Advertisement
ResearchIn-Press PreviewMetabolism Open Access | 10.1172/JCI167371
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Siripoksup, P. in: JCI | PubMed | Google Scholar |
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Cao, G. in: JCI | PubMed | Google Scholar
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Cluntun, A. in: JCI | PubMed | Google Scholar |
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Maschek, J. in: JCI | PubMed | Google Scholar |
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Pearce, Q. in: JCI | PubMed | Google Scholar
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Lang, M. in: JCI | PubMed | Google Scholar |
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Jeong, M. in: JCI | PubMed | Google Scholar
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Eshima, H. in: JCI | PubMed | Google Scholar |
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Ferrara, P. in: JCI | PubMed | Google Scholar
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Opurum, P. in: JCI | PubMed | Google Scholar |
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Mahmassani, Z. in: JCI | PubMed | Google Scholar
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Peterlin, A. in: JCI | PubMed | Google Scholar |
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Watanabe, S. in: JCI | PubMed | Google Scholar
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Walsh, M. in: JCI | PubMed | Google Scholar |
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Taylor, E. in: JCI | PubMed | Google Scholar |
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Cox, J. in: JCI | PubMed | Google Scholar
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Drummond, M. in: JCI | PubMed | Google Scholar |
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Rutter, J. in: JCI | PubMed | Google Scholar |
1Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, United States of America
2Metabolomics Core Research Facility, Univeristy of Utah, Salt Lake City, United States of America
3Metabolomics Core Research Facility, University of Utah, Salt Lake City, United States of America
4Diabetes & Metabolism Research Center, University of Utah, United States of America
5Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, United States of America
Find articles by Funai, K. in: JCI | PubMed | Google Scholar |
Published April 23, 2024 - More info
Carbohydrates and lipids provide the majority of substrates to fuel mitochondrial oxidative phosphorylation (OXPHOS). Metabolic inflexibility, defined as an impaired ability to switch between these fuels, is implicated in a number of metabolic diseases. Here we explore the mechanism by which physical inactivity promotes metabolic inflexibility in skeletal muscle. We developed a mouse model of sedentariness, small mouse cage (SMC) that, unlike other classic models of disuse in mice, faithfully recapitulated metabolic responses that occur in humans. Bioenergetic phenotyping of skeletal muscle mitochondria displayed metabolic inflexibility induced by physical inactivity, demonstrated by a reduction in pyruvate-stimulated respiration (JO2) in absence of a change in palmitate-stimulated JO2. Pyruvate resistance in these mitochondria was likely driven by a decrease in phosphatidylethanolamine (PE) abundance in the mitochondrial membrane. Reduction in mitochondrial PE by heterozygous deletion of phosphatidylserine decarboxylase (PSD) was sufficient to induce metabolic inflexibility measured at the whole-body level, as well as at the level of skeletal muscle mitochondria. Low mitochondrial PE in C2C12 myotubes was sufficient to increase glucose flux towards lactate. We further implicate that resistance to pyruvate metabolism is due to attenuated mitochondrial entry via mitochondrial pyruvate carrier (MPC). These findings suggest a mechanism by which mitochondrial PE directly regulates MPC activity to modulate metabolic flexibility in mice.