Supplemental carnitine and exercise

¹ From the Harbor-UCLA Medical Center, Torrance, CA.

² Presented at the workshop Role of Dietary Supplements for Physically Active People, held in Bethesda, MD, June 3–4, 1996.

³ Address reprint requests to EP Brass, Department of Medicine, Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90274.

ABSTRACT  
Carnitine is an endogenous compound with well-established roles in intermediary metabolism. An obligate for optimal mitochondrial fatty acid oxidation, it is a critical source of energy and also protects the cell from acyl-CoA accretion through the generation of acylcarnitines. Carnitine homeostasis is affected by exercise in a well-defined manner because of the interaction of the carnitine-acylcarnitine pool with key metabolic pathways. Carnitine supplementation has been hypothesized to improve exercise performance in healthy humans through various mechanisms, including enhanced muscle fatty acid oxidation, altered glucose homeostasis, enhanced acylcarnitine production, modification of training responses, and altered muscle fatigue resistance. Available experimental clinical studies designed to assess the effect of carnitine on exercise metabolism or performance in healthy humans do not permit definitive conclusions to be drawn. In the aggregate, however, these studies suggest that carnitine supplementation does not improve maximal oxygen uptake or metabolic status during exercise in healthy humans. Carnitine administration for 1 mo in humans increases plasma carnitine concentrations but does not increase muscle carnitine content. Additional clinical trials integrating physiologic, biochemical, and pharmacologic assessments are needed to definitively clarify any effects of carnitine on exercise performance in healthy persons.

Key Words: Carnitine • acylcarnitine • muscle metabolism • exercise • respiratory quotient • oxygen consumption • athletic performance

INTRODUCTION  
Carnitine (L-3-hydroxytrimethylamminobutanoate) is an endogenous compound with well-established functions in intermediary metabolism. Biological reactions involving carnitine can be described as follows:

CARNITINE HOMEOSTASIS IN HUMANS  
Carnitine in humans is derived from both dietary sources and endogenous biosynthesis. Meat and dairy products are major dietary sources of this compound (4). Lysine provides the biosynthetic precursor for carnitine's carbon backbone, with the final steps of synthesis occurring in the liver and kidney (5). Irreversible loss of carnitine from humans is through urinary excretion of carnitine and acylcarnitines. Carnitine and acylcarnitines are both filtered and reabsorbed in the renal tubule with a transport maximum for reabsorption (6).

Substantial compartmentalization of carnitine pools occurs in humans, and there are tissue-specific differences in carnitine homeostasis. Carnitine and acylcarnitine are transported into cells via specific, saturable transport systems. Tissue carnitine export transport systems have also been identified, as have intracellular-extracellular carnitine-acylcarnitine exchange transport systems. Tissues differ in their complement of these transport systems (7), and thus there are differences in tissue carnitine contents, turnover rates, and metabolic availability. A comparison of total carnitine contents (the sum of carnitine and all acylcarnitines) in plasma (60 µmol/L), liver (900 µmol/kg), and skeletal muscle (4000 µmol/kg) illustrates these differences.

CARNITINE METABOLISM DURING EXERCISE IN HEALTHY SUBJECTS  
Metabolic status during exercise can be classified as low intensity (below the individual's lactate threshold) or high intensity (above this threshold) (8). At low work rates, the respiratory quotient remains low, lactate does not accumulate, and exercise can be sustained. In contrast, at high work rates (above the lactate threshold), the respiratory quotient may be 1.00, lactate accumulates in muscle and blood, and subjects become rapidly fatigued.

This low- versus high-intensity paradigm allows evaluation of carnitine metabolism during exercise. At rest, the skeletal muscle carnitine pool is distributed as 80–90% carnitine, 10–20% short-chain acylcarnitine, and <5% long-chain acylcarnitine (9). Exercise for 60 min at low intensity has no effect on the skeletal muscle carnitine pool. However, after only 10 min of high-intensity exercise, the muscle carnitine pool is redistributed to 40% carnitine and 60% short-chain acylcarnitine (9, 10). This redistribution is accentuated over a further 20 min of exercise and does not fully normalize over a 60-min recovery period (9). In contrast with these dramatic shifts in the muscle carnitine pool, only minimal changes are seen in the plasma or urine carnitine pools.

