The effect of a physiological increase in temperature on mitochondrial fatty acid oxidation in rat myofibers

We investigated the effect of temperature increase on mitochondrial fatty acid (FA) and carbohydrate oxidation in the slow-oxidative skeletal muscles (soleus) of rats. We measured mitochondrial respiration at 35°C and 40°C with the physiological substrates pyruvate + 4 mM malate (Pyr) and palmitoyl-CoA (PCoA) + 0.5 mM malate + 2 mM carnitine in permeabilized myofibers under nonphosphorylating ([Formula: see text]) or phosphorylating ([Formula: see text]) conditions. Mitochondrial efficiency was calculated by the respiratory control ratio (RCR = [Formula: see text]/[Formula: see text]). We used guanosine triphosphate (GTP), an inhibitor of uncoupling protein (UCP), to study the mechanisms responsible for alterations of mitochondrial efficiency. We measured hydrogen peroxide (H2O2) production under nonphosphorylating and phosphorylating conditions at both temperatures and substrates. We studied citrate synthase (CS) and 3-hydroxyl acyl coenzyme A dehydrogenase (3-HAD) activities at both temperatures. Elevating the temperature from 35°C to 40°C increased PCoA-[Formula: see text] and decreased PCoA-RCR, corresponding to the uncoupling of oxidative phosphorylation (OXPHOS). GTP blocked the heat-induced increase of PCoA-[Formula: see text]. Rising temperature moved toward a Pyr-[Formula: see text] increase, without significance. Heat did not alter H2O2 production, resulting from either PCoA or Pyr oxidation. Heat induced an increase in 3-HAD but not in CS activities. In conclusion, heat induced OXPHOS uncoupling for PCoA oxidation, which was at least partially mediated by UCP and independent of oxidative stress. The classically described heat-induced glucose shift may actually be mostly due to a less efficient FA oxidation. These findings raise questions concerning the consequences of heat-induced alterations in mitochondrial efficiency of FA metabolism on thermoregulation. NEW & NOTEWORTHY Ex vivo exposure of skeletal myofibers to heat uncouples substrate oxidation from ADP phosphorylation, decreasing the efficiency of mitochondria to produce ATP. This heat effect alters fatty acids (FAs) more than carbohydrate oxidation. Alteration of FA oxidation involves uncoupling proteins without inducing oxidative stress. This alteration in lipid metabolism may underlie the preferential use of carbohydrates in the heat and could decrease aerobic endurance.

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Cardioprotective Effects of PPARβ/δ Activation against Ischemia/Reperfusion Injury in Rat Heart Are Associated with ALDH2 Upregulation, Amelioration of Oxidative Stress and Preservation of Mitochondrial Energy Production

International Journal of Molecular Sciences ◽

10.3390/ijms22126399 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6399

Author(s):

Ioanna Papatheodorou ◽

Eleftheria Galatou ◽

Georgios-Dimitrios Panagiotidis ◽

Táňa Ravingerová ◽

Antigone Lazou

Keyword(s):

Oxidative Stress ◽

Mrna Expression ◽

Energy Production ◽

Citrate Synthase ◽

Ischemia Reperfusion Injury ◽

Ex Vivo ◽

Uncoupling Protein ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Isocitrate Dehydrogenase 2

Accumulating evidence support the cardioprotective properties of the nuclear receptor peroxisome proliferator activated receptor β/δ (PPARβ/δ); however, the underlying mechanisms are not yet fully elucidated. The aim of the study was to further investigate the mechanisms underlying PPARβ/δ-mediated cardioprotection in the setting of myocardial ischemia/reperfusion (I/R). For this purpose, rats were treated with PPARβ/δ agonist GW0742 and/or antagonist GSK0660 in vivo and hearts were subjected to ex vivo global ischemia followed by reperfusion. PPARβ/δ activation improved left ventricular developed pressure recovery, reduced infarct size (IS) and incidence of reperfusion-induced ventricular arrhythmias while it also up-regulated superoxide dismutase 2, catalase and uncoupling protein 3 resulting in attenuation of oxidative stress as evidenced by the reduction in 4-hydroxy-2-nonenal protein adducts and protein carbonyl formation. PPARβ/δ activation also increased both mRNA expression and enzymatic activity of aldehyde dehydrogenase 2 (ALDH2); inhibition of ALDH2 abrogated the IS limiting effect of PPARβ/δ activation. Furthermore, upregulation of PGC-1α and isocitrate dehydrogenase 2 mRNA expression, increased citrate synthase activity as well as mitochondrial ATP content indicated improvement in mitochondrial content and energy production. These data provide new mechanistic insight into the cardioprotective properties of PPARβ/δ in I/R pointing to ALDH2 as a direct downstream target and suggesting that PPARβ/δ activation alleviates myocardial I/R injury through coordinated stimulation of the antioxidant defense of the heart and preservation of mitochondrial function.

