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 ␤-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. insulin resistance; type 2 diabetes; mitochondrial dysfunction; skeletal muscle; fatty acid oxidation; aconitase; sirtuin-3 WORLDWIDE, THE PREVALENCE OF TYPE 2 DIABETES MELLITUS (T2DM) has reached epidemic proportions, which is due largely to increasing age and increasing incidence of obesity (21). Insulin resistance is a major characteristic of T2DM and refers to the inability of cells to respond adequately to insulin, which consequently leads to impaired glucose uptake, reduced glucose clearance, and hyperinsulinemia (15, 51). Because about 80% of glucose uptake in the postprandial state occurs in skeletal muscle, skeletal muscle is the largest "glucose sink" in the body, and therefore, it is considered a key player in the pathogenesis of insulin resistance. Although many studies demonstrate that mitochondrial dysfunction may accompany insulin resistance in skeletal muscle, the role of mitochondrial dysfunction in the pathogenesis of T2DM remains unclear. The difficulty lies in determining exactly which aspects of mitochondrial dysfunction are involved as well as the chronology of mitochondrial/cellular events that lead to T2DM (39, 44).The primary function of mitochondria is ATP production via oxidative phosphorylation (OXPHOS)...

CoA protects against the deleterious effects of caloric overload in Drosophila

“…Increased long-chain carnitine esters have been observed in the serum, liver, muscle, and urine of individuals with obesity and T2D (41)(42)(43)(44)(45)(46), although reduced levels of long-chain acyl-carnitines have also been associated with metabolic syndrome and T2D ( 47 ). Rodent models of obesity and T2D also accumulate acyl-carnitines (48)(49)(50). In Drosophila , acyl-carnitines decline with age, along with obesity ( 51,52 ).…”

Skeletal muscle insulin resistance: role of mitochondria and other ROS sources

“…The results obtained in these animal models are mostly in agreement with those obtained in human studies. The most used protocol to induce insulin resistance is overfeeding with high-fat/high-sugar diets in rats (Chanseaume et al 2006, Gomes et al 2012, Crescenzo et al 2013, Warren et al 2014 or 233:1 in mice (de Wilde et al 2008, Shelley et al 2009, Yuzefovych et al 2013, however, models of genetic obesity were also used (Holmström et al 2012). However, other observations report discrepant results, showing that high-fat feeding in rats was associated with no variation (Atgié et al 1993, De Feyter et al 2008a or even a higher mitochondrial capacity (Hancock et al 2008), and IR could be related to incomplete intramitochondrial β-oxidation (Koves et al 2008).…”

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

“…2014, 2015; Warren et al. 2014). Our experience with 6‐week fructose feeding in Sprague‐Dawley rats showed that insulin‐stimulated glucose uptake was decreased in the heart without overt signs of cardiac dysfunction (Lou et al.…”

“…On the other hand, the skeletal muscle revealed fiber‐specific (glycolytic extensor digitorum longus vs. oxidative soleus) differences in their respective onset of metabolic derangements and oxidative stress, despite an overall conserved mitochondrial function and capacity (Warren et al. 2014). In this study, we aimed to characterize and elucidate the metabolic (mal)adaptations as well as oxidative stress that occur in fructose‐induced type‐2 diabetic hearts at early stages of the disease.…”