Two-pore domain potassium (K_2P) channels influence basic cellular parameters such as resting membrane potential, cellular excitability, or intracellular Ca²⁺-concentration [Ca²⁺]_i While the physiological importance of K_2P channels in different organ systems (e.g., heart, central nervous system, or immune system) has become increasingly clear over the last decade, their expression profile and functional role in skeletal muscle cells (SkMC) remain largely unknown. The mouse SkMC cell line C2C12, wild-type mouse muscle tissue, and primary mouse muscle cells (PMMs) were analyzed using quantitative PCR, Western blotting, and immunohistochemical stainings as well as functional analysis including patch-clamp measurements and Ca²⁺ imaging. Mouse SkMC express TWIK-related acid-sensitive K⁺ channel (TASK) 2, TWIK-related K⁺ channel (TREK) 1, TREK2, and TWIK-related arachidonic acid stimulated K⁺ channel (TRAAK). Except TASK2 all mentioned channels were upregulated in vitro during differentiation from myoblasts to myotubes. TASK2 and TREK1 were also functionally expressed and upregulated in PMMs isolated from mouse muscle tissue. Inhibition of TASK2 and TREK1 during differentiation revealed a morphological impairment of myoblast fusion accompanied by a downregulation of maturation markers. TASK2 and TREK1 blockade led to a decreased K⁺ outward current and a decrease of ACh-dependent Ca²⁺ influx in C2C12 cells as potential underlying mechanisms. K_2P-channel expression was also detected in human muscle tissue by immunohistochemistry pointing towards possible relevance for human muscle cell maturation and function. In conclusion, our findings for the first time demonstrate the functional expression of TASK2 and TREK1 in muscle cells with implications for differentiation processes warranting further investigations in physiologic and pathophysiologic scenarios.

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