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Myostatin and Muscular Dystrophy
Summary
The use of broad-spectrum TGF-β antagonists may be an effective strategy for promoting muscle growth in a variety of myopathies, including Duchenne muscular dystrophy.
Description
Myostatin (GDF8) is a TGF-β family member that negatively regulates the growth and morphogenesis of skeletal muscle. Mice engineered to lack myostatin have twice the muscle mass of normal mice, and similar effects are seen in cattle, sheep, dogs and humans where there is a loss-of-function mutation in the myostatin gene.
There is considerable interest in developing strategies to modulate myostatin activity in clinical settings where enhancing muscle growth may be beneficial. In this regard, loss of myostatin activity has been demonstrated to increase muscle mass and function in mdx mice, a model for Duchenne muscular dystrophy.
Intriguingly, recent studies have indicated that myostatin is not the only TGF-β family member that negatively regulates muscle growth. Transgenic overexpression of follistatin, a binding protein for multiple TGF-β ligands, in myostatin-null mice (Mstn-/-) resulted in a quadrupling of muscle mass, i.e. a further doubling of muscle mass compared with mice lacking myostatin alone. In addition, increased TGF-β activity impedes the physiological response of satellite cells to regenerate muscle in multiple genetically defined forms of myopathy.
Together, these studies demonstrate that: (i) muscle mass in mice is controlled by multiple TGF-β ligands acting in concert; and (ii) targeting myostatin alone may not be the most effective strategy for enhancing muscle growth in patients with muscle wasting and muscle degenerative diseases.
Funding
- National Health and Medical Research Council