Myotube hypertrophy is associated with cancer-like metabolic reprogramming and limited by PHGDH

Abstract

Muscle fiber size and oxidative metabolism are inversely related, suggesting that a glycolytic metabolism may offer a growth advantage in muscle fibers. However, the mechanisms underlying this advantage remains unknown. Nearly 100 years ago, Warburg reported that cancer cells take up more glucose to produce glycolytic intermediates for anabolic reactions such as amino acid-protein synthesis. The aim of this study was to test whether glycolysis contributes to anabolic signalling responses and hypertrophy in post-mitotic muscle cells. Skeletal muscle hypertrophy was induced in vitro by treating mouse C2C12 myotubes with IGF-1. 14C glucose was added to differentiation medium and radioactivity in isolated protein was measured. We exposed differentiated C2C12 and primary mouse myotubes, to 2-deoxyglucose (2DG) and PHGDH siRNA upon which we assessed myotube diameter and signaling pathways involved in the regulation of muscle fiber size. Here, we present evidence that, hypertrophying C2C12 myotubes undergo a cancer-like metabolic reprogramming. First, IGF-1-induced C2C12 myotube hypertrophy increases shunting of carbon from glucose into protein. Second, reduction of glycolysis through 2-deoxy-D-glucose (2DG) lowers C2C12 and primary myotube size 16-40%. Third, reducing the cancer metabolism-associated enzyme PHGDH decreases C2C12 and primary myotube size 25-52%, whereas PHGDH overexpression increases C2C12 myotube size ≈20%. Fourth, the muscle hypertrophy-promoting kinase AKT regulates PHGDH expression. Together these results suggest that glycolysis is important for hypertrophying C2C12 myotubes by reprograming their metabolism similar to cancer cells.

Evidence of myomiR regulation of the pentose phosphate pathway during mechanical load‐induced hypertrophy

“…The role of metabolic reprograming during skeletal muscle growth has only recently been investigated. For example, it was demonstrated the participation of important metabolic processes, such as the polyamine pathway, hexosamine biosynthetic pathway, and serine synthesis pathways play a role in skeletal muscle hypertrophy (Lambert et al, 2018 ; Stadhouders et al, 2020 ; Tabbaa et al, 2021 ). Therefore, overlooked metabolic networks may be contributing to the regulation of muscle mass.…”

Does a Hypertrophying Muscle Fibre Reprogramme its Metabolism Similar to a Cancer Cell?

“…We observed that 14 C from glucose ended up in protein and that IGF-1 increased the incorporation of 14 C into protein significantly by ≈ 71% [49]. Note that the data in B are from a not yet peer-reviewed preprint [49]. CPM counts per minute glucose is channelled into anabolism.…”

“…In this experiment, we incubated C2C12 myotubes with radioactive 14 C-glucose and treated them with combinations of 100 ng mL −1 of insulin-like growth factor (IGF-1) or 100 ng mL −1 of rapamycin. We observed that 14 C from glucose ended up in protein and that IGF-1 increased the incorporation of 14 C into protein significantly by ≈ 71% [49]. Note that the data in B are from a not yet peer-reviewed preprint [49].…”

“…Phgdh expression also transiently increases in response to β 2 -agonist stimulation [48] but not after human resistance exercise [21]. In vitro, Phgdh knock down reduces C2C12 myotube size, suggesting that the increased Phgdh activity promotes hypertrophy [49].…”

Effects of Acute and Chronic Resistance Exercise on the Skeletal Muscle Metabolome

“…However, it is still unclear what their fate in skeletal muscle is and whether those amino acids are increasingly metabolized or the general acetylation is blunted. Another pathway that is activated by RE and involved in the regulation of protein synthesis and muscle hypertrophy is the cancer-like reprogramming inducing the synthesis of serine and glycine via PHGDH [ 8 , 73 ]. RE stimulates the expression of pyruvate kinase muscle 2 (PKM2), which in C2C12 myotubes has been shown to induce hypertrophy [ 74 ].…”