Genetically increasing flux through β-oxidation in skeletal muscle increases mitochondrial reductive stress and glucose intolerance

Am J Physiol Endocrinol Metab. 2021 Apr 5. doi: 10.1152/ajpendo.00010.2021. Online ahead of print.ABSTRACTElevated mitochondrial 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 β-oxidation flux were studied. In mice overexpressing peroxisome proliferator activated receptor-α in muscle (MCK-PPARα), 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 β-oxidation flux and glucose intolerance. Crossing MCAT (mitochondrial-targeted catalase) with MCK-PPARα 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-PPARα mice were characterized by much lower whole body, fat and lean mass as ...

Source: Am J Physiol Endocri... - April 5, 2021 Category: Endocrinology Authors: Cody D Smith Chein-Te Lin Shawna L McMillin Luke A Weyrauch Cameron Alan Schmidt Cheryl A Smith Irwin J Kurland Carol A Witczak P Darrell Neufer Source Type: research