Editors' ChoiceMEDICINE

Unhinging Muscle Injury

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Science Signaling  28 Oct 2014:
Vol. 7, Issue 349, pp. ec300
DOI: 10.1126/scisignal.aaa1501

Muscle injury stimulates the release of transforming growth factor–β (TGF-β) from the extracellular matrix where TGF-β is sequestered in a complex with latent TGF-β binding proteins (LTBPs). Polymorphisms in LTBP4 correlate with disease severity in Duchenne muscular dystrophy. The hinge region of LTBP4 undergoes proteolytic cleavage to release latent TGF-β and in mice this hinge region is longer than in humans. Ceco et al. found that, in vitro, serine proteases cleaved human LTBP4 more efficiently than mouse LTPB4. Furthermore, mice engineered to express human LTBP4 exhibited increased TGF-β signaling and muscle hypertrophy and, after injury, had enhanced muscle damage. When expressed in mdx mice, a muscular dystrophy model, human LTBP4 resulted in worse symptoms and weaker muscles. Injection of antibodies that block proteolysis of the hinge region of LTBP4 reduced muscle damage following injury in the hTLBP4/mdx mice. Thus, blocking LTBP4 cleavage may be an approach to reduce muscle injury and symptoms of muscular dystrophy.

E. Ceco, S. Bogdanovich, B. Gardner, T. Miller, A. DeJesus, J. U. Earley, M. Hadhazy, L. R. Smith, E. R. Barton, J. D. Molkentin, E. M. McNally, Targeting latent TGF-β release in muscular dystrophy. Sci. Transl. Med. 6, 259ra144 (2014). [Abstract]

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