Targeted deletion of Kcne3 impairs skeletal muscle function in mice

KCNE3 (MiRP2) forms heteromeric voltage-gated K⁺ channels with the skeletal muscle-expressed KCNC4 (K_v3.4) α subunit. KCNE3 was the first reported skeletal muscle K⁺ channel disease gene, but the requirement for KCNE3 in skeletal muscle has been questioned. Here, we confirmed KCNE3 transcript and protein expression in mouse skeletal muscle using Kcne3^-/- tissue as a negative control. Whole-transcript microarray analysis (770,317 probes, interrogating 28,853 transcripts) findings were consistent with Kcne3 deletion increasing gastrocnemius oxidative metabolic gene expression and the proportion of type IIa fast-twitch oxidative muscle fibers, which was verified using immunofluorescence. The down-regulated transcript set overlapped with muscle unloading gene expression profiles (≥1.5-fold change; P < 0.05). Gastrocnemius K⁺ channel a subunit remodeling arising from Kcne3 deletion was highly specific, involving just 3 of 69 α subunit genes probed: known KCNE3 partners KCNC4 and KCNH2 (mERG) were down-regulated, and KCNK4 (TRAAK) was up-regulated (P < 0.05). Functionally, Kcne3^-/- mice exhibited abnormal hind-limb clasping upon tail suspension (63% of Kcne3^-/- mice ≥10-mo-old vs. 0% age-matched Kcne3^+/+ littermates). Whereas 5 of 5 Kcne3^+/+ mice exhibited the typical biphasic decline in contractile forcewith repetitive stimuli of hind-limbmuscle, both in vivo and in vitro, this was absent in 6 of 6 Kcne3^-/- mice tested. Finally, myoblasts isolated from Kcne3^-/- mice exhibit faster-inactivating and smaller sustained outward currents than those fromKcne3^+/+ mice. Thus, Kcne3 deletion impairs skeletalmuscle function in mice.