β-Alanine and orotate as supplements for cardiac protection

Correspondence to Dr James J DiNicolantonio; [email protected] CARNOSINE: ACID BUFFER, ANTIOXIDANT AND AID TO MUSCLE CONTRACTION β-Alanine is a rate-limiting precursor for synthesis of the dipeptide carnosine (β-alanyl-L-histidine), which is produced within and stored in high concentrations in skeletal muscle, heart and olfactory receptor neurons. 2 β-Alanine supplementation has been shown to boost the carnosine content of skeletal muscle. This reflects the fact that the Km of carnosine synthase for β-alanine (in excess of 1 mM) is far higher than the β-alanine content of tissues; its Km for histidine is two orders of magnitude lower, such that intracellular histidine levels are not ratelimiting for carnosine synthesis. β-alanine is produced in the liver during catabolism of uracil; after its release to plasma, it can be transported into tissues that require it for carnosine synthesis. Plasma levels of β-alanine also increase when carnosine is ingested in flesh foods; particularly in humans, carnosinase activity in plasma rapidly cleaves carnosine to its precursors β-alanine and histidine. The pKa of the imidazole ring of carnosine is 6.83, which makes it an ideal physiological buffer for tissues when glycolytic production of lactic acid is high. (The pKa of free histidine’s imidazole ring is around 6, so converting histidine to carnosine makes it a more effective buffer.) Most studies with supplemental β-alanine have focused on skeletal muscle and athletic performance; many studies have concluded that β-alanine supplementation can both boost muscle carnosine content and aid performance in high-intensity anaerobic workouts in which lactic acid is generated, presumably by preventing counterproductive reductions in intracellular pH. The fact that carnosine concentrations in fast-twitch muscles are higher than those in slow-twitch muscles is consistent with this paradigm. Carnosine also has versatile antioxidant activity, likewise reflecting the properties of its imidazole ring. This can serve efficiently as an electron donor, preventing lipid peroxidation; it also quenches singlet oxygen and interacts with superoxide in a way that stabilises it. 6 Like histidine, carnosine can chelate copper and iron, and this chelation prevents these ions from catalysing Fenton chemistry, hence blocking production of hydroxyl radicals. Moreover, carnosine-copper complexes possess superoxide dismutase activity. Further, carnosine binds covalently to reactive degradation products of peroxidised lipids, preventing them from reacting with other cellular targets. Carnosine may also function in skeletal muscle and heart to amplify the impact of cytoplasmic calcium on muscular contraction. 10 It seems to do so by sensitising the contractile apparatus to free calcium; some, but not all, studies suggest that it also can upregulate calcium release from the sarcoplasmic reticulum.