TGFβ and BMP signaling in skeletal muscle: potential significance for muscle-related disease

• The TFGβ superfamily is divided in two subfamilies with opposite function on muscle mass: myostatin/activin/TGFβ and BMP/GDF.
• Myostatin is a negative regulator of muscle growth.
• BMPs are positive regulators of muscle growth and are dominant over myostatin signaling.
• Both BMPs and myostatin impinge on the Akt/mTOR pathway.
• The effects of myostatin and BMPs on muscle mass require the transcription factors Smad2/3 and Smad1/5/8, respectively.
• BMP signaling negatively regulates a novel ubiquitin ligase named MUSA1 that is crucial for muscle atrophy.

The transforming growth factor beta (TGFβ) superfamily comprises a large number of secreted proteins that regulate various fundamental biological processes underlying embryonic development and the postnatal regulation of many cell types and organs. Sequence similarities define two ligand subfamilies: the TGFβ/activin subfamily and the bone morphogenetic protein (BMP) subfamily. The discovery that myostatin, a member of the TGFβ/activin subfamily, negatively controls muscle mass attracted attention to this pathway. However, recent findings of a positive role for BMP-mediated signaling in muscle have challenged the model of how the TGFβ network regulates skeletal muscle phenotype. This review illustrates how this complex network integrates crosstalk among members of the TGFβ superfamily and downstream signaling elements to regulate muscle in health and disease.