Inverse regulation of the cytosolic Ca²⁺ buffer parvalbumin and mitochondrial volume in muscle cells via SIRT1/PGC-1α axis.

Sylvie Ducreux,Beat Schwaller,Patrick Gregory

doi:10.1371/journal.pone.0044837

Abstract

Skeletal muscles show a high plasticity to cope with various physiological demands. Different muscle types can be distinguished by the force, endurance, contraction/relaxation kinetics (fast-twitch vs. slow-twitch muscles), oxidative/glycolytic capacity, and also with respect to Ca2+-signaling components. Changes in Ca2+ signaling and associated Ca2+-dependent processes are thought to underlie the high adaptive capacity of muscle fibers. Here we investigated the consequences and the involved mechanisms caused by the ectopic expression of the Ca2+-binding protein parvalbumin (PV) in C2C12 myotubes in vitro, and conversely, the effects caused by its absence in in fast-twitch muscles of parvalbumin null-mutant (PV−/−) mice in vivo. The absence of PV in fast-twitch muscle tibialis anterior (TA) resulted in an increase in the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and of its positive regulator, the deacetylase sirtuin 1 (SIRT1). TA muscles from PV−/− mice also have an increased mitochondrial volume. Mild ionophore treatment of control (PV-devoid) C2C12 myotubes causing a moderate elevation in [Ca2+]c resulted in an increase in mitochondrial volume, together with elevated PGC-1α and SIRT1 expression levels, whilst it increased PV expression levels in myotubes stably transfected with PV. In PV-expressing myotubes the mitochondrial volume, PGC-1α and SIRT1 were significantly lower than in control C2C12 myotubes already at basal conditions and application of ionophore had no effect on either one. SIRT1 activation causes a down-regulation of PV in transfected myotubes, whilst SIRT1 inhibition has the opposite effect. We conclude that PV expression and mitochondrial volume in muscle cells are inversely regulated via a SIRT1/PGC-1α signaling axis.

Highlights

Excitable cells, including muscle and nerve cells, need to cope with a vast range of activities, from low activity under basal or ‘‘resting’’ conditions to maximal activity occurring during brief, fast movements or complex cognitive processes, for example
An inverse correlation exists between PV expression levels and mitochondrial volume in fast-twitch muscle fibers [16] and neurons [18,19]
Since PV is not expressed in mammalian type I fibers and PV expression is rapidly lost in type II fibers cultured in vitro, we verified that C2C12 control myotubes (WT) are devoid of PV expression

Summary

Introduction

Excitable cells, including muscle and nerve cells, need to cope with a vast range of activities, from low activity under basal or ‘‘resting’’ conditions to maximal activity occurring during brief, fast movements or complex cognitive processes, for example. This requires rapidly adapting systems, both for energy metabolism and for intracellular signaling and the two need to be interconnected. Besides the functional crosstalk between Ca2+ signaling components, there exists a complex crosstalk at the level of transcription/translation and the signaling pathways involved in this process are slowly emerging [6,7]

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Results

Conclusion