Functional improvement of dystrophic muscle by myostatin blockade

Abstract

Mice1,2 and cattle3 with mutations in the myostatin (GDF8) gene show a marked increase in body weight and muscle mass, indicating that this new member of the TGF-β superfamily is a negative regulator of skeletal muscle growth. Inhibition of the myostatin gene product is predicted to increase muscle mass and improve the disease phenotype in a variety of primary and secondary myopathies. We tested the ability of inhibition of myostatin in vivo to ameliorate the dystrophic phenotype in the mdx mouse model of Duchenne muscular dystrophy (DMD)4,5,6,7,8. Blockade of endogenous myostatin by using intraperitoneal injections of blocking antibodies for three months resulted in an increase in body weight, muscle mass, muscle size and absolute muscle strength in mdx mouse muscle along with a significant decrease in muscle degeneration and concentrations of serum creatine kinase. The functional improvement of dystrophic muscle by myostatin blockade provides a novel, pharmacological strategy for treatment of diseases associated with muscle wasting such as DMD, and circumvents the major problems associated with conventional gene therapy in these disorders.

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Figure 1: Metabolic consequences of myostatin blockade in vivo in mdx mice.
Figure 2: Increase in muscle mass and strength by myostatin blockade.
Figure 3: Decreased muscle damage resulting from myostatin blockade.

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Acknowledgements

We thank L. Sweeney, C. Bönnemann, J. Khurana (University of Pennsylvania) and L. Edvinsson (Glostrup Hospital, University of Copenhagen and Lund) for guidance and helpful discussions, and N. Wolfman (Wyeth Research/Genetics Institute) for providing reagents and helpful discussions. T.S.K. was a paid consultant for Wyeth Research/Genetics Institute during the study. The study was supported in part by a grant from Wyeth Research/Genetics Institute and a predoctoral fellowship to T.O.B.K. from the Faculty of Medicine, Copenhagen University, Denmark.

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Correspondence to Tejvir S. Khurana.

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(1) T.S.K. was a paid consultant for Wyeth Research/Genetics Institute during the study. (2) T.S.K. has past and current sponsored research agreements (grants) in place with Wyeth Research/Genetics Institute. The grants have been used in part, to cover costs associated with the current study. (3) L.A.W. is an employee of Wyeth Research/Genetics Institute and owns stock in the company.

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Bogdanovich, S., Krag, T., Barton, E. et al. Functional improvement of dystrophic muscle by myostatin blockade. Nature 420, 418–421 (2002). https://doi.org/10.1038/nature01154

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