Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

Shawna E. Wicks, Bolormaa Vandanmagsar, Kimberly R. Haynie, Scott E. Fuller, Jaycob D. Warfel, Jacqueline M. Stephens, Miao Wang, Xianlin Han, Jingying Zhang, Robert C. Noland, Randall L. Mynatt

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46 Scopus citations

Abstract

The correlations between intramyocellular lipid (IMCL), decreased fatty acid oxidation (FAO), and insulin resistance have led to the hypothesis that impaired FAO causes accumulation of lipotoxic intermediates that inhibit muscle insulin signaling. Using a skeletal muscle-specific carnitine palmitoyltransferase-1 KO model, we show that prolonged and severe mitochondrial FAO inhibition results in increased carbohydrate utilization, along with reduced physical activity; increased circulating nonesterified fatty acids; and increased IMCLs, diacylglycerols, and ceramides. Perhaps more importantly, inhibition of mitochondrial FAO also initiates a local, adaptive response in muscle that invokes mitochondrial biogenesis, compensatory peroxisomal fat oxidation, and amino acid catabolism. Loss of its major fuel source (lipid) induces an energy deprivation response in muscle coordinated by signaling through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity.

Original languageEnglish (US)
Pages (from-to)E3300-E3309
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number25
DOIs
StatePublished - Jun 23 2015
Externally publishedYes

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Keywords

  • Carbohydrate
  • Carnitine palmitoyltransferase
  • Fatty acid
  • Lipid
  • Muscle

ASJC Scopus subject areas

  • General

Cite this

Wicks, S. E., Vandanmagsar, B., Haynie, K. R., Fuller, S. E., Warfel, J. D., Stephens, J. M., Wang, M., Han, X., Zhang, J., Noland, R. C., & Mynatt, R. L. (2015). Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism. Proceedings of the National Academy of Sciences of the United States of America, 112(25), E3300-E3309. https://doi.org/10.1073/pnas.1418560112