scholarly journals The role of protein-mediated transport in regulating mitochondrial long-chain fatty acid oxidation

2008 ◽  
Vol 33 (1) ◽  
pp. 141-142
Author(s):  
Graham Paul Holloway
Keyword(s):  
Skeletal Muscle ◽  
Plasma Membrane ◽  
Fatty Acid ◽  
Muscle Contraction ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Mitochondrial Content ◽  
Palmitate Oxidation ◽  
Long Chain

This thesis is an investigation of the role of fatty acid translocase (FAT/CD36), plasma membrane associated fatty acid binding protein (FABPpm), and carnitine palmitoyltransferase I (CPTI) in transporting long-chain fatty acids (LCFAs) across mitochondrial membranes. Maximal CPTI activity, as well as the sensitivity of CPTI for its substrate palmitoyl-CoA (P-CoA) and its inhibitor malonyl-CoA (M-CoA), were measured in mitochondria isolated from human vastus lateralis muscles at rest and following muscle contraction. Exercise did not alter maximal CPTI activity or the sensitivity of CPTI for P-CoA. In contrast, exercise progressively attenuated the ability of M-CoA to inhibit CPTI activity. Mitochondrial FAT/CD36 protein content was also measured at rest, during, and following 2 h of cycling at ~60% maximal oxygen uptake. Exercise progressively increased the content of mitochondrial FAT/CD36 (+59%), which was significantly (p < 0.05) correlated with palmitate oxidation during exercise (r = 0.52), while palmitate oxidation was inhibited ~80% by the administration of a specific FAT/CD36 inhibitor. These data suggest that alterations in CPTI M-CoA sensitivity and increases in mitochondrial FAT/CD36 coordinate exercise-induced increases in fatty acid oxidation. FABPpm, another plasma membrane transport protein, has identical amino acid sequence to mitochondrial aspartate aminotransferase (mAspAT). Since FABPpm contributes to plasma membrane fatty acid transport, the role of FABPpm with respect to mitochondrial LCFA transport was investigated. However, unlike FAT/CD36, muscle contraction did not induce an increase in mitochondrial FABPpm protein in rat or human skeletal muscle. In addition, electrotransfecting FABPpm cDNA into rat skeletal muscle upregulated this protein in mitochondria by 80% without altering mitochondrial palmitate oxidation. In contrast, electrotransfection increased mAspAT activity  by 90%, and this was correlated (r = 0.75; p < 0.01) with FABPpm protein. These data suggest that FABPpm does not contribute to the regulation of mitochondrial LCFA transport. Previously, it has been suggested that mitochondria from obese individuals contain an inherent dysfunction to oxidize LCFAs. In age-matched lean (BMI = 23.3 ± 0.7 kg·m–2) and obese (BMI = 37.6 ± 2.2 kg·m–2) individuals, isolated mitochondrial palmitate oxidation was not altered. In addition, mitochondrial FAT/CD36 content was not different in lean and obese individuals. In contrast, citrate synthase and β-hydroxyacyl-CoA dehydrogenase, common markers of total mitochondrial content, were decreased with obesity. Therefore, the decrease in mitochondrial content appeared to account for the observed reductions in whole-muscle LCFA oxidation.

FAT/CD36-null mice reveal that mitochondrial FAT/CD36 is required to upregulate mitochondrial fatty acid oxidation in contracting muscle

2009 ◽  
Vol 297 (4) ◽  
pp. R960-R967 ◽  
Author(s):  
Graham P. Holloway ◽  
Swati S. Jain ◽  
Veronic Bezaire ◽  
Xiao Xia Han ◽  
Jan F. C. Glatz ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Fatty Acid ◽  
Muscle Contraction ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Fatty Acid Transport ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Palmitate Oxidation ◽  
Oxidation Rates ◽  
Mitochondrial Fatty Acid

