Proteomic identification and functional validation of activins and bone morphogenetic protein 11 as candidate novel muscle mass regulators

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DOIResolve DOI: http://doi.org/10.1210/me.2008-0290
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TypeArticle
Journal titleMolecular Endocrinology
Volume22
Issue12
Pages26892702; # of pages: 14
AbstractMyostatin 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, myostatinknockout 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.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); NRC Institute for Biological Sciences
Peer reviewedYes
NPARC number15544835
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Record identifier134dfb45-c65e-4111-9be7-6387049e8e67
Record created2010-08-16
Record modified2016-05-09
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