Blockade of Metallothioneins 1 and 2 Increases Skeletal Muscle Mass and Strength

ABSTRACT

Metallothioneins are proteins that are involved in intracellular zinc storage and transport. Their expression levels have been reported to be elevated in several settings of skeletal muscle atrophy. We therefore investigated the effect of metallothionein blockade on skeletal muscle anabolism in vitro and in vivo. We found that concomitant abrogation of metallothioneins 1 and 2 results in activation of the Akt pathway and increases in myotube size, in type IIb fiber hypertrophy, and ultimately in muscle strength. Importantly, the beneficial effects of metallothionein blockade on muscle mass and function was also observed in the setting of glucocorticoid addition, which is a strong atrophy-inducing stimulus. Given the blockade of atrophy and the preservation of strength in atrophy-inducing settings, these results suggest that blockade of metallothioneins 1 and 2 constitutes a promising approach for the treatment of conditions which result in muscle atrophy.

KEYWORDS:

• muscle metabolism

ACKNOWLEDGMENTS

We are grateful to Michaela Kneissel and Estelle Trifilieff for their continuous support during the course of this study. We thank W. Maret (King's College London, UK) for very useful discussion. We are indebted to Laurent Gelman (Friedrich Miescher Institute) and Amy Palmer (University of Colorado) for stimulating discussions. We thank Anne-Ulrike Trendelenburg, Sophie Brachat, and Jun Shi for their help in the course of this study.

We all were Novartis Pharma AG employees at the time of work completion.

S.S. and B.F. conceived and designed the experiments and analyzed the data; A.B., D.S., and S.G. contributed to the design, execution, and analysis of in vitro experiments; E.P. and S.M. contributed to the design, execution, and analysis of animal experiments; J.L.-D. analyzed microarray data; E.N., C.D., and C.F. contributed to the data analysis; B.F. supervised the project; and S.S. D.J.G., and B.F. cowrote the manuscript.