Glycolytic System in Axons Supplement Decreased ATP Levels after Axotomy of the Peripheral Nerve

by Selleckchem | Jun 10 2023

Wallerian degeneration (WD) occurs in the early stages of numerous neurologic disorders, and clarifying WD pathology is crucial for the advancement of neurologic therapies. ATP is acknowledged as one of the key pathologic substances in WD. The ATP-related pathologic pathways that regulate WD have been defined. The elevation of ATP levels in axon contributes to delay WD and protects axons. However, ATP is necessary for the active processes to proceed WD, given that WD is stringently managed by auto-destruction programs. But little is known about the bioenergetics during WD. In this study, we made sciatic nerve transection models for GO-ATeam2 knock-in rats and mice. We presented the spatiotemporal ATP distribution in the injured axons with in vivo ATP imaging systems, and investigated the metabolic source of ATP in the distal nerve stump. A gradual decrease in ATP levels was observed before the progression of WD. In addition, the glycolytic system and monocarboxylate transporters (MCTs) were activated in Schwann cells following axotomy. Interestingly, in axons, we found the activation of glycolytic system and the inactivation of the tricarboxylic acid (TCA) cycle. Glycolytic inhibitors, 2-deoxyglucose (2-DG) and MCT inhibitors, a-cyano-4-hydroxycinnamic acid (4-CIN) decreased ATP and enhanced WD progression, whereas mitochondrial pyruvate carrier (MPC) inhibitors (MSDC-0160) did not change. Finally, ethyl pyruvate (EP) increased ATP levels and delayed WD. Together, our findings suggest that glycolytic system, both in Schwann cells and axons, is the main source of maintaining ATP levels in the distal nerve stump.

Comments:

The passage describes a study focused on understanding the role of ATP (adenosine triphosphate) in Wallerian degeneration (WD), a process that occurs in various neurological disorders. WD refers to the degeneration and subsequent clearance of axons following nerve injury. The study aimed to investigate the spatiotemporal distribution of ATP in injured axons and determine the metabolic source of ATP in the distal nerve stump.

The researchers used sciatic nerve transection models in rats and mice that had a specific genetic modification, known as GO-ATeam2 knock-in, which allowed for in vivo ATP imaging. They observed a gradual decrease in ATP levels before the onset of WD. Furthermore, they examined the metabolic changes in Schwann cells (supporting cells in the peripheral nervous system) and axons following axotomy (nerve injury).

The study revealed that following axotomy, the glycolytic system (a metabolic pathway that breaks down glucose) and monocarboxylate transporters (MCTs) were activated in Schwann cells. In contrast, in axons, the glycolytic system was activated, while the tricarboxylic acid (TCA) cycle (also known as the Krebs cycle or citric acid cycle, a key metabolic pathway in mitochondria) was inactivated.

To further understand the role of these metabolic changes, the researchers tested the effects of various inhibitors. They found that glycolytic inhibitors (2-deoxyglucose and 4-CIN) and MCT inhibitors decreased ATP levels and accelerated WD progression. However, inhibitors targeting the mitochondrial pyruvate carrier (MPC) did not affect ATP levels or WD progression. Finally, ethyl pyruvate (EP), a compound that can be converted into ATP, increased ATP levels and delayed WD.

Overall, the study suggests that the glycolytic system, both in Schwann cells and axons, serves as the primary source for maintaining ATP levels in the distal nerve stump following injury. The findings shed light on the bioenergetics of WD and provide insights into potential therapeutic approaches that can modulate ATP levels to influence WD progression in neurologic disorders.