Sarm1-Dependent Metabolic Reprogramming of Schwann Cells Following Nerve Injury.

Area of Science:

• Neuroscience
• Cell Biology
• Peripheral Nerve Regeneration

Background:

• Schwann cells (SCs) are critical for axon regeneration after peripheral nerve injury.
• The early injury response of SCs, preceding their repair phenotype, is not well understood.
• Sarm1 is a known regulator of axon degeneration, but its role in SCs is unclear.

Purpose of the Study:

• To investigate the role of Sarm1 in the early response of Schwann cells to peripheral nerve injury.
• To elucidate the molecular mechanisms by which Sarm1 influences the SC injury response and transition to a repair state.

Main Methods:

• Single-nucleus RNA sequencing was employed to compare wild-type and Sarm1 knockout SCs 24 hours post-nerve injury.
• Functional validation included assessing mitochondrial respiration and an in vitro axon degeneration model.

Main Results:

• Sarm1 deletion in SCs led to increased expression of genes related to oxidative phosphorylation and the TCA cycle.
• Sarm1 knockout SCs exhibited enhanced mitochondrial respiration and improved axon protection in vitro.
• Sarm1 appears to regulate the metabolic shift in SCs from oxidative phosphorylation to glycolysis post-injury.

Conclusions:

• Sarm1 plays a critical role in the early SC injury response, gating the metabolic transition to a pro-regenerative state.
• Sarm1-deficient SCs adopt a protective, oxidative phosphorylation-dependent phenotype (PASCs), enhancing axon survival.
• These findings redefine Sarm1's role beyond axon-autonomous degeneration and offer new therapeutic targets for neuropathies.