FIGURE 1.

Summary of therapeutic invention points in the myostatin signaling pathway. Myostatin binds to its receptor complex ActRIIB/Alk 4 or 5 on skeletal muscle resulting in activation of the Smad 2/3, mitogen-activated protein kinase and inhibition of the PI3K intracellular signaling pathways that together result in gene transcriptional changes and effects on protein synthesis that ultimately give rise to muscle atrophy. Myostatin pathway inhibitors act extracellularly by either binding myostatin directly (Fstl3, Follistatin, myostatin antibody, GASP1, myostatin propeptide, decorin peptides, ActRIIB-Fc) or by binding its receptor complex (ActRIIB antibody) in order to block myostatin engaging its receptor complex and activating downstream signaling. Some of the inhibitors are naturally occurring (myostatin propeptide, Gasp1, follistatin, Fstl3) whereas others are engineered (myostatin antibody, ActRIIB antibody, ActRIIB-Fc). ---I represent inhibitory activities. → represent activating activities. Ab = antibody.