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

Research output: Contribution to journalArticle

36 Citations (Scopus)

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

Fingerprint

Fatty Acids
Fats
Muscles
Carnitine O-Palmitoyltransferase
Lipids
AMP-Activated Protein Kinases
Ceramides
Diglycerides
Organelle Biogenesis
Locomotion
Nonesterified Fatty Acids
Insulin Resistance
Skeletal Muscle
Obesity
Carbohydrates
Insulin
Amino Acids

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., ... 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

Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism. / Wicks, Shawna E.; Vandanmagsar, Bolormaa; Haynie, Kimberly R.; Fuller, Scott E.; Warfel, Jaycob D.; Stephens, Jacqueline M.; Wang, Miao; Han, Xianlin; Zhang, Jingying; Noland, Robert C.; Mynatt, Randall L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 25, 23.06.2015, p. E3300-E3309.

Research output: Contribution to journalArticle

Wicks, SE, Vandanmagsar, B, Haynie, KR, Fuller, SE, Warfel, JD, Stephens, JM, Wang, M, Han, X, Zhang, J, Noland, RC & Mynatt, RL 2015, 'Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 25, pp. E3300-E3309. https://doi.org/10.1073/pnas.1418560112
Wicks, Shawna E. ; Vandanmagsar, Bolormaa ; Haynie, Kimberly R. ; Fuller, Scott E. ; Warfel, Jaycob D. ; Stephens, Jacqueline M. ; Wang, Miao ; Han, Xianlin ; Zhang, Jingying ; Noland, Robert C. ; Mynatt, Randall L. / Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 25. pp. E3300-E3309.
@article{3c9944fd14474c249feb2c30688a2fa5,
title = "Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism",
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.",
keywords = "Carbohydrate, Carnitine palmitoyltransferase, Fatty acid, Lipid, Muscle",
author = "Wicks, {Shawna E.} and Bolormaa Vandanmagsar and Haynie, {Kimberly R.} and Fuller, {Scott E.} and Warfel, {Jaycob D.} and Stephens, {Jacqueline M.} and Miao Wang and Xianlin Han and Jingying Zhang and Noland, {Robert C.} and Mynatt, {Randall L.}",
year = "2015",
month = "6",
day = "23",
doi = "10.1073/pnas.1418560112",
language = "English (US)",
volume = "112",
pages = "E3300--E3309",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "25",

}

TY - JOUR

T1 - Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism

AU - Wicks, Shawna E.

AU - Vandanmagsar, Bolormaa

AU - Haynie, Kimberly R.

AU - Fuller, Scott E.

AU - Warfel, Jaycob D.

AU - Stephens, Jacqueline M.

AU - Wang, Miao

AU - Han, Xianlin

AU - Zhang, Jingying

AU - Noland, Robert C.

AU - Mynatt, Randall L.

PY - 2015/6/23

Y1 - 2015/6/23

N2 - 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.

AB - 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.

KW - Carbohydrate

KW - Carnitine palmitoyltransferase

KW - Fatty acid

KW - Lipid

KW - Muscle

UR - http://www.scopus.com/inward/record.url?scp=84934973181&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84934973181&partnerID=8YFLogxK

U2 - 10.1073/pnas.1418560112

DO - 10.1073/pnas.1418560112

M3 - Article

VL - 112

SP - E3300-E3309

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 25

ER -