The plasma membrane fatty acid transport protein FAT/CD36 is also present at the mitochondria, where it may contribute to the regulation of fatty acid oxidation, although this has been challenged. Therefore, we have compared enzyme activities and rates of mitochondrial palmitate oxidation in muscles of wild-type (WT) and FAT/CD36 knockout (KO) mice, at rest and after muscle contraction. In WT and KO mice, carnitine palmitoyltransferase-I, citrate synthase, and β-hydroxyacyl-CoA dehydrogenase activities did not differ in subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria of WT and FAT/CD36 KO mice. Basal palmitate oxidation rates were lower ( P < 0.05) in KO mice (SS −18%; IMF −13%). Muscle contraction increased fatty acid oxidation (+18%) and mitochondrial FAT/CD36 protein (+16%) in WT IMF but not in WT SS, or in either mitochondrial subpopulation in KO mice. This revealed that the difference in IMF mitochondrial fatty acid oxidation between WT and KO mice can be increased ∼2.5-fold from 13% under basal conditions to 35% during muscle contraction. The FAT/CD36 inhibitor sulfo- N-succinimidyl oleate (SSO), inhibited palmitate transport across the plasma membrane in WT, but not in KO mice. In contrast, SSO bound to mitochondrial membranes and reduced palmitate oxidation rates to a similar extent in both WT and KO mitochondria (∼80%; P < 0.05). In addition, SSO reduced state III respiration with succinate as a substrate, without altering mitochondrial coupling (P/O ratios). Thus, while SSO inhibits FAT/CD36-mediated palmitate transport at the plasma membrane, SSO has undefined effects on mitochondria. Nevertheless, the KO animals reveal that FAT/CD36 contributes to the regulation of mitochondrial fatty acid oxidation, which is especially important for meeting the increased metabolic demands during muscle contraction.

Skeletal muscle lipid metabolism with obesity

2003 ◽  
Vol 284 (4) ◽  
pp. E741-E747 ◽  
Author(s):  
Matthew W. Hulver ◽  
Jason R. Berggren ◽  
Ronald N. Cortright ◽  
Ronald W. Dudek ◽  
R. Peter Thompson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Fatty Acyl ◽  
Normal Weight ◽  
Acid Oxidation ◽  
Palmitate Oxidation ◽  
Lower Fatty Acid ◽  
Skeletal Muscle Lipid ◽  
Long Chain

The objectives of this study were to 1) examine skeletal muscle fatty acid oxidation in individuals with varying degrees of adiposity and 2) determine the relationship between skeletal muscle fatty acid oxidation and the accumulation of long-chain fatty acyl-CoAs. Muscle was obtained from normal-weight [ n = 8; body mass index (BMI) 23.8 ± 0.58 kg/m2], overweight/obese ( n = 8; BMI 30.2 ± 0.81 kg/m2), and extremely obese ( n = 8; BMI 53.8 ± 3.5 kg/m2) females undergoing abdominal surgery. Skeletal muscle fatty acid oxidation was assessed in intact muscle strips. Long-chain fatty acyl-CoA concentrations were measured in a separate portion of the same muscle tissue in which fatty acid oxidation was determined. Palmitate oxidation was 58 and 83% lower in skeletal muscle from extremely obese (44.9 ± 5.2 nmol · g−1 · h−1) patients compared with normal-weight (71.0 ± 5.0 nmol · g−1 · h−1) and overweight/obese (82.2 ± 8.7 nmol · g−1 · h−1) patients, respectively. Palmitate oxidation was negatively ( R = −0.44, P = 0.003) associated with BMI. Long-chain fatty acyl-CoA content was higher in both the overweight/obese and extremely obese patients compared with normal-weight patients, despite significantly lower fatty acid oxidation only in the extremely obese. No associations were observed between long-chain fatty acyl-CoA content and palmitate oxidation. These data suggest that there is a defect in skeletal muscle fatty acid oxidation with extreme obesity but not overweight/obesity and that the accumulation of intramyocellular long-chain fatty acyl-CoAs is not solely a result of reduced fatty acid oxidation.

