PKM2 Determines Myofiber Hypertrophy In Vitro and Increases in Response to Resistance Exercise in Human Skeletal Muscle.

Sander A J Verbrugge,Sebastian Gehlert,Richard T Jaspers,Henning Wackerhage,Martin Schönfelder,Daniel Jacko,Lian E M Stadhouders,Carla Offringa,Gerard M J De Wit,Thorben Aussieker,Ilse S P Vogel

doi:10.3390/ijms21197062

Abstract

Nearly 100 years ago, Otto Warburg investigated the metabolism of growing tissues and discovered that tumors reprogram their metabolism. It is poorly understood whether and how hypertrophying muscle, another growing tissue, reprograms its metabolism too. Here, we studied pyruvate kinase muscle (PKM), which can be spliced into two isoforms (PKM1, PKM2). This is of interest, because PKM2 redirects glycolytic flux towards biosynthetic pathways, which might contribute to muscle hypertrophy too. We first investigated whether resistance exercise changes PKM isoform expression in growing human skeletal muscle and found that PKM2 abundance increases after six weeks of resistance training, whereas PKM1 decreases. Second, we determined that Pkm2 expression is higher in fast compared to slow fiber types in rat skeletal muscle. Third, by inducing hypertrophy in differentiated C2C12 cells and by selectively silencing Pkm1 and/or Pkm2 with siRNA, we found that PKM2 limits myotube growth. We conclude that PKM2 contributes to hypertrophy in C2C12 myotubes and indicates a changed metabolic environment within hypertrophying human skeletal muscle fibers. PKM2 is preferentially expressed in fast muscle fibers and may partly contribute to the increased potential for hypertrophy in fast fibers.

Highlights

With age, we lose skeletal muscle mass and force, which impacts on daily activities and generally decreases quality of life [1]
We first investigated whether resistance exercise changes pyruvate kinase muscle (PKM) isoform expression in growing human skeletal muscle and found that PKM2 abundance increases after six weeks of resistance training, whereas PKM1 decreases
An altered regulation of glycolytic enzymes including PKM2 helps to reprogram metabolism so that glycolytic intermediates and other metabolites are increasingly channeled into anabolic reactions that support the accretion of biomass [15]

Summary

Introduction

We lose skeletal muscle mass and force, which impacts on daily activities and generally decreases quality of life [1]. Sufficient muscle mass is important for the prevention of obesity and type 2 diabetes, and metabolic health, and improves the chances of surviving critical illness or severe trauma [2]. Resistance exercise stimulates muscle protein synthesis which maintains or increases muscle mass [3]. Key candidate resistance exercise stimuli are mechanical load, metabolic stress and exercise-induced muscle damage [4] known to activate the serine/threonine kinase mTOR within the mTORC1 complex [5]. This is an important step because mTORC1 is the major but not sole regulator of muscle protein synthesis [6]

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Methods

Conclusion