| Autor: |
Siripoksup P; Diabetes & Metabolism Research Center.; Department of Physical Therapy and Athletic Training., Cao G; Diabetes & Metabolism Research Center.; Department of Biochemistry., Cluntun AA; Diabetes & Metabolism Research Center.; Department of Biochemistry., Maschek JA; Metabolomics Core Research Facility.; Department of Nutrition & Integrative Physiology, and., Pearce Q; Metabolomics Core Research Facility., Brothwell MJ; Diabetes & Metabolism Research Center.; Department of Nutrition & Integrative Physiology, and., Jeong MY; Diabetes & Metabolism Research Center.; Department of Biochemistry., Eshima H; Diabetes & Metabolism Research Center.; Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA., Ferrara PJ; Diabetes & Metabolism Research Center.; Department of Nutrition & Integrative Physiology, and., Opurum PC; Diabetes & Metabolism Research Center.; Department of Nutrition & Integrative Physiology, and., Mahmassani ZS; Diabetes & Metabolism Research Center.; Department of Physical Therapy and Athletic Training.; Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA., Peterlin AD; Diabetes & Metabolism Research Center.; Department of Nutrition & Integrative Physiology, and., Watanabe S; Diabetes & Metabolism Research Center.; Department of Nutrition & Integrative Physiology, and., Walsh MA; Diabetes & Metabolism Research Center.; Department of Physical Therapy and Athletic Training., Taylor EB; Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA., Cox JE; Diabetes & Metabolism Research Center.; Department of Biochemistry.; Metabolomics Core Research Facility., Drummond MJ; Diabetes & Metabolism Research Center.; Department of Physical Therapy and Athletic Training.; Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA., Rutter J; Diabetes & Metabolism Research Center.; Department of Biochemistry.; Howard Hughes Medical Institute, University of Utah, Salt Lake City, Utah, USA., Funai K; Diabetes & Metabolism Research Center.; Department of Physical Therapy and Athletic Training.; Department of Biochemistry.; Department of Nutrition & Integrative Physiology, and.; Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA. |
| Abstrakt: |
Carbohydrates and lipids provide the majority of substrates to fuel mitochondrial oxidative phosphorylation. 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 the 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 toward 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. |
