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Ascorbic Acid, Carnitine and Fatigue R

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Ascorbic Acid, Carnitine and Fatigue R Med. Sci..Res., 1988; 15,'12l-,723 FOfUm 72r Ascorbic acid, carnitine and fatigue R. Elwyn Hughes Department of Applied Biologt, University of l4lales Institute of Science and TÞchnologt, CardifÍ, Wales This paper reviews the evidence that ascorbic acid (vitamin and the fatty acyl-carnitine esters are transported across the C) may have a contributory role in the prevention of fatigue inner mitochondrial membrane by a carnitine-acyl in humàns. translocase. Fatty acid-CoA esters are released by a carnitine The biochemical history of carnitine (B-hydroxy-7-N- acyl (palmitoyl)transferase II on the inner membrane and trimethylammonium butyrate) is characterised by alter- the cycle is repeated [3, 15]. A lack of carnitine, or a nating periods of activity and dormancy. The re-emergence diminished or defective activity of one or more of the ofinterest during the past 15 years has been characterised by transport system enzymes, will reduce the availability of fatty a source energy. This, apart from producing a three main areas of emphasis - the endogenous biosynthe- acids as of sis of carnitine from lysine, the involvement of carnitine as a generally reduced 'energy status', could be of critical co-factor in the metabolism of long-chain fatty acids, and the significance in situations where the bulk of the energy identifrcation of the comparatively rare, but metabolically metabolism is believed to be derived from fatty acid metabolism such as in the newly-born infant or in the interesting, camitine deficiency diseases [1 - 4]. - [16] metabolism of normal cardiac muscle U7l. It has been Biosynthesis of c¡rnitine suggested that endogenous production of carnitine is impaired in the newly-born infant and that consequently Two essential amino acids - methionine and lysine - are involved in the biosynthesis of carnitine. Lysine is there is a requirement for a supply of dietary carnif.ine to methylated to produce the protein-bound trimethyl-lysine maintain the necessary tissue concentrations. The rate- which is then hydroxylated to form trimethylaminobutyrate limiting factor in carnitine production is the ascorbic acid- (3=hydroxyltrimethylJysine) ; in a second hydroxylation step dependent 7-butyrobetaine hydroxylase [18] and the ascor- trimethylaminobutyrate (7-butyrobetaine) is converted into bic acid intake of a newly-born child would, of course, be low carnitine [3]. These two hydroxylations are catalysed by compared with that of a developing child on a mixed diet, as separate ferrous-requiring oxygenases and both are human milk contains only 3 mg ascorbic acid per 100 ml. stimulated in vitroby the addition of ascorbic acid; in the case However, in a recent publication, Olson and Rebouche [19] of the trimethyl-lysine hydroxylase the ascorbic acid is have indicated that 7-butyrobetaine hydroxylase is not partially replaceable by other reductants but the requirement rate-limiting for carnitine formation in the human infant. hydroxylase for ascorbic acid would of the 7-butyrobetaine Carnitine dise¡ses appear to be specihc [5, 61. The identification and characterisation of the various carnitine More recently, the earlier in vitro work has been extended produced the to whole animal studies. A number of reports have indicated discases have useful information about that the formation of carnitine is impaired in guinea-pigs carnitine- energy relationship. Two types of primary carnitine deprived of dietary ascorbic acid [7-10]. In perfusion deficiency have been recognised - the muscle or myopathic which is largely confined to the skeletal muscle system, studies it was shownrthat 'scorbutic' guinea-pig livers had a form and a systemic form rqhich is a more generalised disease [151. significantly reduced capacity for converting 7-butyrobetaine in man are, theoretically, to carnitine and that this defect could be corrected by prior The causes of carnitine deficiency lesion has been defltned. A perfusion with ascorbic acid [l l]. These and other aspects of multiple and no sinþ,le biochemical deficiencies the the relationship between ascorbic acid and carnitine common feature of the carnitine is progressively increasing muscle weakness and fatigue a biosynthesis have been recently reviewed t12, l3]; England - point to the main thesis of this review and Seifter [l3J in their survey of the fìeld concluded that of central importance The clinical notes for the ltrst reported case of systemic there is in vitro stimulation of both hydroxylases by ascorbic [20]. observation a gradual acid, that there are variable decreases in tissue carnitine carnitine deltciency carry the "... weakness ... he could no longer run .'. concentrations when guinea-pigs are deprived of ascorbic development of muscle of breath after walking half a block .'. he was acid, and that the evidence, on balance, suggests that there is he became short Similarly, a 2O yeat-old male who a reduced activity of liver hydroxylase in always fatigued" [21]. 