title: Early mitochondrial dysfunction in glycolytic muscle, but not oxidative muscle, of the fructose-fed insulin-resistant rat.
abstract: Although evidence that type 2 diabetes mellitus (T2DM) is accompanied by mitochondrial dysfunction in skeletal muscle has been accumulating, a causal link between mitochondrial dysfunction and the pathogenesis of the disease remains unclear. Our study focuses on an early stage of the disease to determine whether mitochondrial dysfunction contributes to the development of T2DM. The fructose-fed (FF) rat was used as an animal model of early T2DM. Mitochondrial respiration and acylcarnitine species were measured in oxidative (soleus) and glycolytic [extensor digitorum longus (EDL)] muscle. Although FF rats displayed characteristic signs of T2DM, including hyperglycemia, hyperinsulinemia, and hypertriglyceridemia, mitochondrial content was preserved in both muscles from FF rats. The EDL muscle had reduced complex I and complex I and II respiration in the presence of pyruvate but not glutamate. The decrease in pyruvate-supported respiration was due to a decrease in pyruvate dehydrogenase activity. Accumulation of C14:1 and C14:2 acylcarnitine species and a decrease in respiration supported by long-chain acylcarnitines but not acetylcarnitine indicated dysfunctional β-oxidation in the EDL muscle. In contrast, the soleus muscle showed preserved mitochondrial respiration, pyruvate dehydrogenase activity, and increased fatty acid oxidation, as evidenced by overall reduced acylcarnitine levels. Aconitase activity, a sensitive index of reactive oxygen species production in mitochondria, was reduced exclusively in EDL muscle, which showed lower levels of the antioxidant enzymes thioredoxin reductase and glutathione peroxidase. Here, we show that the glycolytic EDL muscle is more prone to an imbalance between energy supply and oxidation caused by insulin resistance than the oxidative soleus muscle.
authors.affiliation: Campus Saint-Jean, University of Alberta, Edmonton, Alberta, Canada;
authors.forename: Blair E
authors.initials: BE
authors.lastname: Warren
authors.forename: Phing-How
authors.initials: PH
authors.lastname: Lou
authors.forename: Eliana
authors.initials: E
authors.lastname: Lucchinetti
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhang
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Clanachan
authors.forename: Andreas
authors.initials: A
authors.lastname: Affolter
authors.forename: Martin
authors.initials: M
authors.lastname: Hersberger
authors.forename: Michael
authors.initials: M
authors.lastname: Zaugg
authors.forename: Hélène
authors.initials: H
authors.lastname: Lemieux
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D004040:Dietary Carbohydrates / Q000009:adverse effects; D018450:Disease Progression; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D005632:Fructose / Q000009:adverse effects; D018698:Glutamic Acid / Q000378:metabolism; D006019:Glycolysis; D007333:Insulin Resistance; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D011236:Prediabetic State / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004040:Dietary Carbohydrates; D005227:Fatty Acids; D011768:Pyruvate Dehydrogenase Complex; D017382:Reactive Oxygen Species; C116917:acylcarnitine; D005632:Fructose; D018698:Glutamic Acid; D019289:Pyruvic Acid; D000154:Aconitate Hydratase; D002331:Carnitine
keywords: aconitase; fatty acid oxidation; insulin resistance; mitochondrial dysfunction; sirtuin-3; skeletal muscle; type 2 diabetes