Meldonium Supplementation in Professional Athletes: Career Destroyer or Lifesaver?

Abstract

Meldonium is a substance with known anti-anginal effects demonstrated by numerous studies and human clinical trials; however, it does not possess marketing authorization within the European Union, only in ex-Soviet republics. Since 2016, meldonium has been included by the World Anti-doping Agency (WADA) on the S4 list of metabolic modulators. In performance athletes, meldonium is now considered a doping agent due to its capacity to decrease lactate production during and after exercise, its capability to enhance the storage and utilization of glycogen, and its protective action against oxidative stress. Together, these attributes can significantly improve aerobic endurance, cardiac function, and capacity as well as shorten recovery times (allowing higher intensity training), thereby enhancing performance. The purpose of this review is to highlight the most important mechanisms underlying the protective effect of meldonium against mitochondrial dysfunction (MD), which is responsible for oxidative stress, inflammation, and the cardiac changes known as "athletic heart syndrome." Meldonium acts as an inhibitor of γ-butyrobetaine hydroxylase (BBOX), preventing the de novo synthesis of carnitine and its absorption at the intestinal level via the organic cation/carnitine transporter 2 (OCTN2) and directing the oxidation of fatty acids to the peroxisomes. The decrease in mitochondrial β-oxidation of fatty acids leads to a reduction in lipid peroxidation products that cause oxidative stress and prevent the formation of acyl/acetyl-carnitines involved in numerous pathological disorders. Given the recent findings of the potentially detrimental effects of prolonged high-intensity exercise on cardiovascular health and coronary atherosclerosis, there may be legitimate arguments for the justification of the use of substances like meldonium as protective supplements for athletes.

Keywords: carnitine inhibitor; doping; meldonium; metabolic modulators; performance athletes.

Figure 1. Chemical structure of meldonium (A) and GBB (B)

GBB: γ-butyrobetaine. Source: This image is the original work of the authors, and the image was created by ChemDraw.

Figure 2. Meldonium mechanism of action

In the cytoplasm, the activated fatty acid as acyl-CoA binds to L-carnitine, forming acyl-carnitine by carnitine palmitoyltransferase-1 (CPT1). Acyl-carnitine is transferred into the mitochondria under the action of carnitine/acyl-carnitine translocase (CACT). Inside the mitochondria, acyl-carnitine is converted back to acyl-CoA and L-carnitine by the action of carnitine palmitoyltransferase-2 (CPT2) and enters the process of β-oxidation (β-OX) to form acetyl-CoA. Acetyl-CoA is further metabolized in the Krebs cycle or transformed into acetyl-carnitine by the enzyme carnitine acetyltransferase (CrAT). Within the mitochondria, meldonium inhibits the CrAT enzyme, thus regulating the ratio of acetyl-CoA/acetyl-carnitine. By inhibiting the enzyme γ-butyrobetaine hydroxylase (BBOX), meldonium inhibits the synthesis of L-carnitine at the final step, the transformation of γ-butyrobetaine (GBB) into L-carnitine, thereby reducing its concentration in the cell. Fatty acids are redirected to peroxisomes where they are transported and oxidized independently of L-carnitine. Meldonium induces increased gene expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and peroxisome proliferator-activated receptor alpha (PPAR-α). At the intestinal level, meldonium inhibits organic cation/carnitine transporter type 2 (OCTN2) and decreases the absorption of dietary L-carnitine into the body, which is then eliminated through urine. Additionally, meldonium inhibits the formation of trimethylamine (TMA) from GBB by intestinal microbiota and promotes the elimination of trimethylamine-N-oxide (TMAO) through urine. At the renal level, meldonium reduces the reabsorption of L-carnitine. Green marks signify inhibition and red marks signify activation of a pathway. Source: This image is the original work of the authors, and the image was created by BioRender.com.

Figure 3. Cardioprotective effect of meldonium in hypoxic conditions induced by effort

In athletes, prolonged efforts can cause athletic heart syndrome by promoting inflammation, ROS (reactive oxygen species) production, hypoxia, MD (mitochondrial dysfunction), and accumulation of acyl-carnitine. Meldonium inhibits carnitine metabolism and decreases FA β-oxidation (fatty acids beta-oxidation) in the mitochondria. At the same time, meldonium activates glucose metabolism by activating 6PF1K (6-phosphofructo-1-kinase) and pyruvate dehydrogenase and shifts the production of ATP in case of aerobic effort from lipids to carbohydrates. This mechanism of action for meldonium presents a favorable overall effect on the athletes’ heart. PPARδ: Peroxisome proliferator-activated receptor delta; PPAR-α: Peroxisome proliferator-activated receptor alpha. Source: This image is the original work of the authors, and the image was created by BioRender.com.