Defective branched-chain amino acid catabolism in dorsal root ganglia contributes to mechanical pain.
EMBO Rep
; 24(11): e56958, 2023 11 06.
Article
en En
| MEDLINE
| ID: mdl-37721527
ABSTRACT
Impaired branched-chain amino acid (BCAA) catabolism has recently been implicated in the development of mechanical pain, but the underlying molecular mechanisms are unclear. Here, we report that defective BCAA catabolism in dorsal root ganglion (DRG) neurons sensitizes mice to mechanical pain by increasing lactate production and expression of the mechanotransduction channel Piezo2. In high-fat diet-fed obese mice, we observed the downregulation of PP2Cm, a key regulator of the BCAA catabolic pathway, in DRG neurons. Mice with conditional knockout of PP2Cm in DRG neurons exhibit mechanical allodynia under normal or SNI-induced neuropathic injury conditions. Furthermore, the VAS scores in the plasma of patients with peripheral neuropathic pain are positively correlated with BCAA contents. Mechanistically, defective BCAA catabolism in DRG neurons promotes lactate production through glycolysis, which increases H3K18la modification and drives Piezo2 expression. Inhibition of lactate production or Piezo2 silencing attenuates the pain phenotype of knockout mice in response to mechanical stimuli. Therefore, our study demonstrates a causal role of defective BCAA catabolism in mechanical pain by enhancing metabolite-mediated epigenetic regulation.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Mecanotransducción Celular
/
Ganglios Espinales
Límite:
Animals
/
Humans
Idioma:
En
Revista:
EMBO Rep
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2023
Tipo del documento:
Article
País de afiliación:
China