Muscle Growth Triggered by Myostatin Inhibition Does Not Involve Satellite Cells

Inhibition of the myostatin/activin signaling pathway stimulates muscle growth in a fashion that does not significantly involve the incorporation of muscle stem cells (satellite cells) into myofibers.

Satellite cells are small mononuclear progenitor cells with virtually no cytoplasm found in mature muscle. They are found sandwiched between the basement membrane and sarcolemma (cell membrane) of individual muscle fibers. Satellite cells are able to differentiate and fuse to augment existing muscle fibers and to form new fibers. These cells represent the oldest known adult stem cell niche, and are involved in the normal growth of muscle, as well as regeneration following injury or disease. In undamaged muscle, the majority of satellite cells are quiescent; they neither differentiate nor undergo cell division. In response to mechanical strain or injury, satellite cells become activated. Activated satellite cells initially proliferate as skeletal myoblasts before undergoing myogenic differentiation.

Myostatin (also known as growth differentiation factor 8 or GDF-8) is a protein that in humans is encoded by the MSTN gene. Myostatin is a secreted growth differentiation factor that is a member of the TGF-beta protein family that inhibits muscle differentiation and growth. Myostatin is produced primarily in skeletal muscle cells, circulates in the blood, and acts on muscle tissue, by binding a cell-bound receptor called the activin type II receptor. Animals lacking myostatin or animals treated with substances such as follistatin that block the binding of myostatin to its receptor have significantly larger muscles.

Investigators at John Hopkins University (Baltimore, MD, USA) sought to identify which class of muscle cells - fibrous cells called myofibers, or stem cells called satellite cells - were directly affected by inhibition of myostatin activity.

They reported in the August 6, 2012, online edition of the journal Proceedings of the National Academy of Sciences of the USA (PNAS) that muscle growth caused by inhibiting myostatin did not significantly involve the incorporation of satellite cells into myofibers. Myostatin/activin A inhibition caused muscle growth in mice lacking either syndecan4 or Pax7, both of which are important for satellite cell function and development. Furthermore, muscle growth after pharmacological blockade of this pathway occurred without significant satellite cell proliferation and fusion to myofibers and without an increase in the number of myonuclei per myofiber.

"More work is needed to determine whether these findings are applicable to various clinical conditions, such as exercise, injury, and sarcopenia—degenerative loss of muscle mass associated with aging," said senior author Dr. Chen-Ming Fan, adjunct professor of molecular biology at Johns Hopkins University. "However, our findings initially indicate that many different diseases affecting the muscular system could potentially be responsive to drugs that inhibit myostatin and thus promote muscle growth, without regard to the status of the muscle stem cell pool."

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