7-butyrobetaine deficiency was "... able to avitaminotic C guinea-pigs. It is diffìcult to quantify the presented with myopathic carnitine yards ground and had great difficulty in amount (or proportion) of ascoibic acid required for the walk only 100 on level generalised weakness..." carnitine biosynthetic pathway. Dietary carnitine signif- climbing stairs ... there was muscular bear similarity to the clinical icantly prolonged the life span of scorbutic guinea-pigs, but [221. These descriptions a (avitaminosis C) in only by some l0%, which would suggest that the require- descriptions of the earli'features of scurvy man. ment for ascorbic' acid för carnitine biosynthesis is small when compared with its main metabolic iole in the Fetiguein human scurvy formation of collagen [14]. References to the early emergence in scurvy of fatigue and Metabolic role of carnitinè lassitude were ìnvariable features of the earliest clinical The essential role of carnitine in both man and animals is descriptions of the disease [23]. Eugalenus in 1658 spoke of that it is required for the'transport of long-chain fatty acids "spontaneous debility" [24], Lister, in 1696, wrote of into the mitochondrial matrix where, by B-oxidation, they "weakness of limbs and considerable fatigue" [25] and may be used as a source of energy [31. Fatty acid:CoA esters Sydenham in 1742 of "spontaneous lassitude and difficulty of are transesterifîed by carnitine acyl (palmitoyl)transferase I breathing after exercise" [261. Naval surgeons with first hand 722 Forum R. Elwyn Hughes experience ofscurvy were equally clear in.their descriptions: the total calories, excreted two and a half times as much free "The signes of the Scurvie are many, namely a general urinary carnitine as a corresponding group where the protein lazinesse ... shortnesse and difficultie ofbreathing, especially accounted for only 8.50/o of the calories [41]. when they moove themsçlves" commented Woodall in 1639 Ascorbic acidr carnitine and fatigue I27l and Lind, over a century later, wrote: 'i... this lassitude, with a breathlessness upon motion, are observed to be among In contrast to the influence of dietary protein on urinary the most common concomitants of the distemper" [28]. carnitine in rats, changing the ascorbic acid status of guinea- Practising 'land physicians' in the last century made similar pigs from hypovitaminosis C (produced by giving 0.2 mg observations. Shapter, a careful clinical observer, describing ascorbic acid per 100 g body weight daily) to tissue saturation an outbreak ofscurvy in Exeter in I 847. perhaps put the matter did not produce any resultant change in the excretion of most clearly: "... the spongy and swollen gum appears to me to carnitine [,11] and in young and elderly women no relationship have been erroneously estimated as amongst the primary and was found between plasma carnitine and leucocyte ascorbic most obvious manifestations of the scurvy ... I am inclined to acid although thirteen of the elderly women included in the say there is a class of well-marked symptoms preceding this... study had a leucocyte ascorbic acid concentration below l5 The first or initiatory stage ... has appeared to me to be ¡r,g/10 cells, customarily regarded as the 'scurvy risk' cut off characterised by ... debility ... weakness, listlessness and a point [421. This would appear to suggest that protein is a more disinclination to exercise" [291. powerful determinant of carnitine biosynthesis than ascorbic More recent cases of scurvy have also underlined the early acid. Nevertheless, there is some evidence that in man a emergence of fatigue. In 1952 it was noted in a çase history that relationship exists between ascorbic acid status and carnitine the patient had, during the year before admission, ',become formation; in elderly men and women a highly significant increasingly weak and easily fatigued" [30] and reports of positive correlation was found between urinary free carnitine experimentally induced sçurvy in human volunteers similarly and leucocyte ascorbic acid [42]. These are findings difficult to drew attention to the early emergence of fatigue [3]-33]. reconcile but there are indications both from accounts of Crandon, who placed himself on a scorbutogenic dief, carnitine deficiency diseases and from studies with normal commented that a feeling of fatigue developed from the adults that the relationship between serum carnitine and tissue beginning of the 3rd month of dehciency, a full 6 to 8 weeks carnitine concentrations is an equally brratic one [20, 43]. before the emergence of the traditional'overt'signs of scurvy There is therefore no direct evidence that muscle carnitine in such as perifollicular hyperkeratotic papules, petechiae, poor man is related to vitamin C status - and confounding factors wound healing and softening of the gums [34] . such as dietary protein intake reduce the possibility ofan easy It will be noted that the fatigue of scurvy, like the fall in resolution of.the question. Nor does ihe plasma carnitine muscle carnitine in hypovitaminotic C guinea-pigs [7], concentrati,on present the type of correlation with age and sex evidences itselfbefore the traditional overt signs ofscurvy and found for ascorbic acid 144, 451.
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