L-Carnitine Mechanism of Action [Everything You Need To Know]


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Overview

L-carnitine is a compound that has been studied as an ergogenic aid for increasing exercise capacity in healthy individuals.

Preliminary research suggests that it may have benefits in terms of acute physical performance, such as greater maximum oxygen consumption and power output.

Although more research is needed, preliminary research suggests that supplementing with l-carnitine may aid in the recovery process after exercise.

L-carnitine is shown to reduce markers of cellular injury, free radical formation, and muscular soreness in response to muscular damage.

Supplementation is shown to enhance blood flow and oxygen delivery to muscles via enhanced endothelial function, resulting in reduced hypoxia-induced cellular and biochemical disruptions.

L-Carnitine supplementation has also been linked to an increase in muscle mass and a reduction in body weight, as well as enhanced physical and mental endurance, according to studies conducted on older individuals.

A role of l-carnitine in the prevention of age-related muscle protein deterioration and mitochondrial homeostasis regulation is suggested based on current animal research.

 

An introduction to L-carnitine

L-carnitine is a quaternary amine (3-hydroxy-4-N-trimethylaminobutyrate) that occurs naturally in all mammal species.

It was revealed in 1959 that l-carnitine is contained in muscle extracts and that it supports fatty acid oxidation in the liver and heart.

The significance of l-carnitine in fatty acid oxidation was first recognized when the structural identification of l-carnitine was made in 1927.

The transport of acetylated fatty acids into the mitochondria and their subsequent β-oxidation in the matrix is dependent on carnitine acyltransferase, which binds l-carnitine to acetyl groups via carnitine acyltransferase.

The Krebs cycle consumes the products of β-oxidation (two carbon molecules) to generate adenosine triphosphate (ATP) as a source of energy.

L-carnitine is also recognized for its significant biological function in keeping the free CoA/acetyl-CoA ratio stable.

Transesterification with l-carnitine, under conditions of stress and high acyl-CoA accumulation, may assist in the biochemistry of the Krebs cycle.

l-carnitine_function

(Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872767/)

In the image above, we can see that l-carnitine transports long-chain fatty acids into the mitochondria by forming a long chain acetylcarnitine ester.

The enzyme carnitine palmitoyltransferase I (CPT I) and carnitine palmitoyltransferase II (CPT II) move the complex into the mitochondrial matrix.

The fatty acids are broken down by the process of β-oxidation to produce 2-carbon molecules that enter the Krebs cycle and provide energy in the form of adenosine triphosphate (ATP).

L-carnitine can also act as a buffer by maintaining levels of Acetyl-CoA and coenzyme A, both of which it binds.

 

L-carnitine in the body

Endogenous synthesis of l-carnitine occurs in the liver, kidney, and brain from essential amino acids lysine and methionine.

It is also present in animal-based foods.

Vitamin C, vitamin B6, niacin, and reduced iron are required cofactors for its synthesis.

L-Carnitine is formed in the body through the process of l-carnitine synthesis. This accounts for just 25% of total daily requirements. As a result, dietary or nutritional supplements are required to meet these needs.

L-Carnitine is primarily stored in the heart and muscular tissue at tissue levels, with an estimated 95 percent concentration.

It has been shown that the muscular content is around 70 times greater than blood plasma reserves, which contain approximately 40–50 µM/L.

As a result, l-carnitine uptake is determined by an energy-dependent transport process in opposition to the concentration gradient.

Organic cation transporters (OCTNs) help to control l-carnitine distribution and intracellular homeostasis by regulating its intestinal uptake as well as renal reabsorption.

L-carnitine deficiency is caused by hereditary or acquired malfunctions in the transport systems, causing cardiomyopathy and skeletal muscle myopathy.

Carnitine is an amino acid that serves as a shuttle for long-chain fatty acids in the body. It is estimated that, in omnivorous humans, 75% of the body’s carnitine pool comes from dietary intake.

However, l-carnitine consumption varies considerably. The major source is red meat, which has a value of up to 140–190 mg l-carnitine per 100 g uncooked meat (e.g., beef and venison).

This means that L-carnitine is not derived from plants in significant amounts, as it is in animal sources.

 

l-Carnitine and Exercise

Many studies have shown a link between l-carnitine levels in the plasma and muscle and enhanced exercise capacity.

Researchers began researching the effect of l-carnitine supplementation on metabolism during exercise in the early 80s when commercial quantities of l-carnitine became available.

