Lac-production accounts for the generation of 94% of the hydrogen cation (H+) concentration in skeletal muscle . SC79 Accumulation of H+, as a result of high-intensity exercise, may lead to a decline in intracellular pH from around 7.0 at rest 
to as low as 6.0 . H+ accumulation may contribute to fatigue by Quisinostat chemical structure interfering with several metabolic processes affecting force production . More specifically, the accumulation of H+ in skeletal muscle disrupts the recovery of phosphorylcreatine  and its role as a temporal buffer of ADP accumulation [6, 7], inhibits glycolysis  and disrupts functioning of the muscle contractile machinery [9, 10]. The extent of the decrease in intracellular pH with the production of H+ during exercise is mediated by intramuscular buffers and secondarily by H+ transport from muscle. Physicochemical buffers need to be present in high concentrations in the muscle and also require a pKa that is within the exercise-induced pH transit range. Carnosine
(β-alanyl-L-histidine) selleck compound is a cytoplasmic dipeptide found in high concentrations in skeletal muscle  and has a pKa of 6.83 for the imidazole ring, which makes it a suitable buffer over the physiological pH range [12, 13]. Carnosine is formed by bonding histidine and β-alanine in a reaction GPX6 catalysed by carnosine synthase, although, in humans, formation of carnosine in the skeletal muscle is limited by the availability of β-alanine . Data from a recent meta-analysis  provides support for the assertion that the main mechanism supporting an effect of increased muscle carnosine on exercise performance and capacity is through an increase in intramuscular buffering capacity. Other studies also provide some indirect evidence
to support this role [16, 17], although this is by no means the only purported physiological role for carnosine that could influence exercise performance and capacity (for review see ). Despite the role played by intramuscular buffers, pH will still fall concomitant with Lac- accumulation. As a result, it is vital to transport H+ and Lac- out of the muscle cell to prevent further reductions in intracellular pH, to reduce cellular concentrations of Lac- and allow extracellular buffers to assist in acid–base regulation. During dynamic exercise, transport of H+ out of the muscle cell provides the main control over intracellular pH, although physicochemical buffers and, to a lesser extent, metabolic buffers provide the first line of defence. However, under conditions where muscle blood flow is occluded, physicochemical buffers provide the only defence against local changes in pH.