Myostatin and its Role in the Complex Signaling Pathway of Muscle Metabolism
Myostain first came onto the scene as an important player in muscular diseases around 1997 and since then has exploded into new research developments. Myostatin, also know as, growth differentiation factor-8, is a member of the TGF (beta) β super family of signal transduction proteins that regulate the differentiation and proliferation of cells. It also plays an important role in the regulation of skeletal muscle mass, repair and other keys roles in metabolism. Due to the fact that the amount of metabolically active lean tissue can have significant effects on the metabolism of the whole body a mutation in myostatin can lead to the development of obesity and diabetes as well.
Cellular responses are initiated when TGF-β and related proteins bind to two different types of serine/threonine kinase receptors, known as type I and type II. The type II receptor is activated by the ligand binding of the type I receptor, which then initiates intracellular signals specifically by SMAD proteins. SMAD proteins consist of a group of molecules that function intracelluarly as signal transducers and are downstream of the TGF- β receptors. There are 8 different SMAD proteins, in mammals, which have been identified. These 8 different SMAD proteins are divided, by function, into three different subfamilies: receptor-regulated SMADS (R-SMADS), common-partner SMADS (Co-SMADS), and inhibitory SMADS (I-SMADS). Type I serine/kinase receptors activate R-SMADS through phosphorylation and consist of SMAD1, SMAD2, SMAD3, SMAD5, and SMAD8. SMAD2 and SMAD3 are active in the TGF- β and activin pathways, while SMAD1, SMAD5, and SMAD8 are responsible for signal mediation in the bone morphogenetic proteins (BMP) and anti-Müllerian pathways. A positive regulator for the above pathways is the Co-SMAD, SMAD4, while SMAD6 and SMAD7, which are I-SMADS, bind to the intracellular domain of type I receptors. In addition the I-SMADS compete with the R-SMADS for activation by the type I receptors, which results in the inhibition of TGF- β signaling. Furthermore SMAD6 inhibits BMP signaling while SMAD7 inhibits TGF- β signaling.
The phosphorylation and activation of the active type II and type I receptor complexes starts the TGF- β and activin signaling, which in turn causes SMAD2 and SMAD3 to form hetero-oligomers with SMAD4 trans locating the entire complex into the nucleus. They regulate transcription by binding to various cellular partners and DNA downstream of the response genes. SMAD7 forms a complex with SMAD2/3 thus inhibiting the signaling which then disturbs the formation of the complex between SMAD2/3 and SMAD4 consequently preventing further signal propagation. The stimulation of TGF- β and activin promote the transcription of SMAD7, providing a regulatory feedback mechanism that terminates signaling through activated receptors.
AcTRIIB has been shown to be the type II receptor for myostatin; additional evidence suggests that the binding between AcTRIIB and myostatin is specific. The activin-binding protein follistatin and myostatin propeptide inhibits the binding of myostatin to the AcTRIIB receptor disrupting the signal transduction. The participation of SMAD2/3 and SMAD4 is required for signal transduction of myostatin, while SMAD7 negatively regulates the signaling of myostain. Subsequently gene expression studies have shown that myostatin, through SMAD2, SMAD3 and SMAD4 induces SMAD7 expression, suggesting that SMAD7 acts as a negative feedback inhibitor for the myostatin signal pathway.
To initiate signaling myostatin binds to the type II receptor AcTRIIB. Myostatin’s own propeptide follistatin, as well as soluble AcTRIIB, can block the signal transduction of myostatin. SMAD3 is essential for myostatin induced transcription activity, which has been demonstrated by mutating SMAD3 and showing that