Myotube growth is associated with cancer-like metabolic reprogramming and is limited by phosphoglycerate dehydrogenase

Abstract

The Warburg effect links growth and glycolysis in cancer. A key purpose of the Warburg effect is to generate glycolytic intermediates for anabolic reactions, such as nucleotides → RNA/DNA and amino acids → protein synthesis. The aim of this study was to investigate whether a similar 'glycolysis-for-anabolism' metabolic reprogramming also occurs in hypertrophying skeletal muscle. To interrogate this, we first induced C2C12 myotube hypertrophy with IGF-1. We then added ¹⁴C glucose to the differentiation medium and measured radioactivity in isolated protein and RNA to establish whether ¹⁴C had entered anabolism. We found that especially protein became radioactive, suggesting a glucose → glycolytic intermediates → non-essential amino acid(s) → protein series of reactions, the rate of which was increased by IGF-1. Next, to investigate the importance of glycolytic flux and non-essential amino acid synthesis for myotube hypertrophy, we exposed C2C12 and primary mouse myotubes to the glycolysis inhibitor 2-Deoxy-d-glucose (2DG). We found that inhibiting glycolysis lowered C2C12 and primary myotube size. Similarly, siRNA silencing of PHGDH, the key enzyme of the serine biosynthesis pathway, decreased C2C12 and primary myotube size; whereas retroviral PHGDH overexpression increased C2C12 myotube size. Together these results suggest that glycolysis is important for hypertrophying myotubes, which reprogram their metabolism to facilitate anabolism, similar to cancer cells.

Keywords: Glycolysis; Hypertrophy; Insulin-like growth factor I; Metabolism; Skeletal muscle; Warburg effect.