Deletion of quinolinate phosphoribosyltransferase gene accelerates frailty phenotypes and neuromuscular decline with aging in a sex-specific pattern

Tae Chung, Taylor Bopp, Chris Ward, Francesca M. Notarangelo, Robert Schwarcz, Reyhan Westbrook, Qian Li Xue, Jeremy Walston, Ahmet Hoke

Research output: Contribution to journalArticlepeer-review

Abstract

Decline in neuromuscular function with aging is known to be a major determinant of disability and all-cause mortality in late life. Despite the importance of the problem, the neurobiology of age-associated muscle weakness is poorly understood. In a previous report, we performed untargeted metabolomics on frail older adults and discovered prominent alteration in the kynurenine pathway, the major route of dietary tryptophan degradation that produces neurotoxic intermediate metabolites. We also showed that neurotoxic kynurenine pathway metabolites are correlated with increased frailty score. For the present study, we sought to further examine the neurobiology of these neurotoxic intermediates by utilizing a mouse model that has a deletion of the quinolinate phosphoribosyltransferase (QPRT) gene, a rate-limiting step of the kynurenine pathway. QPRT−/− mice have elevated neurotoxic quinolinic acid level in the nervous system throughout their lifespan. We found that QPRT−/− mice have accelerated declines in neuromuscular function in an age- and sex-specific manner compared to control strains. In addition, the QPRT−/− mice show premature signs of frailty and body composition changes that are typical for metabolic syndrome. Our findings suggest that the kynurenine pathway may play an important role in frailty and age-associated muscle weakness.

Original languageEnglish (US)
Article numbere13849
JournalAging Cell
Volume22
Issue number7
DOIs
StatePublished - Jul 2023

Keywords

  • age-associated muscle weakness
  • aging
  • frailty
  • kynurenine
  • neurodegeneration
  • neuromuscular junction
  • quinolinic acid
  • sarcopenia

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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