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Targeted deletion of Kcne3 impairs skeletal muscle function in mice.

ABSTRACT: KCNE3 (MiRP2) forms heteromeric voltage-gated K⁺ channels with the skeletal muscle-expressed KCNC4 (K_v3.4) ? 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 ? subunit remodeling arising from Kcne3 deletion was highly specific, involving just 3 of 69 ? 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 force with repetitive stimuli of hind-limb muscle, 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 from Kcne3^+/+ mice. Thus, Kcne3 deletion impairs skeletal muscle function in mice.-King, E. C., Patel, V., Anand, M., Zhao, X., Crump, S. M., Hu, Z., Weisleder, N., Abbott, G. W. Targeted deletion of Kcne3 impairs skeletal muscle function in mice.

SUBMITTER: King EC

PROVIDER: S-EPMC5472403 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Targeted deletion of Kcne3 impairs skeletal muscle function in mice.

King Elizabeth C EC Patel Vishal V Anand Marie M Zhao Xiaoli X Crump Shawn M SM Hu Zhaoyang Z Weisleder Noah N Abbott Geoffrey W GW

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20170329 7

KCNE3 (MiRP2) forms heteromeric voltage-gated K+ channels with the skeletal muscle-expressed KCNC4 (Kv3.4) 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 pr ...[more]

PMID: 28356343

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Targeted deletion of Kcne3 impairs skeletal muscle function in mice.

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Targeted deletion of <i>Kcne3</i> impairs skeletal muscle function in mice.

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