J Clin Invest 109(5): 595-601

Suppression of body fat accumulation in myostatin-deficient mice

Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Address correspondence to: Se-Jin Lee, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, Maryland 21205, USA. Phone: (410) 614-0198; Fax: (410) 955-0831; E-mail: ude.imhj@eeljs.

Received 2001 Jun 19; Accepted 2002 Jan 30.

Abstract

Myostatin is a TGF-β family member that acts as a negative regulator of muscle growth. Mice lacking the myostatin gene (Mstn) have a widespread increase in skeletal muscle mass resulting from a combination of muscle fiber hypertrophy and hyperplasia. Here we show that Mstn-null mice have a significant reduction in fat accumulation with increasing age compared with wild-type littermates, even in the setting of normal food intake (relative to body weight), normal body temperature, and a slightly decreased resting metabolic rate. To investigate whether myostatin might be an effective target for suppressing the development of obesity in settings of abnormal fat accumulation, we analyzed the effect of the Mstn mutation in two genetic models of obesity, agouti lethal yellow (A^y) and obese (Lep^ob/ob). In each case, loss of Mstn led to a partial suppression of fat accumulation and of abnormal glucose metabolism. Our findings raise the possibility that pharmacological agents that block myostatin function may be useful not only for enhancing muscle growth, but also for slowing or preventing the development of obesity and type 2 diabetes.

Abstract

Acknowledgments

This work was supported by NIH grant R01HD35887 and by a grant from American Home Products (to S.-J. Lee). We thank Paul Dunlap for assistance with the metabolic rate determinations and Dan Lane, Monica Kumar, Randall Reed, and Mosi Beckett for the Ucp3 and S26 probes. Myostatin was licensed by Johns Hopkins University to MetaMorphix Inc. (MMI) and sublicensed to American Home Products. The authors are entitled to a share of sales royalty received by the University from sales of this factor. The authors and the University own MMI stock, which is subject to certain restrictions under University policy. S.-J. Lee is a consultant to MMI. The terms of these arrangements are being managed by the University in accordance with its conflict-of-interest policies.

Acknowledgments

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