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Fatty acid oxidation and triacylglycerol hydrolysis are enhanced after chronic leptin treatment in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00303.2001 ◽

2002 ◽

Vol 282 (3) ◽

pp. E593-E600 ◽

Cited By ~ 65

Author(s):

Gregory R. Steinberg ◽

Arend Bonen ◽

David J. Dyck

Keyword(s):

Fatty Acid ◽

Citrate Synthase ◽

Uncoupling Protein ◽

Oxidative Capacity ◽

Hormone Sensitive Lipase ◽

Acid Oxidation ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Triacylglycerol Hydrolysis ◽

Hormone Sensitive

Leptin acutely increases fatty acid (FA) oxidation and triacylglycerol (TG) hydrolysis and decreases TG esterification in oxidative rodent muscle. However, the effects of chronic leptin administration on FA metabolism in skeletal muscle have not been examined. We hypothesized that chronic leptin treatment would enhance TG hydrolysis as well as the capacity to oxidize FA in soleus (SOL) muscle. Female Sprague-Dawley rats were infused for 2 wk with leptin (LEPT; 0.5 mg · kg−1 · day−1) by use of subcutaneously implanted miniosmotic pumps. Control (AD-S) and pair-fed (PF-S) animals received saline-filled implants. Subsequently, FA metabolism was monitored for 45 min in isolated, resting, and contracting (20 tetani/min) SOL muscles by means of pulse-chase procedures. Food intake (−33 ± 2%, P < 0.01) and body mass (−12.5 ± 4%, P = 0.01) were reduced in both LEPT and PF-S animals. Leptin levels were elevated (+418 ± 7%, P < 0.001) in treated animals but reduced in PF-S animals (−73 ± 8%, P< 0.05) relative to controls. At rest, TG hydrolysis was increased in leptin-treated rats (1.8 ± 2.2, AD-S vs. 23.5 ± 8.1 nmol/g wet wt, LEPT; P < 0.001). In contracting SOL muscles, TG hydrolysis (1.5 ± 0.6, AD-S vs. 3.6 ± 1.0 μmol/g wet wt, LEPT; P = 0.02) and palmitate oxidation (18.3 ± 6.7, AD-S vs. 45.7 ± 9.9 nmol/g wet wt, LEPT; P < 0.05) were both significantly increased by leptin treatment. Chronic leptin treatment had no effect on TG esterification either at rest or during contraction. Markers of overall (citrate synthase) and FA (hydroxyacyl-CoA dehydrogenase) oxidative capacity were unchanged with leptin treatment. Protein expression of hormone-sensitive lipase (HSL) was also unaltered following leptin treatment. Thus leptin-induced increases in lipolysis are likely due to HSL activation (i.e., phosphorylation). Increased FA oxidation secondary to chronic leptin treatment is not due to an enhanced oxidative capacity and may be a result of enhanced flux into the mitochondrion (i.e., carnitine palmitoyltransferase I regulation) or electron transport uncoupling (i.e., uncoupling protein-3 expression).

