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.

In obese rat muscle transport of palmitate is increased and is channeled to triacylglycerol storage despite an increase in mitochondrial palmitate oxidation

2009 ◽  
Vol 296 (4) ◽  
pp. E738-E747 ◽  
Author(s):  
Graham P. Holloway ◽  
Carley R. Benton ◽  
Kerry L. Mullen ◽  
Yuko Yoshida ◽  
Laelie A. Snook ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Zucker Rats ◽  
Acid Oxidation ◽  
Fatty Acid Transport ◽  
Acid Transport ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Palmitate Oxidation ◽  
Mitochondrial Fatty Acid ◽  
Obese Zucker Rats

Intramuscular triacylglycerol (IMTG) accumulation in obesity has been attributed to increased fatty acid transport and/or to alterations in mitochondrial fatty acid oxidation. Alternatively, an imbalance in these two processes may channel fatty acids into storage. Therefore, in red and white muscles of lean and obese Zucker rats, we examined whether the increase in IMTG accumulation was attributable to an increased rate of fatty acid transport rather than alterations in subsarcolemmal (SS) or intermyofibrillar (IMF) mitochondrial fatty acid oxidation. In obese animals selected parameters were upregulated, including palmitate transport (red: +100%; white: +51%), plasmalemmal FAT/CD36 (red: +116%; white: +115%; not plasmalemmal FABPpm, FATP1, or FATP4), IMTG concentrations (red: ∼2-fold; white: ∼4-fold), and mitochondrial content (red +30%). Selected mitochondrial parameters were also greater in obese animals, namely, palmitate oxidation (SS red: +91%; SS white: +26%; not IMF mitochondria), FAT/CD36 (SS: +65%; IMF: +65%), citrate synthase (SS: +19%), and β-hydroxyacyl-CoA dehydrogenase activities (SS: +20%); carnitine palmitoyltransferase-I activity did not differ. A comparison of lean and obese rat muscles revealed that the rate of change in IMTG concentration was eightfold greater than that of fatty acid oxidation (SS mitochondria), when both parameters were expressed relative to fatty transport. Thus fatty acid transport, esterification, and oxidation (SS mitochondria) are upregulated in muscles of obese Zucker rats, with these effects being most pronounced in red muscle. The additional fatty acid taken up is channeled primarily to esterification, suggesting that upregulation in fatty acid transport as opposed to altered fatty acid oxidation is the major determinant of intramuscular lipid accumulation.

Lipid metabolism, exercise and insulin action

2006 ◽  
Vol 42 ◽  
pp. 47-59 ◽  
Author(s):  
Arend Bonen ◽  
G. Lynis Dohm ◽  
Luc J.C. van Loon
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Insulin Signalling ◽  
Acid Oxidation ◽  
Fatty Acid Transport ◽  
Acid Transport ◽  
Severely Obese

Skeletal muscle constitutes 40% of body mass and takes up 80% of a glucose load. Therefore, impaired glucose removal from the circulation, such as that which occurs in obesity and type 2 diabetes, is attributable in large part to the insulin resistance in muscle. Recent research has shown that fatty acids, derived from adipose tissue, can interfere with insulin signalling in muscle. Hence, insulin-stimulated GLUT4 translocation to the cell surface is impaired, and therefore, the rate of glucose removal from the circulation into muscle is delayed. The mechanisms provoking lipid-mediated insulin resistance are not completely understood. In sedentary individuals, excess intramyocellular accumulation of triacylglycerols is only modestly associated with insulin resistance. In contrast, endurance athletes, despite accumulating large amounts of intramyocellular triacylglycerols, are highly insulin sensitive. Thus it appears that lipid metabolites, other than triacylglycerols, interfere with insulin signalling. These metabolites, however, are not expected to accumulate in athletic muscles, as endurance training increases the capacity for fatty acid oxidation by muscle. These observations, and others in severely obese individuals and type 2 diabetes patients, suggest that impaired rates of fatty acid oxidation are associated with insulin resistance. In addition, in obesity and type 2 diabetes, the rates of fatty acid transport into muscle are also increased. Thus, excess intracellular lipid metabolite accumulation, which interferes with insulin signalling, can occur as a result of impaired rates of fatty acid oxidation and/or increased rates of fatty acid transport into muscle. Accumulation of excess intramyocellular lipid can be avoided by exercise, which improves the capacity for fatty acid oxidation.

