferation and reduces cardiac mass (Atraza et al 2007, McKoy et al 2007, while one study reported that myostatin does not regulate cardiac hypertrophy or fibrosis (Cohn et al 2007). Therefore, the effect of myostatin on cardiac hypertrophy is controversial.…”

Antibody-Directed Myostatin Inhibition Improves Diaphragm Pathology in Young but not Adult Dystrophic mdx Mice

“…These findings are consistent with those of Cohn and colleagues 32 who found no difference in heart mass, fiber CSA, or fibrosis in hearts of Mstn Ϫ/Ϫ mice, but contrast with those of Artaza and colleagues who found increased heart mass in Mstn Ϫ/Ϫ mice. 33 However, the latter study found no impairment in cardiac function in Mstn Ϫ/Ϫ mice 33 and more recently, aged Mstn Ϫ/Ϫ mice were reported to have improved cardiac function and reduced cardiac fibrosis compared with age-matched control mice. 34 Myostatin blockade therefore does not impair cardiac function and may actually have beneficial cardiac outcomes.…”