Targeted metabolomics connects thioredoxin-interacting protein (TXNIP) to mitochondrial fuel selection and regulation of specific oxidoreductase enzymes in skeletal muscle

Karen L. DeBalsi, Kari E. Wong, Timothy R. Koves, Dorothy H. Slentz, Sarah E. Seiler, April H. Wittmann, Olga R. Ilkayeva, Robert D. Stevens, Christopher G.R. Perry, Daniel S. Lark, Simon T. Hui, Luke Szweda, P. Darrell Neufer, Deborah M. Muoio

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Thioredoxin-interacting protein (TXNIP) is an α-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 with 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 forTXNIPin coordinating mitochondrial fuel switching in response to nutrient availability.

Original languageEnglish (US)
Pages (from-to)8106-8120
Number of pages15
JournalJournal of Biological Chemistry
Volume289
Issue number12
DOIs
StatePublished - Mar 21 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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