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Skeletal muscle mitochondrial FAT/CD36 content and palmitate oxidation are not decreased in obese women

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00639.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. E1782-E1789 ◽

Cited By ~ 98

Author(s):

Graham P. Holloway ◽

A. Brianne Thrush ◽

George J. F. Heigenhauser ◽

Narendra N. Tandon ◽

David J. Dyck ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Citrate Synthase ◽

Intrinsic Defect ◽

Acid Oxidation ◽

Obese Women ◽

Mitochondrial Content ◽

Mitochondrial Fatty Acid Oxidation ◽

Mitochondrial Fatty Acid

A reduction in fatty acid oxidation has been associated with lipid accumulation and insulin resistance in the skeletal muscle of obese individuals. We examined whether this decrease in fatty acid oxidation was attributable to a reduction in muscle mitochondrial content and/or a dysfunction in fatty acid oxidation within mitochondria obtained from skeletal muscle of age-matched, lean [body mass index (BMI) = 23.3 ± 0.7 kg/m2] and obese women (BMI = 37.6 ± 2.2 kg/m2). The mitochondrial marker enzymes citrate synthase (−34%), β-hydroxyacyl-CoA dehydrogenase (−17%), and cytochrome c oxidase (−32%) were reduced ( P < 0.05) in obese participants, indicating that mitochondrial content was diminished. Obesity did not alter the ability of isolated mitochondria to oxidize palmitate; however, fatty acid oxidation was reduced at the whole muscle level by 28% ( P < 0.05) in the obese. Mitochondrial fatty acid translocase (FAT/CD36) did not differ in lean and obese individuals, but mitochondrial FAT/CD36 was correlated with mitochondrial fatty acid oxidation ( r = 0.67, P < 0.05). We conclude that the reduction in fatty acid oxidation in obese individuals is attributable to a decrease in mitochondrial content, not to an intrinsic defect in the mitochondria obtained from skeletal muscle of obese individuals. In addition, it appears that mitochondrial FAT/CD36 may be involved in regulating fatty acid oxidation in human skeletal muscle.

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Maternal Fat-1 Transgene Protects Offspring from Excess Weight Gain, Oxidative Stress, and Reduced Fatty Acid Oxidation in Response to High-Fat Diet

Nutrients ◽

10.3390/nu12030767 ◽

2020 ◽

Vol 12 (3) ◽

pp. 767 ◽

Cited By ~ 1

Author(s):

Kristen E. Boyle ◽

Margaret J. Magill-Collins ◽

Sean A. Newsom ◽

Rachel C. Janssen ◽

Jacob E. Friedman

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Fatty Acid ◽

Weight Gain ◽

Fatty Acid Oxidation ◽

High Fat Diet ◽

Overweight And Obesity ◽

Acid Oxidation ◽

High Fat ◽

Mitochondrial Fatty Acid

Overweight and obesity accompanies up to 70% of pregnancies and is a strong risk factor for offspring metabolic disease. Maternal obesity-associated inflammation and lipid profile are hypothesized as important contributors to excess offspring liver and skeletal muscle lipid deposition and oxidative stress. Here, we tested whether dams expressing the fat-1 transgene, which endogenously converts omega-6 (n-6) to omega-3 (n-3) polyunsaturated fatty acid, could protect wild-type (WT) offspring against high-fat diet induced weight gain, oxidative stress, and disrupted mitochondrial fatty acid oxidation. Despite similar body mass at weaning, offspring from fat-1 high-fat-fed dams gained less weight compared with offspring from WT high-fat-fed dams. In particular, WT males from fat-1 high-fat-fed dams were protected from post-weaning high-fat diet induced weight gain, reduced fatty acid oxidation, or excess oxidative stress compared with offspring of WT high-fat-fed dams. Adult offspring of WT high-fat-fed dams exhibited greater skeletal muscle triglycerides and reduced skeletal muscle antioxidant defense and redox balance compared with offspring of WT dams on control diet. Fat-1 offspring were protected from the reduced fatty acid oxidation and excess oxidative stress observed in offspring of WT high-fat-fed dams. These results indicate that a maternal fat-1 transgene has protective effects against offspring liver and skeletal muscle lipotoxicity resulting from a maternal high-fat diet, particularly in males. Altering maternal fatty acid composition, without changing maternal dietary composition or weight gain with high-fat feeding, may highlight important strategies for n-3-based prevention of developmental programming of obesity and its complications.

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