Summermatter, Serge, Bouzan, Anais, Pierrel, Eliane, Melly, Stefan, Gutzwiller, Sabine, Fryer, Christy, Nolin, Erin, Dornelas, Christina, Leighton-Davies, Juliet, Palmer , Amy, Qin, Yan, Glass, David and Fournier, Brigitte (2017) Blockade of metallothioneins 1 and 2 increases skeletal muscle mass and strength. Molecular and cellular biology, 37 (5). e000305-e000316. ISSN 1098-5549; 0270-7306

Abstract

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. Here, we demonstrate that these genes are also induced coincident with aging. We therefore investigated the effect of metallothionein blockade on skeletal muscle anabolism in vitro and in vivo, and found that concomitant abrogation of metallothionein 1 and 2 activates the Akt pathway, promotes myotube growth, specifically drives type IIb fiber hypertrophy and ultimately increases muscle strength. Silencing of metallothioneins results in elevated cytosolic zinc; increasing intracellular zinc levels are sufficient to mimic the effects of metallothionein blockade on myotube hypertrophy. We thereby provide direct evidence of the mechanisms by which metallothioneins can modulate skeletal muscle mass. Importantly, the beneficial effects of metallothionein blockade on muscle mass and function are preserved in the presence of a strong catabolic stimulus: treatment with glucocorticoids. Taken together, our results suggest that blockade of metallothioneins constitutes a promising approach for the treatment of muscle diseases.

Item Type:	Article
Date Deposited:	22 Mar 2017 00:45
Last Modified:	08 Jun 2020 00:45
URI:	https://oak.novartis.com/id/eprint/28474