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

2007 ◽  
Vol 292 (6) ◽  
pp. E1782-E1789 ◽  
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.

scholarly journals Acute insulin deprivation results in altered mitochondrial substrate sensitivity conducive to greater fatty acid transport

2020 ◽  
Vol 319 (2) ◽  
pp. E345-E353
Author(s):  
Paula M. Miotto ◽  
Heather L. Petrick ◽  
Graham P. Holloway
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Insulin Action ◽  
Oxidative Capacity ◽  
Acid Oxidation ◽  
Fatty Acid Transport ◽  
Acid Transport ◽  
Mitochondrial Fatty Acid ◽  
Metabolic Inflexibility ◽  
Cpt I

Type 1 and type 2 diabetes are both tightly associated with impaired glucose control. Although both pathologies stem from different mechanisms, a reduction in insulin action coincides with drastic metabolic dysfunction in skeletal muscle and metabolic inflexibility. However, the underlying explanation for this response remains poorly understood, particularly since it is difficult to distinguish the role of attenuated insulin action from the detrimental effects of reactive lipid accumulation, which impairs mitochondrial function and promotes reactive oxygen species (ROS) emission. We therefore utilized streptozotocin to examine the effects of acute insulin deprivation, in the absence of a high-lipid/nutrient excess environment, on the regulation of mitochondrial substrate sensitivity and ROS emission. The ablation of insulin resulted in reductions in absolute mitochondrial oxidative capacity and ADP-supported respiration and reduced the ability for malonyl-CoA to inhibit carnitine palmitoyltransferase I (CPT-I) and suppress fatty acid-supported respiration. These bioenergetic responses coincided with increased mitochondrial-derived H2O2 emission and lipid transporter content, independent of major mitochondrial substrate transporter proteins and enzymes involved in fatty acid oxidation. Together, these data suggest that attenuated/ablated insulin signaling does not affect mitochondrial ADP sensitivity, whereas the increased reliance on fatty acid oxidation in situations where insulin action is reduced may occur as a result of altered regulation of mitochondrial fatty acid transport through CPT-I.

TBC1D1 reduces palmitate oxidation by inhibiting β-HAD activity in skeletal muscle

2014 ◽  
Vol 307 (9) ◽  
pp. R1115-R1123 ◽  
Author(s):  
A. C. Maher ◽  
J. McFarlan ◽  
J. Lally ◽  
L. A. Snook ◽  
A. Bonen
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Transport ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Rab Gtpase ◽  
Fatty Acid Transport ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Palmitate Oxidation ◽  
Mitochondrial Fatty Acid

In skeletal muscle the Rab-GTPase-activating protein TBC1D1 has been implicated in the regulation of fatty acid oxidation by an unknown mechanism. We determined whether TBC1D1 altered fatty acid utilization via changes in protein-mediated fatty acid transport and/or selected enzymes regulating mitochondrial fatty acid oxidation. We also determined the effects of TBC1D1 on glucose transport and oxidation. Electrotransfection of mouse soleus muscles with TBC1D1 cDNA increased TBC1D1 protein after 2 wk ( P < 0.05), without altering its paralog AS160. TBC1D1 overexpression decreased basal palmitate oxidation (−22%) while blunting 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)-stimulated palmitate oxidation (−18%). There was a tendency to increase fatty acid esterification (+10 nmol·g−1·60 min−1, P = 0.07), which reflected the reduction in fatty acid oxidation (−12 nmol·g−1·60 min−1). Concomitantly, basal (+21%) and AICAR-stimulated glucose oxidation (+8%) were increased in TBC1D1-transfected muscles relative to their respective controls ( P < 0.05), independent of changes in GLUT4 and glucose transport. The reductions in TBC1D1-mediated fatty acid oxidation could not be attributed to changes in the transporter FAT/CD36, muscle mitochondrial content, CPT1 expression or the expression and phosphorylation of AS160, acetyl-CoA carboxylase, or AMPK. However, TBC1D1 overexpression reduced β-HAD enzyme activity (−18%, P < 0.05). In conclusion, TBC1D1-mediated reduction of muscle fatty acid oxidation appears to occur via inhibition of β-HAD activity.

scholarly journals Overexpression of Long-Chain Acyl-CoA Synthetase 5 Increases Fatty Acid Oxidation and Free Radical Formation While Attenuating Insulin Signaling in Primary Human Skeletal Myotubes

