Myostatin expression is elevated following cardiomyocyte damage and it has been directly linked to cachexic loss of muscle mass in heart failure patients [19]. A role for myostatin in bone homeostasis has been investigated as well. Examination of bones from myostatin null mice has revealed improved bone strength and bone mineral density in the limbs [20], [21] and [22], L5 vertebrae [23] and jaw [24]. It is unclear from these studies if the increased bone mass is due to adaptive responses caused by increased load from larger muscles at these attachment sites rather than a direct effect of KU-60019 in vivo myostatin signaling in bone or simply due to developmental related effects. More recently, it has been shown that myostatin

is expressed at the fracture callus following injury [25]. In addition, myostatin null mice have increased blastema size, total osseous tissue and callus strength in a fibular osteotomy model [26].

The authors suggest that myostatin may regulate the initial recruitment and proliferation of progenitor cells in the callus. Together these data support a role for TSA HDAC myostatin in bone homeostasis and repair. Similar to other members of the BMP family, myostatin activates signaling upon binding to a heterodimeric complex made up of two type 2 receptors: Activin Receptor 2B/2A (ActRIIB)/ActRIIA and two type 1 receptors: Activin Receptor-Like Kinase 4/5 (Alk4/Alk5) [27]. Signals are transduced via Smad2/3 phosphorylation followed by translocation into the nucleus to modulate transcription. Both activin receptors, ActRIIA and ActRIIB, can bind multiple ligands [28] and [29] including myostatin although with different affinities [30]. Intact and ovariectomized mice treated with a soluble ActRIIA receptor have been reported to have induced bone formation, bone volume and biomechanical strength [31]. Interestingly, these treated animals had no reported increase in body weight or muscle mass. While a soluble ActRIIA molecule has been shown to neutralize myostatin activity in an in vitro

model Clomifene of cell differentiation, the lack of any reported muscle phenotype in vivo may be due to differences in ligand binding affinities or pharmacokinetic properties of the protein [28]. In contrast, mice treated with a soluble ActRIIB receptor demonstrate a dramatic increase in body weight and isolated muscle mass [32]. Furthermore, it was shown that the soluble ActRIIB receptor increased muscle mass in the myostatin null mice suggesting that additional ActRIIB ligands may function as negative regulators of skeletal muscle. ActRIIB is known to be expressed on the surface of many cell types including osteoblasts [33] and research has shown bone marrow stromal cells (BMSCs) isolated from the myostatin null mice express ActRIIB and have enhanced osteogenic potential [34]. Collectively, these data support a potential role of myostatin as well as other ActRIIB ligands in regulating bone homeostasis.