Metabolic flexibility secures skeletal progenitor function upon reduced glycolysis driven by PFKFB3 loss

Area of Science:

• Cell Biology
• Metabolism
• Biochemistry

Background:

• Glycolysis is a critical metabolic pathway for bone cells, including skeletal stem and progenitor cells (SSPCs).
• The in vivo role of glycolysis in SSPC function is not well understood.
• Skeletal stem cells are vital for bone development, maintenance, and regeneration.

Purpose of the Study:

• To investigate the impact of reduced glycolysis on SSPC biology and function in vivo.
• To explore the adaptive metabolic mechanisms employed by SSPCs when glucose metabolism is impaired.

Main Methods:

• Conditional deletion of phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3), a key glycolytic regulator, in mice.
• Metabolic profiling and functional assays of PFKFB3-deficient SSPCs.
• Assessment of bone mass and structure in mutant mice.

Main Results:

• PFKFB3 deletion reduced glycolytic flux by over 30% and glucose-carbon incorporation into metabolic pathways.
• PFKFB3-deficient SSPCs maintained metabolic homeostasis and functional properties despite reduced glycolysis.
• Bone mass was preserved in mutant mice, even under conditions of high metabolic demand.
• Compensatory mechanisms included increased amino acid and pyruvate uptake for anaplerosis and biosynthesis.

Conclusions:

• SSPCs exhibit significant metabolic flexibility, adapting to reduced glucose metabolism by utilizing alternative nutrient sources.
• This metabolic reprogramming is an adaptive strategy that preserves SSPC function and bone formation under metabolic stress.
• PFKFB3 plays a crucial role in regulating glycolytic flux in SSPCs, but SSPCs can compensate for its loss.