2019 ◽  
Vol 16 (7) ◽  
pp. 1157 ◽  
Author(s):  
Hyo-Bum Kwak ◽  
Tracey Woodlief ◽  
Thomas Green ◽  
Julie Cox ◽  
Robert Hickner ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Free Radical ◽  
Fatty Acid Oxidation ◽  
Insulin Signaling ◽  
Human Skeletal Muscle ◽  
Acid Oxidation ◽  
Protein Levels ◽  
Human Skeletal Muscle Cells ◽  
Mitochondrial Fatty Acid

In rodent skeletal muscle, acyl-coenzyme A (CoA) synthetase 5 (ACSL-5) is suggested to localize to the mitochondria but its precise function in human skeletal muscle is unknown. The purpose of these studies was to define the role of ACSL-5 in mitochondrial fatty acid metabolism and the potential effects on insulin action in human skeletal muscle cells (HSKMC). Primary myoblasts isolated from vastus lateralis (obese women (body mass index (BMI) = 34.7 ± 3.1 kg/m2)) were transfected with ACSL-5 plasmid DNA or green fluorescent protein (GFP) vector (control), differentiated into myotubes, and harvested (7 days). HSKMC were assayed for complete and incomplete fatty acid oxidation ([1-14C] palmitate) or permeabilized to determine mitochondrial respiratory capacity (basal (non-ADP stimulated state 4), maximal uncoupled (carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP)-linked) respiration, and free radical (superoxide) emitting potential). Protein levels of ACSL-5 were 2-fold higher in ACSL-5 overexpressed HSKMC. Both complete and incomplete fatty acid oxidation increased by 2-fold (p < 0.05). In permeabilized HSKMC, ACSL-5 overexpression significantly increased basal and maximal uncoupled respiration (p < 0.05). Unexpectedly, however, elevated ACSL-5 expression increased mitochondrial superoxide production (+30%), which was associated with a significant reduction (p < 0.05) in insulin-stimulated p-Akt and p-AS160 protein levels. We concluded that ACSL-5 in human skeletal muscle functions to increase mitochondrial fatty acid oxidation, but contrary to conventional wisdom, is associated with increased free radical production and reduced insulin signaling.

Investigating fatty acid transport and β- fatty acid oxidation (FAO) in placentas exposed to hyperglycemia

Placenta ◽  
2014 ◽  
Vol 35 (9) ◽  
pp. A29
Author(s):  
Charlotte Hulme ◽  
Melissa Westwood ◽  
Alexander E.P. Heazell ◽  
Jenny Myers
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Fatty Acid Transport ◽  
Acid Transport

scholarly journals ADCK2 Haploinsufficiency Reduces Mitochondrial Lipid Oxidation and Causes Myopathy Associated with CoQ Deficiency

2019 ◽  
Vol 8 (9) ◽  
pp. 1374 ◽  
Author(s):  
Vázquez-Fonseca ◽  
Schaefer ◽  
Navas-Enamorado ◽  
Santos-Ocaña ◽  
Hernández-Camacho ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Mouse Model ◽  
Fatty Acid Oxidation ◽  
Physical Performance ◽  
Liver Dysfunction ◽  
Mitochondrial Myopathy ◽  
Integrated Analysis ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid

Fatty acids and glucose are the main bioenergetic substrates in mammals. Impairment of mitochondrial fatty acid oxidation causes mitochondrial myopathy leading to decreased physical performance. Here, we report that haploinsufficiency of ADCK2, a member of the aarF domain-containing mitochondrial protein kinase family, in human is associated with liver dysfunction and severe mitochondrial myopathy with lipid droplets in skeletal muscle. In order to better understand the etiology of this rare disorder, we generated a heterozygous Adck2 knockout mouse model to perform in vivo and cellular studies using integrated analysis of physiological and omics data (transcriptomics–metabolomics). The data showed that Adck2+/− mice exhibited impaired fatty acid oxidation, liver dysfunction, and mitochondrial myopathy in skeletal muscle resulting in lower physical performance. Significant decrease in Coenzyme Q (CoQ) biosynthesis was observed and supplementation with CoQ partially rescued the phenotype both in the human subject and mouse model. These results indicate that ADCK2 is involved in organismal fatty acid metabolism and in CoQ biosynthesis in skeletal muscle. We propose that patients with isolated myopathies and myopathies involving lipid accumulation be tested for possible ADCK2 defect as they are likely to be responsive to CoQ supplementation.

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