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bioRxiv · 10.1101/2020.12.22.424062

Fructose 1,6-bisphosphate sensing by pyruvate kinase isozymes M2 (PKM2) controls MyoD stability and myogenic differentiation

Kim, M.·Zhang, Y.·Birchmeier, C.
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Abstract

Glucose exerts beneficial effects on myogenesis and muscle physiology. However, the mechanisms by which glucose regulates myogenesis remain ill-defined or incompletely understood. Here, we show that low glycolysis destabilizes MyoD protein, a master myogenic transcription factor. Intriguingly, MyoD is not controlled by the cellular energy status per se, but by the level of fructose 1,6-bisphosphate, an intermediate metabolite of glycolysis. Fructose 1,6-bisphosphate is sensed by pyruvate kinase M2 (PKM2). In the presence of fructose 1,6-bisphosphate, PKM2 form tetramers that sequester the Huwe1 E3 ubiquitin ligase to the cytoplasm. Reduced fructose 1,6-bisphosphate levels dissociate the tetramer, releasing Huwe1 into the nucleus where it targets MyoD for degradation. Genetic or pharmacological modulation of PKM2-Huwe1 axis restores myogenic differentiation in glucose restricted conditions. Our results show that glucose metabolism directly regulates protein stability of a key myogenic factor and provide a rationale for enhancing myogenesis.

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Kim, M., Zhang, Y., Birchmeier, C.. 2020-12-22. Fructose 1,6-bisphosphate sensing by pyruvate kinase isozymes M2 (PKM2) controls MyoD stability and myogenic differentiation. https://doi.org/10.1101/2020.12.22.424062

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