Deficiency of very long-chain acyl-CoA dehydrogenase (VLCAD) results in accumulation of C14 -C18 acylcarnitines and low free carnitine. Carnitine supplementation is still controversial. VLCAD knockout (VLCAD Ϫ/Ϫ ) mice exhibit a similar clinical and biochemical phenotype to those observed in humans. VLCAD Ϫ/Ϫ mice were fed with carnitine dissolved in drinking water. Carnitine, acylcarnitines, and ␥-butyrobetaine were measured in blood and tissues. Measurements were performed under resting conditions, after exercise and after 24 h of regeneration. HepG2 cells were incubated with palmitoyl-CoA and palmitoyl-carnitine, respectively, to examine toxicity. With carnitine supplementation, acylcarnitine production was significantly induced. Nevertheless, carnitine was low in skeletal muscle after exercise. Without carnitine supplementation, liver carnitine significantly increased after exercise, and after 24 h of regeneration, carnitine concentrations in skeletal muscle completely replenished to initial values. Incubation of hepatic cells with palmitoylCoA and palmitoyl-carnitine revealed a significantly reduced cell viability after incubation with palmitoyl-carnitine. The present study demonstrates that carnitine supplementation results in significant accumulation of potentially toxic acylcarnitines in tissues. The expected prevention of low tissue carnitine was not confirmed. The principle mechanism regulating carnitine homeostasis seems to be endogenous carnitine biosynthesis, also under conditions with increased demand of carnitine such as in VLCAD-deficiency. V ery long-chain acyl-CoA dehydrogenase (VLCAD or ACADVL, EC 1.3.99.3) is one of several enzymes of mitochondrial -oxidation. Deficiency of VLCAD is the most common mitochondrial -oxidation defect of long-chain fatty acids, with an occurrence of approximately 1:50.000 to 1:100.000 births (1). In humans, VLCAD-deficiency (VLCADD) is characterized by phenotypic heterogeneity. Phenotypic presentation is heterogeneous and different forms of presentation are distinguished: a severe early onset form presenting with cardiomyopathy and Reye-like symptoms; a hepatic phenotype that usually expresses in infancy with recurrent hypoketotic hypoglycemia; and a milder, later-onset, myopathic form with episodic muscle weakness and rhabdomyolysis (2). However, the hepatic phenotype of infancy will often become a muscular phenotype during childhood and adolescence. Exercise or catabolic stress such as illnesses trigger clinical symptoms. With the start of neonatal screening programs for fatty acid oxidation defects the majority of patients are asymptomatic at time of diagnosis and remain asymptomatic with preventive measures during the first years of follow-up. Especially for this group of patients, there is a need to define risk factors for the manifestation of clinical symptoms with special respect to physical exercise. Deficient oxidation of long-chain acyl-CoAs, especially during catabolism, results in accumulation of long-chain acylcarnitines.Carnitine is an es...
Whenever studied in a quantitative fashion, hypertonicity-induced cation channels (HICCs) are found to be the main mediators of regulatory volume increase. In most instances, these channels are either inhibited by amiloride (but insensitive to Gd3+ and flufenamate) or they are efficiently blocked by Gd3+ and flufenamate (but insensitive to amiloride). Of note, however, from two preparations so far a mixed type of pharmacology has also been reported. Whereas the ion selectivity of amiloride-sensitive HICCs has not been studied in much detail yet, amiloride-insensitive channels are either equally permeable to Na+, K+, Cs+ and Li+ but impermeable to N-methyl-D-glucamine (NMDG+) or they exhibit a permeability to Li+ and NMDG+ that amounts to some 50% when compared with that of Na+. Also in this respect, however, some peculiarities do exist. Concerning the actual molecular correlate, evidence was reported that HICCs may be related to the (amiloride-sensitive) epithelial Na+ channel and/or to transient receptor potential channels. Recent findings suggest that HICCs may contribute to cell proliferation, just as the K+ channels that are employed in regulatory volume decrease are mediators of the opposing process, i.e. apoptosis.
Dietary modification with medium-chain triglyceride (MCT) supplementation is one crucial way of treating children with long-chain fatty acid oxidation disorders. Recently, supplementation prior to exercise has been reported to prevent muscular pain and rhabdomyolysis. Systematic studies to determine when MCT supplementation is most beneficial have not yet been undertaken. We studied the effects of an MCT-based diet compared with MCT administration only prior to exercise in very-long-chain acyl-CoA dehydrogenase (VLCAD) knockout (KO) mice. VLCAD KO mice were fed an MCT-based diet in same amounts as normal mouse diet containing long-chain triglycerides (LCT) and were exercised on a treadmill. Mice fed a normal LCT diet received MCT only prior to exercise. Acylcarnitine concentration, free carnitine concentration, and acyl-coenzyme A (CoA) oxidation capacity in skeletal muscle as well as hepatic lipid accumulation were determined. Long-chain acylcarnitines significantly increased in VLCAD-deficient skeletal muscle with an MCT diet compared with an LCT diet with MCT bolus prior to exercise, whereas an MCT bolus treatment significantly decreased long-chain acylcarnitines after exercise compared with an LCT diet. C8-carnitine was significantly increased in skeletal muscle after MCT bolus treatment and exercise compared with LCT and long-term MCT treatment. Increased hepatic lipid accumulation was observed in long-term MCT-treated KO mice. MCT seems most beneficial when given in a single dose directly prior to exercise to prevent acylcarnitine accumulation. In contrast, continuous MCT treatment produces a higher skeletal muscle content of long-chain acylcarnitines after exercise and increases hepatic lipid storage in VLCAD KO mice.
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