Proteomic Identification and Functional Validation of Activins and Bone Morphogenetic Protein 11 as Candidate Novel Muscle Mass Regulators

Myostatin is a secreted TGF-β family member that controls skeletal muscle growth. Humans, cattle, and dogs carrying natural loss-of-function mutations in the myostatin gene and myostatin knockout mice exhibit significant increases in skeletal muscle mass. Treatment of adult mice with antimyostatin antibodies also resulted in significant muscle mass increases. However, myostatin-knockout mice that were treated with a soluble form of the activin type II receptor (ActRII) B increased their muscle mass by an additional 15–25%, indicating that there is at least one additional ligand, in addition to myostatin, that functions to limit muscle growth. Here, both soluble ActRII and -IIB fragment-crystallizable proteins were used to affinity purify their native ligands from human and mouse sera. Using mass spectrometry-based proteomics and in vitro binding assays we have identified and confirmed that a number of TGF-β family members, including myostatin, activins-A, -B, and -AB, bone morphogenetic proteins (BMPs) -9...