Mitochondrial function and dysfunction in exercise and insulin resistanceThis paper article is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 440-446 ◽  
Author(s):  
Graham P. Holloway
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Peer Review Process ◽  
Acid Oxidation ◽  
Fatty Acid Transport ◽  
Acid Transport ◽  
Mitochondrial Content ◽  
Mitochondrial Fatty Acid

Fatty acid translocase (FAT/CD36) represents a novel flexible regulatory system, influencing rates of mitochondrial fatty acid metabolism in both human and rodent skeletal muscle. During exercise, the subcellular redistribution of FAT/CD36 provides a mechanism to increase not only plasma membrane fatty acid transport, but also mitochondrial fatty acid oxidation. This FAT/CD36-mediated coordination of long chain fatty acid (LCFA) transport and oxidation is an intriguing model in the context of insulin resistance. It was believed for almost a decade that reductions in fatty acid oxidation increased intramuscular lipids, thereby contributing to insulin resistance. A reduction in mitochondrial content may reduce the capacity of skeletal muscle LCFA oxidation; however, work from my laboratory has shown that, in some insulin-resistant muscles, mitochondrial content and fatty acid oxidation are both increased, yet these muscles accumulate lipids because of a considerably greater increase in fatty acid transport. Therefore, an alternative model is being considered, in which the balance between LCFA uptake and oxidation is a determining factor in the development of insulin resistance. A permanent redistribution of the LCFA transport protein FAT/CD36 to the sarcolemmal has been consistently found, which results in an increased rate of LCFA transport. This work suggests that the accumulation of skeletal muscle lipids, regardless of changes in mitochondria, is attributable to an increased rate of LCFA transport that exceeds the capacity for oxidation.

scholarly journals The Role of Skeletal Muscle in The Pathogenesis of Altered Concentrations of Branched-Chain Amino Acids (Valine, Leucine, and Isoleucine) in Liver Cirrhosis, Diabetes, and Other Diseases

2021 ◽  
pp. 293-305
Author(s):  
M Holeček
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Liver Cirrhosis ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Branched Chain Amino Acids ◽  
Acid Oxidation ◽  
Amino Group ◽  
Branched Chain

The article shows that skeletal muscle plays a dominant role in the catabolism of branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) and the pathogenesis of their decreased concentrations in liver cirrhosis, increased concentrations in diabetes, and nonspecific alterations in disorders with signs of systemic inflammatory response syndrome (SIRS), such as burn injury and sepsis. The main role of skeletal muscle in BCAA catabolism is due to its mass and high activity of BCAA aminotransferase, which is absent in the liver. Decreased BCAA levels in liver cirrhosis are due to increased use of the BCAA as a donor of amino group to α-ketoglutarate for synthesis of glutamate, which in muscles acts as a substrate for ammonia detoxification to glutamine. Increased BCAA levels in diabetes are due to alterations in glycolysis, citric acid cycle, and fatty acid oxidation. Decreased glycolysis and citric cycle activity impair BCAA transamination to branched-chain keto acids (BCKAs) due to decreased supply of amino group acceptors (α-ketoglutarate, pyruvate, and oxaloacetate); increased fatty acid oxidation inhibits flux of BCKA through BCKA dehydrogenase due to increased supply of NADH and acyl-CoAs. Alterations in BCAA levels in disorders with SIRS are inconsistent due to contradictory effects of SIRS on muscles. Specifically, increased proteolysis and insulin resistance tend to increase BCAA levels, whereas activation of BCKA dehydrogenase and glutamine synthesis tend to decrease BCAA levels. The studies are needed to elucidate the role of alterations in BCAA metabolism and the effects of BCAA supplementation on the outcomes of specific diseases.

Transcriptional response of skeletal muscle to a low protein perinatal diet in rat offspring at different ages: The role of key enzymes of glucose-fatty acid oxidation

2017 ◽  
Vol 41 ◽  
pp. 117-123 ◽  
Author(s):  
José Luiz de Brito Alves ◽  
Ana Elisa Toscano ◽  
João Henrique da Costa-Silva ◽  
Hubert Vidal ◽  
Carol Góis Leandro ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Transcriptional Response ◽  
Acid Oxidation ◽  
Key Enzymes ◽  
Rat Offspring ◽  
Low Protein ◽  
Different Ages
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