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Myomaker is a membrane activator of myoblast fusion and muscle formation

2013; Nature Portfolio; Volume: 499; Issue: 7458 Linguagem: Inglês

10.1038/nature12343

1476-4687

Douglas P. Millay, Jason ORourke, Lillian B. Sutherland, Svetlana Bezprozvannaya, John M. Shelton, Rhonda Bassel‐Duby, Eric N. Olson,

Tissue Engineering and Regenerative Medicine

Fusion of myoblasts is essential for the formation of multi-nucleated muscle fibres. However, the identity of muscle-specific proteins that directly govern this fusion process in mammals has remained elusive. Here we identify a muscle-specific membrane protein, named myomaker, that controls myoblast fusion. Myomaker is expressed on the cell surface of myoblasts during fusion and is downregulated thereafter. Overexpression of myomaker in myoblasts markedly enhances fusion, and genetic disruption of myomaker in mice causes perinatal death due to an absence of multi-nucleated muscle fibres. Remarkably, forced expression of myomaker in fibroblasts promotes fusion with myoblasts, demonstrating the direct participation of this protein in the fusion process. Pharmacological perturbation of the actin cytoskeleton abolishes the activity of myomaker, consistent with previous studies implicating actin dynamics in myoblast fusion. These findings reveal a long-sought myogenic fusion protein that controls mammalian myoblast fusion and provide new insights into the molecular underpinnings of muscle formation. A muscle-specific membrane protein called myomaker is transiently expressed during myogenesis and is both necessary and sufficient to drive myoblast fusion in vivo and in vitro. The formation of skeletal muscle fibres depends on the fusion of myoblasts to produce multi-nucleated muscle fibres. Eric Olson and colleagues have identified and characterized a previously unknown skeletal-muscle-specific protein, myomaker, which is required for their fusion into multinucleated fibres. Genetic deletion of myomaker in mice completely abolished myoblast fusion, forced myomaker expression in muscle cells caused excessive fusion, and misexpression in fibroblasts conferred the ability to fuse with myoblasts. These findings provide new insight into the molecular mechanism of muscle formation, and the ability of myomaker to drive fusion of non-muscle cells with muscle cells suggests a novel strategy for enhancing muscle repair.