Given its fundamental part in the β-oxidation of fats for energy production and its function in the regulation of the acetyl-CoA pool, research on l-carnitine as an ergogenic aid initially focused on how it affects exercise.

The improvement in body composition was also shown when l-carnitine was supplemented with an exercise program.

In a double-blind, placebo-controlled trial conducted by Arenas et al. (1991), dietary supplementation of 1 g of l-carnitine twice daily for 6 months resulted in an increase in muscle l-carnitine.

Only endurance runners (and to a lesser extent sprinters) showed significant decreases in muscle-free l-carnitine as a result of exercise.

L-carnitine supplementation reestablished these levels later on.

During exercise, L-carnitine has been said to promote fat oxidation and preserve muscle glycogen, and a proposed transformation of fat into energy is likely to be apparent in the form of weight loss.

This means that long-chain fatty acids are the major source of energy during light to moderate activity.

L-carnitine has also been found to preserve the need for amino acids as a source of energy, allowing them to be utilized for new protein synthesis.

 

l-Carnitine Mechanism of Action

Exercising can cause muscle damage and pain, which may affect one’s quality of life and limit future exercise.

L-carnitine has been shown to aid with recovery after exercise through several pathways, including enhancing exercise performance and promoting fat loss through different mechanisms.

Maggini et al. investigated whether l-carnitine intake can improve power output during a post-exercise recovery period in a pilot study.

After an initial strenuous exercise in 9 of the 12 persons who took 2 g l-carnitine daily for 5 days, there was a significant increase in power output.

Administration of l-carnitine alone before exhaustive cycling exercise did not enhance performance during the second round of exercise after 3 hours in contrast to when it was coadministered with creatine.

Giamberardino et al. investigated the effects of l-carnitine in a cross-over study, finding that supplementation alleviated pain, soreness, and creatine kinase – a marker for muscular injury indicating that the nutrient was successful in lowering tissue disruption and subsequent cytoplasmic protein leakage.

The beneficial impact of l-carnitine on reducing exercise-induced hypoxia, subsequent muscle damage, and delayed onset muscle soreness (DOMS) was further verified in a series of research carried out by Kraemer and coworkers.

It was shown that daily ingestion of 2 g l-carnitine reduced muscle damage after strenuous exercise when compared to a placebo in a magnetic resonance imaging (MRI) study when compared to a placebo.

Myoglobin and creatine kinase were similarly decreased, suggesting that this process is inhibited.

A decrease in purine metabolism markers including hypoxanthine and xanthine oxidase was also observed.

 

l-Carnitine on Blood Flow

In animal studies and human clinical trials, l-carnitine’s effects on endothelial function and nitric oxide release have been confirmed.

Kraemer et al. developed a new hypothesis, suggesting that l-carnitine supplementation reduced structural and biochemical muscle damage and accelerated tissue healing by preventing carnitine insufficiency in the endothelial cells, which improved blood flow and oxygen supply.

This shift in paradigm grew out of early research by Dubelaar and Hülsmann.

It was proved that muscle contractile force in dogs was significantly enhanced and accompanied with a greater blood flow after infusion with l-carnitine, regardless of reduced muscular l-carnitine content.

L-Carnitine also improved the capacity of endothelial cells to control blood flow during ischemia by extending their capacity to regulate blood flow.

This suggested an alternative pathway independent of muscle l-carnitine accumulation and energy production.

The researchers assumed that greater force was owing to a change in the blood vessels surrounding the muscles which were later supported by findings by Nuesch et al.

1 g of l-carnitine increased plasma carnitine levels after maximal exercise in athletes when compared to a significant drop among those who did not get the supplement, according to the findings.

Volek et al. investigated the effect of l-carnitine on endothelial cell function using flow-mediated dilation (FMD) analysis after a high-fat meal in a cross-over trial.

After three weeks of oral l-carnitine treatment, postprandial brachial artery FMD in response to a 5-minute upper arm occlusion improved while peak FMD decreased in the placebo group.

This finding supports the notion that l-carnitine has a beneficial impact on endothelial function by affecting endothelial function.

 

l-Carnitine works as an antioxidant

L-Carnitine’s capability to reduce oxidative stress during exercise recovery is one of the mechanisms it may perform.

Cellular and structural damage, as well as biochemical responses during tissue repair, resulting in muscular damage especially during eccentric exercise (active force generating lengthening contractions).

Alteration of muscle fiber sarcomeres and surrounding tissues can result in long-term damage, necessitating a repair process that may continue for up to 10 days.

Another mechanism by which exercise might induce injury and inflammation is through local hypoxia, which can give free radicals in the cell a pathway to create havoc – reactive oxygen species (ROS) can become a byproduct of this process.

