A quantitative proteomics approach to gain insight into NRF2-KEAP1 skeletal muscle system and its cysteine redox regulation

Rafay Abu, Li Yu, Ashok Kumar, Lie Gao, Vikas Kumar

Research output: Contribution to journalArticlepeer-review

Abstract

Mammalian skeletal muscle (SkM) tissue engages the Nrf2-Keap1-dependent antioxidant defense mechanism to respond adaptively to stress. Redox homeostasis mediated by the reversible modification of selective cysteines is the prevalent mode of regulation. The protein targets of SkM redox regulation are largely unknown. We previously reported the proteomic profiles of soleus (Sol) and extensor digitorum longus (EDL) with Nrf2 or Keap1 gene deletion, using SkM-specific Nrf2 or Keap1 knockout models; iMS-Nrf2flox/flox; and iMS-Keap1flox/flox. Here, we employed these two animal models to understand the global expression profile of red tibialis anterior (RTA) using a label free approach and its redox proteomics using iodoacetyl tandem mass tag (iodoTMTTM)- labeled cysteine quantitation. We quantified 298 proteins that were significantly altered globally in the RTA with Nrf2 deficiency but only 21 proteins in the Keap1 KO samples. These proteins are involved in four intracellular signaling pathways: sirtuin signaling, Nrf2 mediated oxidative stress response, oxidative phosphorylation, and mitochondrion dysfunction. Moreover, we identified and quantified the cysteine redox peptides of 34 proteins, which are associated with mitochondrial oxidative phosphorylation, energy metabolism, and extracellular matrix. Our findings suggest that Nrf2-deficient RTA is implicated in metabolic myopathy, mitochondrial disorders, and motor dysfunction, possibly due to an enhanced oxidative modification of the structure and functional proteins in skeletal myocytes.

Original languageEnglish (US)
Article number1655
JournalGenes
Volume12
Issue number11
DOIs
StatePublished - Nov 2021

Keywords

  • IPA
  • Nrf2/keap1 system
  • Quantitative proteomics
  • Sedox cysteine
  • Skeletal muscle

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint

Dive into the research topics of 'A quantitative proteomics approach to gain insight into NRF2-KEAP1 skeletal muscle system and its cysteine redox regulation'. Together they form a unique fingerprint.

Cite this