Carnitine is a quaternary ammonium compound that is synthesised in the body from the amino acids lysine and methionine and that is essential for the transport of fatty acids into the mitochondrial matrix, where they are oxidised to generate ATP. The carnitine shuttle system consists of three enzymes — carnitine palmitoyltransferases I and II (CPT1 and CPT2), which are located on the outer and inner mitochondrial membranes respectively, and carnitine-acylcarnitine translocase (CACT), which transports the acylcarnitine across the inner mitochondrial membrane. The net result of this carnitine-dependent transport system is that long-chain fatty acids (which cannot diffuse across the inner mitochondrial membrane) are shuttled into the mitochondrial matrix as acylcarnitine esters, where they are released by CPT2 and enter the beta-oxidation pathway. Without adequate carnitine, the beta-oxidation of long-chain fatty acids is impaired, and the body must rely more heavily on glucose and on the shorter-chain fatty acids that can diffuse across the inner mitochondrial membrane for its energy needs. This carnitine-dependent vulnerability of fatty acid oxidation is one of the most important factors in cellular energy metabolism, and its dysregulation is implicated in some of the most common chronic diseases of modern civilisation, including cardiomyopathy, the metabolic syndrome, and type 2 diabetes.
Carnitine Deficiency Syndromes
The clinical importance of carnitine for fatty acid oxidation is most dramatically demonstrated by the carnitine deficiency syndromes — a group of rare genetic disorders that are characterised by low carnitine levels and by the severe metabolic dysfunction that results from impaired fatty acid oxidation. The primary carnitine deficiency syndrome (CDSP, carnitine deficiency of systemic primary carnitine) is caused by mutations in the SLC22A5 gene, which encodes the organic cation transporter OCTN2 that is responsible for the active reuptake of carnitine from the kidney filtrate. In CDSP, the reabsorption of carnitine by the kidney is impaired, leading to very low plasma and tissue carnitine levels, and to a clinical syndrome that is characterised by progressive cardiomyopathy, muscle weakness, and hypoglycaemia. The treatment of CDSP involves carnitine supplementation at high doses (up to 200mg/kg body weight daily in divided doses), which restores tissue carnitine levels and reverses the cardiomyopathy in the majority of patients. The secondary carnitine deficiency syndromes (which are far more common than the primary deficiency) are caused by conditions that deplete carnitine levels without a genetic defect in carnitine transport — including the use of valproic acid or of the antibiotic pivampicillin, the metabolic stresses of pregnancy and lactation, and the dietary patterns that are associated with vegan and vegetarian diets.
The carnitine deficiency syndromes are powerful demonstrations of how essential carnitine is for normal cardiac function. The heart has an extraordinarily high rate of fatty acid oxidation (providing approximately 60-70% of the ATP that is required for cardiac contractility under resting conditions), and this high rate of fatty acid oxidation is dependent on an adequate supply of carnitine. When carnitine is deficient, the heart cannot oxidise fatty acids at a normal rate and must rely more heavily on glucose for its energy needs — but the insulin resistance that often accompanies carnitine deficiency impairs the uptake of glucose by the heart and produces the dual fuel deficiency that is the primary cause of the cardiomyopathy that characterises carnitine deficiency. The reversibility of the cardiomyopathy with carnitine supplementation in primary carnitine deficiency is one of the most dramatic examples of the therapeutic power of targeted nutrient replacement in clinical medicine.
Carnitine and Athletic Performance
Carnitine supplementation has been studied extensively for its potential effects on athletic performance, with the rationale that increasing carnitine availability would increase the rate of fatty acid oxidation during exercise and would thereby improve endurance performance. However, the evidence for carnitine supplementation in athletic performance is mixed — some studies show improvements in time-to-exhaustion and in the rate of perceived exertion during endurance exercise, while others show no significant effect. The most consistent finding is that carnitine supplementation (at 2-4g daily of L-carnitine or L-acetylcarnitine for 3-6 months) improves the rate of post-exercise recovery — it reduces the muscle soreness, the CK elevation, and the strength loss that follow intense exercise, possibly through effects on the carnitine-dependent aspects of the inflammatory response and on the removal of the metabolic waste products of exercise from muscle tissue.
Practical Application
For general carnitine supplementation (as a fat oxidation and cardiac support strategy), the evidence-based dose is 2-4g of L-carnitine daily (or 1-2g of acetyl-L-carnitine daily, which has better CNS penetration and which is preferred for neurological applications). Carnitine should be taken in divided doses (to minimise the GI upset that can occur with large single doses) and should be taken with carbohydrate (which stimulates the release of insulin, which in turn promotes the uptake of carnitine into muscle tissue). The primary clinical indications for carnitine supplementation are primary carnitine deficiency (under specialist supervision), the secondary carnitine deficiency that is associated with valproic acid use or with vegan/vegetarian diets, and the support of cardiac function in people with ischaemic heart disease or with heart failure. For comprehensive fat oxidation and cardiometabolic support, carnitine pairs well with the omega-3 fatty acids (which promote fat oxidation through activation of the PPAR-alpha transcription factor and which have independent cardiovascular benefits), with alpha-lipoic acid (which improves insulin sensitivity and which supports the carnitine-dependent aspects of glucose metabolism), with the B-complex vitamins (which are required for the synthesis of carnitine from lysine and methionine), and with the Mediterranean dietary pattern (which is associated with better fatty acid oxidation and with reduced risk of the metabolic syndrome).
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