Finally, the release of intracellular components into the interstitium, as well as subsequent inflammation, results in DOMS, which is characterized by pain on movement, soreness, swelling, and stiffness of the muscle.

These processes are involved in the synthesis, release, and degradation of subcellular organelles called endomembranes. The breakdown of these molecules is aided by the disruption of sarcolemmal membranes.

Parandak et al. found that l-carnitine supplementation improved antioxidant defenses.

2 g l-carnitine given daily for 14 days increased total antioxidant capacity compared to placebo before and 24 h post-exercise, whereas markers of muscle damage and lipid peroxidation remained significantly lower in comparison to placebo.

Furthermore, Parthimos and colleagues discovered that l-carnitine supplementation post-training improved the overall antioxidant status, which was previously observed in basketball players who did not take supplements.

Ho and colleagues first provided experimental proof for a favorable impact on recovery following exercise in middle-aged healthy men, with a mean age of 45 years, and women, aged 52 years average, while the majority of these studies were conducted in young, healthy individuals.

l-Carnitine reduced stress levels during and after exercise, as indicated by the subjects’ subjective evaluations of muscular soreness.

In Summary

Finally, l-carnitine supplementation is useful for the healthy young active population since it promotes recovery from exercise and minimizes muscular sarcomeres deterioration and pain, which not only reduce the quality of life but also hinder further training.

Moreover, the elderly experiencing lean muscle mass and function decline reduced muscle l-carnitine content, and mitochondrial dysfunction can also benefit from the positive impact of supplementation with l-carnitine.

In particular, the relevance of l-carnitine for older individuals engaged in moderate activity will keep increasing as a result of increased participation by this group.

 

Sources (References):

  • Maggini S., Bänziger K.R., Walter P. l-carnitine supplementation results in improved recovery after strenuous exercise—A preliminary study. Ann. Nutr. Metab. 2000;44:86–88.
  • Giamberardino M.A., Dragani L., Valente R., Di Lisa F., Saggini R., Vecchiet L. Effects of prolonged l-carnitine administration on delayed muscle pain and ck release after eccentric effort. Int. J. Sports Med. 1996;17:320–324. doi: 10.1055/s-2007-972854.
  • Spiering B.A., Kraemer W.J., Hatfield D.L., Vingren J.L., Fragala M.S., Ho J.Y., Thomas G.A., Hakkinen K., Volek J.S. Effects of l-carnitine l-tartrate supplementation on muscle oxygenation responses to resistance exercise. J. Strength Cond. Res. 2008;22:1130–1135. doi: 10.1519/JSC.0b013e31817d48d9.
  • Nuesch R., Rossetto M., Martina B. Plasma and urine carnitine concentrations in well-trained athletes at rest and after exercise. Influence of l-carnitine intake. Drugs Exp. Clin. Res. 1999;25:167–171.
  • Dubelaar ML, Lucas CM, Hülsmann WC: The effect of L-carnitine on force development of the latissimus dorsi muscle in dogs.
  • Volek J.S., Judelson D.A., Silvestre R., Yamamoto L.M., Spiering B.A., Hatfield D.L., Vingren J.L., Quann E.E., Anderson J.M., Maresh C.M., et al. Effects of carnitine supplementation on flow-mediated dilation and vascular inflammatory responses to a high-fat meal in healthy young adults. Am. J. Cardiol. 2008;102:1413–1417. doi: 10.1016/j.amjcard.2008.07.022.
  • Schwane JA, Johnson SR, Vandenakker CB, Armstrong RB: Med Sci Sports Exerc. 1983; 15(1):51-6: Delayed-onset muscular soreness and plasma CPK and LDH activities after downhill running.
  • Parandak K., Arazi H., Khoshkhahesh F., Nakhostin-Roohi B. The effect of two-week l-carnitine supplementation on exercise-induced oxidative stress and muscle damage. Asian J. Sports Med. 2014;5:123–128.
  • Ho J.Y., Kraemer W.J., Volek J.S., Fragala M.S., Thomas G.A., Dunn-Lewis C., Coday M., Hakkinen K., Maresh C.M. l-carnitine l-tartrate supplementation favorably affects biochemical markers of recovery from physical exertion in middle-aged men and women. Metabolism. 2010;59:1190–1199. doi: 10.1016/j.metabol.2009.11.012
  • https://courses.lumenlearning.com/boundless-microbiology/chapter/the-citric-acid-krebs-cycle/

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