329606.fig.005
Figure 5: The precursor of myostatin is promyostatin and consists of a propeptide that binds to myostatin noncovalently to form an inactive complex. When myostatin is activated, it binds to its receptor; activin A bound to the extra cellular domain of a type II receptor (ActRIIB), which is present on muscle membranes. In turn ALK4 or ALK5 phosphorylates intracellular proteins called Smad2/3 and the Smad complex translocates into the nucleus and causes changes in gene transcription that ultimately result in muscle wasting and cachexia. Akt activity is also inhibited. FOXO becomes dephosphorylated and migrates to the nucleus where ubiquitin ligases MuRF1 and Atrogen 1 are synthesized. As a result, muscle proteins are degraded through the ubiquitin proteasome pathway.