Mammalian skeletal muscle does not express functional voltage-gated H⁺ channels

High metabolic activity and existence of a large transmembrane inward electrochemical gradient for H⁺ at rest promote intracellular acidification of skeletal muscle. Exchangers and cotransports efficiently contend against accumulation of intracellular H⁺ and associated deleterious effects on muscle functions. Voltage-gated H⁺ channels have also been found to represent another H⁺ extrusion pathway in cultured muscle cells. Up to now, the skeletal muscle cell was therefore the unique vertebrate excitable cell in which voltage-gated H⁺ currents have been described. In this study, we show that, unlike cultured cells, single mouse muscle fibers do not generate H⁺ currents in response to depolarization. In contrast, expression of human voltage-gated H⁺ channels in mouse muscle gives rise to robust outward voltage-gated H⁺ currents. This result excludes that inappropriate experimental conditions may have failed to reveal voltage-gated H⁺ currents in control muscle. This work therefore demonstrates that fully differentiated mammalian muscle fibers do not express functional voltage-gated H⁺ channels and consequently can no longer be considered as the only vertebrate excitable cells exhibiting voltage-gated H⁺ currents.