The Myostatin Degradation Of Histone Acetyltransferase Enzyme P300 Molecular Mechanism

Myostatin,Growth and Differentiaion Factor 8(GDF-8),is a member of TGF-βsuperfamily,and is a novel negative regulator of muscle growth,as MSTN^-/- mice display a dramatic and wide spread increase in skeletal muscle mass.Loss of Myostatin function is associated with hyperplasia,hypertrophy and less of fat.Myostatin inhibits myoblasts both proliferation and terminal differentiation.Myostatin increases p21 expression and decreases Cdk2 protein and activity,thus resulting in an accumulation of hypophosphorylated Rb protein.In addition,Myostatin down-regulates cyclinD1 expression and induces cyclinD1 degradation through PI3K/AKT/GSK3βpathway. These both lead to arrest of myoblasts in G1-phase of cell cycle.Influence of Myostatin on myoblasts differentiation is associated with down-regulating muscle-specific genes expression such as MyoD,Myogenin and Myf5.Up till now,little is known about molecular mechanisms underlying Myostatin action and downstream effectors regulated by Myostatin.Histone acetylation is one of the best understood histone modifications.The histone acetylation level is controlled by histone acetyltransferases(HATs) and deacetylases (HDACs).Acetylation of histories and transcription factors plays an important regulatory role in developmental processes,proliferation and differentiation.Based on above evidence,we suppose that Myostatin may inhibit myoblasts proliferation and differentiation through affecting the histone acetylation level,and further modulating genes expression.We find that Myostatin decreases the acetylation level of histone H3,and it down-regulates p300 and PCAF in protein level.Further results show that Myostatin induces p300 degradation.PI3K/AKTpathway is involved in p300 degradation mediated by Myostatin and this could be antagonized by IGF-1.Other data indicate that other pathways may be involved in p300 degradaion mediated by Myostatin.Our work provides a new mechanism of Mysotatin regulating genes expression. This will help us to understand how myostatin inhibites myogenesis.