title: Targeted deletion ofKcne3impairs skeletal muscle function in mice.
abstract: KCNE3 (MiRP2) forms heteromeric voltage-gated K+channels with the skeletal muscle-expressed KCNC4 (Kv3.4) α subunit.KCNE3was the first reported skeletal muscle K+channel disease gene, but the requirement forKCNE3in skeletal muscle has been questioned. Here, we confirmed KCNE3 transcript and protein expression in mouse skeletal muscle usingKcne3-/-tissue as a negative control. Whole-transcript microarray analysis (770,317 probes, interrogating 28,853 transcripts) findings were consistent withKcne3deletion 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 α subunit remodeling arising fromKcne3deletion 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% ofKcne3-/-mice ≥10-mo-oldvs.0% age-matchedKcne3+/+littermates). Whereas 5 of 5Kcne3+/+mice exhibited the typical biphasic decline in contractile force with repetitive stimuli of hind-limb muscle, bothin vivoandin vitro,this was absent in 6 of 6Kcne3-/-mice tested. Finally, myoblasts isolated fromKcne3-/-mice exhibit faster-inactivating and smaller sustained outward currents than those fromKcne3+/+mice. Thus,Kcne3deletion 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 ofKcne3impairs skeletal muscle function in mice.
authors.affiliation: Department of Pharmacology, Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: King
authors.affiliation: Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
authors.forename: Vishal
authors.initials: V
authors.lastname: Patel
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Irvine, California, USA.|Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, Irvine, California, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Anand
authors.affiliation: Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Irvine, California, USA.|Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, Irvine, California, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Crump
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Irvine, California, USA.|Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, Irvine, California, USA.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA; noah.weisleder@osumc.edu.
authors.forename: Noah
authors.initials: N
authors.lastname: Weisleder
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Irvine, California, USA; abbottg@uci.edu.|Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, Irvine, California, USA.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Abbott
mesh_terms: D000375:Aging; D000818:Animals; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000235:genetics / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D040081:Protein Array Analysis; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: C498827:Kcne3 protein, mouse; D024642:Potassium Channels, Voltage-Gated
keywords: Kv3.4; MiRP2; myotonia; periodic paralysis; potassium channel