Further insights into the metabolic changes that take place when a person moves from low- to high-intensity exercise are gained by examining the specific acyl moiety present in the muscle acylcarnitine pool. In healthy persons, acetylcarnitine is the dominant acylcarnitine present in the skeletal muscle during high-intensity exercise (11, 12). As predicted based on the equilibration of the carnitine and coenzyme A pools, acetyl-CoA increases in parallel to the accumulation of acetylcarnitine (11). Thus, the acetylcarnitine accumulation provides a window into the muscle's intermediary metabolism. The accumulation of acetyl-CoA suggests a mismatch between acetyl-CoA production and entry into the tricarboxylic acid cycle for complete oxidation. This model is also consistent with the association between acylcarnitine and lactate accumulation, because acetyl-CoA accumulation will inhibit pyruvate dehydrogenase activity.

PHARMACOKINETICS OF SUPPLEMENTAL CARNITINE IN HUMANS  
The pharmacokinetics of carnitine are complex as a result of the diverse homeostatic mechanisms discussed above. From several features of carnitine's pharmacokinetics, it can be predicted that oral carnitine supplementation would have little, if any, affect on muscle carnitine content in humans. If given orally, carnitine has a systemic bioavailability of 5–15% (13, 14). Once in the systemic circulation, carnitine is rapidly distributed into a central compartment with a volume of distribution similar to the extracellular volume (15, 16). If plasma carnitine concentrations exceed the renal reabsorbtion maximum (equivalent to 60–100 µmol carnitine/L in plasma), the excess carnitine is eliminated in the urine with a clearance approximating the glomerular filtration rate (15, 17, 18). Thus, after acute administration of large doses of carnitine, most of the dose is rapidly recovered in the urine (15).

Carnitine can also move from the plasma into tissue compartments after carnitine dosing. The physiologic volume of distribution of carnitine is extremely large because of the sequestration of carnitine in muscle. Carnitine distributes into tissues with a distribution half-life of 2–3 h (19, 20). However, not all tissues are affected in an equivalent manner, and muscle is particularly refractory to acute supplementation because of its slower net turnover (15). Exogenous carnitine may still interact with the skeletal muscle carnitine pool without net uptake through plasma membrane carnitine-acylcarnitine exchange (21, 22), but the functional consequences of such an interaction are unknown. These observations have significant implications for therapeutic strategies predicated on achieving an increase in total muscle carnitine content.

The total body content of carnitine in healthy humans has been estimated as 20 g, or 120 mmol (20). Thus, given the low oral bioavailability and large renal losses after supplementation, very large dosing requirements for an extended period would be necessary to significantly affect carnitine muscle stores in healthy subjects.

Finally, it is important to note that serious questions have been raised about over-the-counter carnitine preparations available to consumers for supplementation. In a study of 12 over-the-counter carnitine formulations, the actual mean carnitine content was only 52% of that indicated on the label (23). Furthermore, 5 of 12 preparations had unsatisfactory pharmaceutical dissolution characteristics under careful evaluation (23). Bioavailability data are available only for the pharmaceutical-grade products, and comparative data are not available between products.

RATIONALE FOR CARNITINE SUPPLEMENTATION TO IMPROVE EXERCISE PERFORMANCE IN HEALTHY HUMANS  
The relation between the muscle carnitine pool and critical bioenergetic pathways has led to speculations concerning the benefits of supraphysiologic carnitine concentrations in healthy humans. Various specific mechanisms have been postulated for a carnitine effect on exercise performance (Table 1).

View this table:
TABLE 1.. Potential mechanisms for a beneficial effect of carnitine supplementation on exercise performance in healthy humans  
Carnitine's obligatory role in mitochondrial fatty acid oxidation suggests that carnitine supplementation might increase fatty acid oxidation, thus making more ATP available for mechanical work (24). If carnitine administration increases muscle fatty acid oxidation, this might also delay the use of muscle glycogen and thus delay fatigue development (25). However, no evidence is available to show whether muscle carnitine content is rate limiting for fatty acid oxidation. Furthermore, because of the pharmacokinetic considerations above, it is not clear whether a significant change in muscle carnitine content will result from carnitine supplementation.

In contrast with the idea of accelerating fatty acid oxidation by carnitine supplementation, data from animal heart models suggest that exogenous carnitine can induce an increase in glucose oxidation at the expense of fatty acid oxidation (26). A shift in the fuel substrate mix to glucose allows more ATP generation per O₂ consumption (8). This factor may be important in ischemic conditions, but its relevance to healthy humans is unclear. The mechanism of carnitine-induced enhanced glucose oxidation may involve activation of pyruvate dehydrogenase secondary to reductions in acetyl-CoA content as acetylcarnitine is generated (27). Activation of pyruvate dehydrogenase would facilitate complete glucose oxidation and minimize lactate accumulation. However, the close equilibrium between acetyl-CoA and acetylcarnitine in vivo (11) makes it difficult to envision sustained transfer of acetyl groups from the coenzyme A to carnitine pools. Demonstration of carnitine effects on pyruvate dehydrogenase requires maximizing acetyl-CoA's inhibitory effect on the enzyme (28).

