Glyoxalase I (GLOI) is the primary enzyme for detoxifying the reactive dicarbonyl methylglyoxal. Pre-clinical models demonstrate that loss of GLOI promotes the development of diabetes in obesogenic conditions. To determine if GLOI is attenuated with human obesity, we compared GLOI expression in skeletal muscle biopsy samples from 5 obese (OB) and 15 age-matched lean, healthy individuals (LH). GLOI protein was ~50% lower (p<0.05), whereas GLOI mRNA was ~2-fold higher in OB muscle (p<0.001). The NRF2/Keap1 axis, which regulates GLOI transcription, was unperturbed by obesity. Given the NAD+-dependent deacetylase SIRT1 is capable of deacetylating GLOI which may prevent GLOI’s degradation, we measured the expression of SIRT1 as well as NAMPT and HIF1α which regulate NAD+ bioavailability. HIF1α mRNA was increased 3-fold (p=0.002) and NAMPT protein was ~50% lower (p=0.2) in OB muscle suggesting a pseudo-hypoxic environment which may attenuate NAD+ bioavailability. SIRT1 protein was ~50% lower in OB muscle (p=0.09). SIRT1 protein (r = 0.673, p = 0.003) and HIF1α transcripts (r = -0.487, p = 0.041) correlated with GLO1 protein expression. NAMPT inhibition in human primary myotubes increased GLOI acetylation (~50%) and GLO1 protein (~40%) both of which were rescued by treatment with the NAD+ precursor nicotinamide riboside. Silencing of NAMPT or SIRT1 also reduced GLOI protein by 50%. These data suggest that OB muscle may be in a pseudo-hypoxic state that limits NAD+ bioavailability and SIRT1 activity promoting GLO1 acetylation and degradation.


E.R. Miranda: None. J. Shadiow: None. D.B. Lombard: None. A.T. Ludlow: None. J.M. Haus: None.


National Institutes of Health (R01DK109948)

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