This Article Full Text Full Text (PDF) Supplemental Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Souza, T. A. Articles by Qiu, Y. Search for Related Content PubMed PubMed Citation Articles by Souza, T. A. Articles by Qiu, Y.

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

Departments of Biological Technologies (T.A.S., X.C., Y.G., J.Z., Y.Q.), Wyeth Research, Cambridge, Massachusetts 02149; Women’s Health and Musculoskeletal Biology (P.S., P.J.Y.), Wyeth Research, Cambridge, Massachusetts 01240; and Institute for Biological Sciences (J.J.H.), National Research Council Canada, Ottawa, Ontario, Canada K1A 0R6

Address all correspondence and requests for reprints to: Yongchang Qiu, 26 Simon Willard Road, Acton, Massachusetts 01720. E-mail: yongchang.qiu{at}genzyme.com.

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, -10, and -11, bind to both ActRIIs. Many of these factors, such as BMPs-11, -9, and -10 were discovered in systemic circulation for the first time, indicating that these ligands may also act in an endocrine fashion. Using a promoter-specific gene reporter assay, we demonstrated that soluble ActRIIB fragment-crystallizable proteins can inhibit the canonical signaling induced by these ligands. In addition, like myostatin, these factors were able to block the differentiation of myoblast cells into myotubes. However, in addition to myostatin, only BMP-11, and activins-A, -B, and -AB could be blocked from inhibiting the myoblast-to-myotube differentiation with both soluble ActRIIs, thus implicating them as potential novel regulators of muscle growth.

This article has been cited by other articles:

				H. Gilson, O. Schakman, S. Kalista, P. Lause, K. Tsuchida, and J.-P. Thissen Follistatin induces muscle hypertrophy through satellite cell proliferation and inhibition of both myostatin and activin Am J Physiol Endocrinol Metab, July 1, 2009; 297(1): E157 - E164. [Abstract] [Full Text] [PDF]