Targeted Metabolomics Connects TXNIP to Mitochondrial Fuel Selection and Regulation of Specific Oxidoreductase Enzymes in Skeletal Muscle [Bioenergetics]

January 30th, 2014 by DeBalsi, K. L., Wong, K. E., Koves, T. R., Slentz, D. H., Seiler, S. E., Wittmann, A. H., Ilkayeva, O. R., Stevens, R. D., Perry, C. G. R.., Lark, D. S., Hui, S. T., Szweda, L., Neufer, P. D., Muoio, D. M.

Thioredoxin-interacting protein (TXNIP) is an a-arrestin family member involved in redox sensing and metabolic control. Growing evidence links TXNIP to mitochondrial function, but the molecular nature of this relationship has remained poorly defined. Herein, we employed targeted metabolomics and comprehensive bioenergetic analyses to evaluate oxidative metabolism and respiratory kinetics in mouse models of total body (TKO) and skeletal muscle-specific (TXNIPSKM-/-) Txnip deficiency. Compared to littermate controls, both TKO and TXNIPSKM-/- mice had reduced exercise tolerance in association with muscle-specific impairments in substrate oxidation. Oxidative insufficiencies in TXNIP null muscles were not due to perturbations in mitochondrial mass, the electron transport chain or emission of reactive oxygen species. Instead, metabolic profiling analyses led to the discovery that TXNIP deficiency causes marked deficits in enzymes required for catabolism of branched chain amino acids, ketones and lactate, along with more modest reductions in enzymes of β-oxidation and the tricarboxylic acid cycle. The decrements in enzyme activity were accompanied by comparable deficits in protein abundance without changes in mRNA expression, implying dysregulation of protein synthesis or stability. Considering that TXNIP expression increases in response to starvation, diabetes and exercise, these findings point to a novel role for TXNIP in coordinating mitochondrial fuel switching in response to nutrient availability.
  • Posted in Journal of Biological Chemistry, Publications
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