An HMGA2-IGF2BP2 Axis Regulates Myoblast Proliferation and Myogenesis

A group of genes that are highly and specifically expressed in proliferating skeletal myoblasts during myogenesis was identified. Expression of one of these genes, Hmga2, increases coincident with satellite cell activation, and later its expression significantly declines correlating with fusion of myoblasts into myotubes. Hmga2 knockout mice exhibit impaired muscle development and reduced myoblast proliferation, while overexpression of HMGA2 promotes myoblast growth. This perturbation in proliferation can be explained by the finding that HMGA2 directly regulates the RNA-binding protein IGF2BP2. Add-back of IGF2BP2 rescues the phenotype. IGF2BP2 in turn binds to and controls the translation of a set of mRNAs, including c-myc, Sp1, and Igf1r. These data demonstrate that the HMGA2-IGF2BP2 axis functions as a key regulator of satellite cell activation and therefore skeletal muscle development. [Display omitted] ► HMGA2 expression is required for normal myoblast proliferation ► Hmga2 knockout mice are deficient in skeletal muscle growth and development ► HMGA2 directly regulates the transcription of Igf2bp2 ► IGF2BP2 promotes myoblast growth, likely via translation of c-Myc, IGF1R, and/or Sp1 Li et al. find that the transcription factor HMGA2 is specifically expressed during muscle satellite stem cell activation and contributes to this process by activating the target gene Igf2bp2. IGF2BP2 (also known as IMP2) in turn promotes the translation of mRNAs important for myoblast growth and proliferation.