Smith 2021 Am J Physiol Endocrinol Metab

From Bioblast
Publications in the MiPMap
Smith CD, Lin CT, McMillin SL, Weyrauch LA, Schmidt CA, Smith CA, Kurland IJ, Witczak CA, Neufer PD (2021) Genetically increasing flux through Ξ²-oxidation in skeletal muscle increases mitochondrial reductive stress and glucose intolerance.

Β» Am J Physiol Endocrinol Metab 320:E938-50. PMID: 33813880 Open Access

Smith Cody D, Lin Chien-Te, McMillin Shawna L, Weyrauch Luke A, Schmidt Cameron A, Smith Cheryl A, Kurland Irwin J, Witczak Carol A, Neufer P Darrell (2021) Am J Physiol Endocrinol Metab

Abstract: Elevated mitochondrial hydrogen peroxide (H2O2) emission and an oxidative shift in cytosolic redox environment have been linked to high-fat-diet-induced insulin resistance in skeletal muscle. To test specifically whether increased flux through mitochondrial fatty acid oxidation, in the absence of elevated energy demand, directly alters mitochondrial function and redox state in muscle, two genetic models characterized by increased muscle Ξ²-oxidation flux were studied. In mice overexpressing peroxisome proliferator-activated receptor-Ξ± in muscle (MCK-PPARΞ±), lipid-supported mitochondrial respiration, membrane potential (ΔΨm), and H2O2 production rate (JH2O2) were increased, which coincided with a more oxidized cytosolic redox environment, reduced muscle glucose uptake, and whole body glucose intolerance despite an increased rate of energy expenditure. Similar results were observed in lipin-1-deficient, fatty-liver dystrophic mice, another model characterized by increased Ξ²-oxidation flux and glucose intolerance. Crossing MCAT (mitochondria-targeted catalase) with MCK-PPARΞ± mice normalized JH2O2 production, redox environment, and glucose tolerance, but surprisingly, both basal and absolute insulin-stimulated rates of glucose uptake in muscle remained depressed. Also surprising, when placed on a high-fat diet, MCK-PPARΞ± mice were characterized by much lower whole body, fat, and lean mass as well as improved glucose tolerance relative to wild-type mice, providing additional evidence that overexpression of PPARΞ± in muscle imposes more extensive metabolic stress than experienced by wild-type mice on a high-fat diet. Overall, the findings suggest that driving an increase in skeletal muscle fatty acid oxidation in the absence of metabolic demand imposes mitochondrial reductive stress and elicits multiple counterbalance metabolic responses in an attempt to restore bioenergetic homeostasis.

Prior work has suggested that mitochondrial dysfunction is an underlying cause of insulin resistance in muscle because it limits fatty acid oxidation and therefore leads to the accumulation of cytotoxic lipid intermediates. The implication has been that therapeutic strategies to accelerate Ξ²-oxidation will be protective. The current study provides evidence that genetically increasing flux through Ξ²-oxidation in muscle imposes reductive stress that is not beneficial but rather detrimental to metabolic regulation. β€’ Keywords: Fat oxidation, Glucose tolerance, Insulin resistance, Mitochondria, Skeletal muscle β€’ Bioblast editor: Plangger M β€’ O2k-Network Lab: US NC Greenville Neufer PD

Labels: MiParea: Respiration 

Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 

Regulation: Fatty acid 

HRR: Oxygraph-2k, TPP 


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