The glycolytic metabolite methylglyoxal drives axon degeneration in vitro and in vivo.

Diabetes impacts 1 in 9 people worldwide, with up to 50% of those patients developing diabetic peripheral neuropathy (DPN). Despite the prevalence of DPN, treatment options for patients remain limited. Methylglyoxal (MGO) is a noxious metabolite elevated in diabetic patients in response to increased glycolytic activity. MGO is thought to participate in complications associated with diabetes, including nociceptive symptoms. Given MGO's known role in driving pain in DPN, we hypothesized that it also contributes to axon degeneration mechanisms. Here, we explore the role of MGO in axon degeneration and its potential contributions to DPN development. We treated primary mouse dorsal root ganglion (DRG) cultures with MGO (5 μM, 10 μM, 500 μM, and 5 mM) and measured neurite length to monitor neurite growth and degeneration. We also administered a single injection of MGO (720 ng) to adult male mice and examined intraepidermal nerve fiber density. Our results reveal that MGO causes axon degeneration in vitro and in vivo. Additionally, at high concentrations (500 μM and 5 mM), MGO reduced the number of somata in primary DRG cultures. Because glyoxalase 1 (GLO1) is the rate-limiting enzyme in the primary pathway that scavenges MGO, we explored a potential role of GLO1 in MGO-induced axon degeneration. To investigate the role of GLO1, we used BALB/cJ and BALB/cByJ mouse substrains, which differ in GLO1 levels due to gene duplication. Increased GLO1 expression was protective in vitro against MGO; however, MGO did not cause fiber loss in vivo. Ultimately, our results demonstrate that MGO is a potential tool for understanding axon degeneration in DPN. Additionally, MGO-driven axon degeneration provides a novel model to further explore the nuanced relationship between axon degeneration and pain.