Early mitochondrial dysfunction in glycolytic muscle, but not oxidative muscle, of the fructose-fed insulin-resistant rat.
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.
['Warren|Blair E|BE|', 'Lou|Phing-How|PH|', 'Lucchinetti|Eliana|E|', 'Zhang|Liyan|L|', 'Clanachan|Alexander S|AS|', 'Affolter|Andreas|A|', 'Hersberger|Martin|M|', 'Zaugg|Michael|M|', 'Lemieux|Hélène|H|']
D000154:Aconitate Hydratase D000818:Animals D002331:Carnitine D003924:Diabetes Mellitus, Type 2 D004040:Dietary Carbohydrates D018450:Disease Progression D004734:Energy Metabolism D005227:Fatty Acids D005632:Fructose D018698:Glutamic Acid D006019:Glycolysis D007333:Insulin Resistance D008297:Male D008931:Mitochondria, Muscle D018482:Muscle, Skeletal D010085:Oxidative Phosphorylation D011236:Prediabetic State D011768:Pyruvate Dehydrogenase Complex D019289:Pyruvic Acid D051381:Rats D017207:Rats, Sprague-Dawley D017382:Reactive Oxygen Species
mitochondrial dysfunction type 2 diabetes skeletal muscle fatty acid oxidation aconitase insulin resistance sirtuin-3