Carnitine content in skeletal muscle falls during high-intensity exercise as acylcarnitines accumulate (9). Thus, carnitine availability might become rate limiting even if baseline values are adequate. Again, no data are available to support this postulate, nor is it clear that supplemental carnitine would overcome any limitation. Muscle carnitine content has been reported to decrease with exercise training (29), but the functional significance of this change or its prevention via supplementation cannot be predicted.

Impairment of muscle contractility due to fatigue may play a role in determining human performance. Through unclear mechanisms, high carnitine concentrations were shown to delay muscle fatigue and permit improved maintenance of contractile force in studies using in vitro animal systems (30, 31). The relevance of these observations to human exercise is unknown.

EFFECT OF CARNITINE SUPPLEMENTATION ON EXERCISE PERFORMANCE IN HEALTHY HUMANS  
Published studies of carnitine supplementation to modify exercise performance in healthy humans are summarized in Tables 2 and 3. Only studies designed to examine carnitine's actions as an adjunct to training are shown in Table 3. In reviewing the body of literature the reader should carefully differentiate the design features of the various studies. Administration of carnitine has varied with respect to route, dose, and duration of treatment; each of these dosing parameters could substantially affect any pharmacologic benefit of carnitine. In addition, the studies involved populations that were diverse in athletic experience, age, and sex. Study endpoints were either performance based [eg, maximal oxygen uptake (
View this table:
TABLE 2.. Effect of carnitine supplementation on exercise performance¹  

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TABLE 3.. Effect of carnitine supplementation on aerobic training  
Most studies in which exercise capacity was studied with use of either O₂max (25, 42, 43), and to enhance fatty acid oxidation (44). Yet, the few positive results are in many ways difficult to comprehend given our understanding of carnitine homeostasis. As discussed above and as emphasized by Hultman et al (47), it is unlikely that carnitine supplementation over a period of days to weeks will change muscle total carnitine content in humans. Available data confirm that muscle carnitine content is not increased by supplementation protocols similar to those described above (15, 39, 40), despite increases in plasma carnitine concentrations (15, 34, 39, 40, Work by Arenas et al (29, 45, 46) provides evidence for a distinct effect of carnitine (Table 3). Importantly, the work by Arenas et al examined only athletes engaged in training programs for periods of 1–6 mo. Under these conditions, carnitine supplementation prevented a training-associated decrease in muscle carnitine content and also increased muscle activity of key oxidative enzymes, including pyruvate dehydrogenase and electron transport chain enzymes. However, the physiologic effect of these changes is unknown and further corroboration of these findings is needed.

Finally, it is important to note that carnitine supplementation may benefit exercise performance in disease states. Patients with chronic renal failure (48) and peripheral vascular disease (49) have been reported to increase their exercise capacity after treatment with carnitine. In both conditions, muscle carnitine content was shown to be increased with long-term supplementation, although the specific mechanism for any effects of carnitine in these disorders has not been defined. Carnitine supplementation has also been suggested to be beneficial in treating chronic fatigue syndrome (50).

CONCLUSIONS AND CONSIDERATIONS FOR FUTURE WORK  
Carnitine is an endogenous compound with well-established functions in cellular metabolism that are clearly important in muscle during exercise. Muscle carnitine homeostasis is perturbed during exercise, and theoretical bases exist for carnitine supplementation to improve exercise function in healthy humans. However, the endogenous carnitine pool may be adequate for metabolic needs, and the muscle pool is refractory to perturbation from exogenous carnitine. In contrast with data in disease states, the preponderance of experimental data suggest that carnitine supplementation does not modify exercise performance in healthy humans.

The negative data available to date may not be definitive with respect to carnitine's effect on exercise performance because of study design limitations. Future studies should include adequately powered, placebo-controlled clinical trials examining physiologically relevant endpoints including O₂. Subject populations should be carefully defined to differentiate athletes from nonathletes and should identify individuals engaged in training programs. Any sex differences in carnitine effects also remain undefined. To maximize interpretation of results, studies should collect and integrate data on carnitine's pharmacology (ie, dose, duration of treatment, and relation of carnitine concentration to effect) with biochemical effects (ie, substrate and intermediate fluxes) and physiologic responses. Duration of carnitine treatment may be a particularly critical variable, given carnitine's pharmacokinetics and the long durations of treatment associated with benefit in disease states (48, 49) or with training (

ACKNOWLEDGMENTS  
The author is a consultant to Sigma Tau Pharmaceuticals. The author appreciates the comments of KE Sietsema on this manuscript.

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