Subunit composition of the K_ATP channels that modulate contractility of skeletal muscle during fatigue

ATP-sensitive potassium (K_ATP) channels are among the most expressed ion channels in skeletal muscle sarcolemma. While all K_ATP subunits can be detected in skeletal muscles, transcripts are enriched for KCNJ11 and ABCC9, suggesting that noncanonical Kir6.2/SUR2A assembly may constitute the majority of sarcolemmal K_ATP channels, but there has been no systematic dissection of K_ATP makeup in skeletal muscles. Here, we used a unique collection of murine lines selectively lacking specific channel-forming subunits (knockout, KO), and combined a genetic and pharmacological approach to determine which subunits of K_ATP channels are functionally relevant for skeletal muscle contraction. Under fatiguing conditions, isometric tetanic contraction experiments on murine extensor digitorum longus (EDL) revealed delayed loss of stimulated forces, and significant development of unstimulated forces, in muscles lacking Kir6.2 or SUR2 subunits, whereas loss of the SUR1 subunit did not impact muscle functionality. While pharmacological inhibition of sarcolemmal channels with glibenclamide causes comparable development of unstimulated force in wild-type muscles, acute pharmacological modulators of sarcolemmal K_ATP channels in isolated Kir6.2 or SUR2 KO muscles resulted in no changes in contractility properties, further consistent with no additional sarcolemmal K_ATP channels including Kir6.1 or SUR1 subunits. Our data show that fast-twitch skeletal muscle EDL relies on functional noncanonical K_ATP channels only made by ABCC9 (SUR2) and KCNJ11 (Kir6.2) gene products for contraction and suggest that similar contractile deficits will be present in ABCC9-dependent intellectual disability myopathy syndrome and KCNJ11-dependent congenital hyperinsulinism.