Journal article
Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism
The Journal of clinical investigation, Vol.134(11), e167371
06/03/2024
DOI: 10.1172/JCI167371
PMCID: PMC11142742
PMID: 38652544
Abstract
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.
Details
- Title: Subtitle
- Sedentary behavior in mice induces metabolic inflexibility by suppressing skeletal muscle pyruvate metabolism
- Creators
- Piyarat Siripoksup - University of UtahGuoshen Cao - University of UtahAhmad A Cluntun - University of UtahJ Alan Maschek - University of UtahQuentinn Pearce - University of UtahMarisa J Lang - University of UtahMi-Young Jeong - University of UtahHiroaki Eshima - University of UtahPatrick J Ferrara - University of UtahPrecious C Opurum - University of UtahZiad S Mahmassani - University of UtahAlek D Peterlin - University of UtahShinya Watanabe - University of UtahMaureen A Walsh - University of UtahEric B Taylor - University of IowaJames E Cox - University of UtahMicah J Drummond - University of UtahJared Rutter - University of UtahKatsuhiko Funai - University of Utah
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.134(11), e167371
- DOI
- 10.1172/JCI167371
- PMID
- 38652544
- PMCID
- PMC11142742
- NLM abbreviation
- J Clin Invest
- eISSN
- 1558-8238
- Language
- English
- Electronic publication date
- 04/23/2024
- Date published
- 06/03/2024
- Academic Unit
- Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984619017302771
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