Stephens FB, Constantin-Teodosiu D, Greenhaff PL.. New insights concerning the role of carnitine in the regulation of fuel metabolism in skeletal muscle. J Physiol 581: 431-444

Centre for Integrated Systems Biology and Medicine, School of Biomedical Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK.
The Journal of Physiology (Impact Factor: 5.04). 07/2007; 581(Pt 2):431-44. DOI: 10.1113/jphysiol.2006.125799
Source: PubMed


In skeletal muscle, carnitine plays an essential role in the translocation of long-chain fatty-acids into the mitochondrial matrix for subsequent beta-oxidation, and in the regulation of the mitochondrial acetyl-CoA/CoASH ratio. Interest in these vital metabolic roles of carnitine in skeletal muscle appears to have waned over the past 25 years. However, recent research has shed new light on the importance of carnitine as a regulator of muscle fuel selection. It has been established that muscle free carnitine availability may be limiting to fat oxidation during high intensity submaximal exercise. Furthermore, increasing muscle total carnitine content in resting healthy humans (via insulin-mediated stimulation of muscle carnitine transport) reduces muscle glycolysis, increases glycogen storage and is accompanied by an apparent increase in fat oxidation. By increasing muscle pyruvate dehydrogenase complex (PDC) activity and acetylcarnitine content at rest, it has also been established that PDC flux and acetyl group availability limits aerobic ATP re-synthesis at the onset of exercise (the acetyl group deficit). Thus, carnitine plays a vital role in the regulation of muscle fuel metabolism. The demonstration that its availability can be readily manipulated in humans, and impacts on physiological function, will result in renewed business and scientific interest in this compound.

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Available from: Tim Constantin, Oct 13, 2015
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    • "Inside the cell, fatty acids can be metabolized to lipid second messengers and b-oxidized in mitochondria. The mitochondrial transmembrane enzyme CPT1 is thought to be rate limiting for fatty acid entry into the mitochondria for b-oxidation [32] [33]. Therefore, we analyzed the mRNA expression level of FATP4 and CPT1 in the blastocysts. "
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    ABSTRACT: We have previously developed chemically defined media suitable for in vitro production (IVP) of porcine embryos and subsequently generated piglets by nonsurgical embryo transfer. In this study, to further improve the culture conditions for IVP of porcine embryos, we evaluated the effect of knockout serum replacement (KSR), a substitute for serum or albumin, on the viability and development of porcine blastocysts. The addition of 5% (v:v) KSR to porcine blastocyst medium (PBM) on Day 5 (Day 0 = IVF) significantly increased the survival and hatching rates of blastocysts and the total cell number of Day-7 blastocysts compared with those in cultures without KSR or addition of 10% fetal bovine serum. Furthermore, the number of cells in the trophectoderm of Day-6 blastocysts and the ATP content of Day-7 blastocysts cultured with 5% KSR were significantly higher than those of blastocysts cultured without KSR. The mRNA expression of a rate-limiting enzyme in β-oxidation, carnitine palmitoyltransferase 1, in Day-6 blastocysts, and a serine proteinase, urokinase-type plasminogen activator, in Day-7 blastocysts cultured in 5% KSR-PBM was significantly higher than that of blastocysts cultured in PBM alone. Four of eight recipients (50%), in which Day-5 blastocysts treated with 5% KSR were transferred nonsurgically, became pregnant. However, the efficiency of piglet production (percentage of piglets born based on the number of embryos transferred) was similar to recipients with transferred blastocysts treated without KSR. The present study demonstrated that the addition of KSR to PBM enhanced the in vitro viability of porcine blastocysts. In addition, our data suggest that KSR improved development to the hatching stage and blastocyst quality by increasing ATP content and hatching-related mRNA expression of blastocysts.
    Theriogenology 03/2015; 83(4):679-686. DOI:10.1016/j.theriogenology.2014.11.003 · 1.80 Impact Factor
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    • "Additionally, high-intensity exercise increases acetylcarnitine accumulation resulting from increased pyruvate dehydrogenase activity following enhanced glycolysis [9]. In these situations, total carnitine content (sum of free-, acetyl-, and acyl-carnitine) does not change [9], indicating that carnitine is converted to acetylcarnitine in muscle cells. Changes in carnitine and acetylcarnitine contents have been generally evaluated by enzymatic assay on the basis of the measurement of CrAT activity [10] [11]. "
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    ABSTRACT: Carnitine is well recognized as a key regulator of long-chain fatty acyl group translocation into the mitochondria. In addition, carnitine, as acetylcarnitine, acts as an acceptor of excess acetyl-CoA, a potent inhibitor of pyruvate dehydrogenase. Here, we provide a new methodology for accurate quantification of acetylcarnitine content and determination of its localization in skeletal muscles. We used matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) to visualize acetylcarnitine distribution in rat skeletal muscles. MALDI-IMS and immunohistochemistry of serial cross-sections showed that acetylcarnitine was enriched in the slow-type muscle fibers. The concentration of ATP was lower in muscle regions with abundant acetylcarnitine, suggesting a relationship between acetylcarnitine and metabolic activity. Using our novel method, we detected an increase in acetylcarnitine content after muscle contraction. Importantly, this increase was not detected using traditional biochemical assays of homogenized muscles. We also demonstrated that acetylation of carnitine during muscle contraction was concomitant with glycogen depletion. Our methodology would be useful for quantification of acetylcarnitine and its contraction-induced kinetics in skeletal muscles.
    Biochimica et Biophysica Acta (BBA) - Bioenergetics 05/2014; 1837(10). DOI:10.1016/j.bbabio.2014.05.356 · 5.35 Impact Factor
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    • "It has also been proposed that the level of free carnitine may regulate mitochondrial FFA uptake during heavy dynamic exercise as it is a substrate for the CPT I reaction [31, 58, 59]. The carnitine content decreases as a function of increasing dynamic exercise intensity and increased glycolytic flux [31, 33]. "
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    ABSTRACT: Fat and carbohydrate are important fuels for aerobic exercise and there can be reciprocal shifts in the proportions of carbohydrate and fat that are oxidized. The interaction between carbohydrate and fatty acid oxidation is dependent on the intracellular and extracellular metabolic environments. The availability of substrate, both from inside and outside of the muscle, and exercise intensity and duration will affect these environments. The ability of increasing fat provision to downregulate carbohydrate metabolism in the heart, diaphragm and peripheral skeletal muscle has been well studied. However, the regulation of fat metabolism in human skeletal muscle during exercise in the face of increasing carbohydrate availability and exercise intensity has not been well studied until recently. Research in the past 10 years has demonstrated that the regulation of fat metabolism is complex and involves many sites of control, including the transport of fat into the muscle cell, the binding and transport of fat in the cytoplasm, the regulation of intramuscular triacylglycerol synthesis and breakdown, and the transport of fat into the mitochondria. The discovery of proteins that assist in transporting fat across the plasma and mitochondrial membranes, the ability of these proteins to translocate to the membranes during exercise, and the new roles of adipose triglyceride lipase and hormone-sensitive lipase in regulating skeletal muscle lipolysis are examples of recent discoveries. This information has led to the proposal of mechanisms to explain the downregulation of fat metabolism that occurs in the face of increasing carbohydrate availability and when moving from moderate to intense aerobic exercise.
    05/2014; 44 Suppl 1(Suppl 1):87-96. DOI:10.1007/s40279-014-0154-1
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