# PFKM governs metabolic shifts throughout skeletal muscle differentiation

## TL;DR

This study shows how the enzyme PFKM controls metabolic changes during muscle cell development, influencing cell fate through its regulation by Wnt signaling and lysosomal degradation.

## Contribution

The study reveals a novel mechanism by which PFKM degradation via Wnt signaling and microautophagy regulates metabolic shifts and muscle cell differentiation.

## Key findings

- PFKM expression increases during skeletal muscle differentiation and is degraded via Wnt signaling and microautophagy.
- PFKM degradation shifts metabolism from glycolysis to the pentose phosphate pathway, affecting cell fate.
- PFKM overexpression promotes differentiation, while its knockdown inhibits it, but can be rescued by 3-phosphoglycerate.

## Abstract

Metabolism is known to influence cell identity, but the underlying mechanisms remain unclear. Here we reveal spatiotemporal dynamics of phosphofructokinase 1 (PFK1), a key glycolytic enzyme, within the skeletal muscle lineage. The expression of PFKM (the muscle isoform of PFK1) is low in muscle stem cells and increases during differentiation. Mechanistically, Wnt signalling rapidly induces lysosomal degradation of PFKM through a methyl arginine degron motif, which gets selectively methylated by the protein arginine methyltransferase (PRMT1) and delivered to lysosomes through microautophagy. PFKM degradation shifts glucose metabolism from glycolysis to the pentose phosphate pathway. PFKM overexpression increases glycolysis and promotes differentiation into terminally differentiated myofibres. On the other hand, PFKM knockdown blunts differentiation, which can be rescued by supplementation with the downstream glycolytic intermediate 3-phosphoglycerate. In sum, our findings highlight the importance of compartmentalized metabolism in cell fate decisions.

Subcellular compartmentalization of the glycolytic enzyme PFKM regulates cell fate and metabolic switch during skeletal muscle differentiation.