title: Disruption of KATP channel expression in skeletal muscle by targeted oligonucleotide delivery promotes activity-linked thermogenesis.
abstract: Despite the medical, social, and economic impact of obesity, only a few therapeutic options, focused largely on reducing caloric intake, are currently available and these have limited success rates. A major impediment is that any challenge by caloric restriction is counterbalanced by activation of systems that conserve energy to prevent body weight loss. Therefore, targeting energy-conserving mechanisms to promote energy expenditure is an attractive strategy for obesity treatment. Here, in order to suppress muscle energy efficiency, we target sarcolemmal ATP-sensitive potassium (KATP) channels which have previously been shown to be important in maintaining muscle energy economy. Specifically, we employ intramuscular injections of cell-penetrating vivo-morpholinos to prevent translation of the channel pore-forming subunit. This intervention results in significant reduction of KATP channel expression and function in treated areas, without affecting the channel expression in nontargeted tissues. Furthermore, suppression of KATP channel function in a group of hind limb muscles causes a substantial increase in activity-related energy consumption, with little effect on exercise tolerance. These findings establish a proof-of-principle that selective skeletal muscle targeting of sarcolemmal KATP channel function is possible and that this intervention can alter overall bodily energetics without a disabling impact on muscle mechanical function.
authors: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors: Siva Rama Krishna
authors: SR
authors: Koganti
authors: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors: Zhiyong
authors: Z
authors: Zhu
authors: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors: Ekaterina
authors: E
authors: Subbotina
authors: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors: Zhan
authors: Z
authors: Gao
authors: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors: Ana
authors: A
authors: Sierra
authors: Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors: Manuel
authors: M
authors: Proenza
authors: Veterans Affairs Medical Center, Iowa City, Iowa, USA.
authors: Liping
authors: L
authors: Yang
authors: Department of Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
authors: Alexey
authors: A
authors: Alekseev
authors: 1] Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA [2] Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA [3] François Abboud Cardiovascular Research Center, University of Iowa, Iowa City, Iowa, USA.
authors: Denice
authors: D
authors: Hodgson-Zingman
authors: 1] Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA [2] Veterans Affairs Medical Center, Iowa City, Iowa, USA [3] Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA [4] François Abboud Cardiovascular Research Center, University of Iowa, Iowa City, Iowa, USA.
authors: Leonid
authors: L
authors: Zingman
mesh_terms: D000818:Animals; D054086:KATP Channels / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D060172:Morpholinos / Q000008:administration & dosage*; D018482:Muscle, Skeletal / Q000378:metabolism*; D010101:Oxygen Consumption; D022722:Thermogenesis
chemical_list: D054086:KATP Channels; D060172:Morpholinos
references: J Gen Physiol. 2014 Jan;143(1):119-34
references: 24344248
references: J Cell Sci. 2012 May 1;125(Pt 9):2105-14
references: 22627029
references: Am J Physiol Cell Physiol. 2000 Feb;278(2):C404-16
references: 10666037
references: Am J Physiol Cell Physiol. 2000 Nov;279(5):C1351-8
references: 11029282
references: Gene. 2000 Oct 3;256(1-2):261-70
references: 11054556
references: Am J Physiol Regul Integr Comp Physiol. 2001 Jul;281(1):R56-65
references: 11404279
references: Mayo Clin Proc. 2002 Feb;77(2):109-13
references: 11838643
references: N Engl J Med. 2002 Feb 21;346(8):591-602
references: 11856799
references: Nat Med. 2002 May;8(5):466-72
references: 11984590
references: J Clin Invest. 2002 Jul;110(2):203-8
references: 12122112
references: Nat Rev Genet. 2002 Aug;3(8):589-600
references: 12154382
references: Can J Appl Physiol. 2002 Jun;27(3):296-315
references: 12180319
references: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13278-83
references: 12271142
references: Diabetes. 2003 Feb;52(2):232-8
references: 12540591
references: Prog Biophys Mol Biol. 2003 Feb;81(2):133-76
references: 12565699
references: J Gen Physiol. 2010 Dec;136(6):597-613
references: 21078869
references: Methods Mol Biol. 2011;709:75-89
references: 21194022
references: Hum Mol Genet. 2011 Feb 1;20(3):413-21
references: 21062902
references: Mol Ther. 2011 Mar;19(3):576-83
references: 21179007
references: Cell Metab. 2010 Jan;11(1):58-69
references: 20074528
references: Nat Rev Drug Discov. 2010 Jun;9(6):465-82
references: 20514071
references: Physiol Rev. 2010 Jul;90(3):799-829
references: 20664073
references: J Physiol. 2010 Oct 1;588(Pt 19):3819-31
references: 20679354
references: J Mol Cell Cardiol. 2011 Jul;51(1):72-81
references: 21439969
references: Muscle Nerve. 2011 Oct;44(4):563-70
references: 21922468
references: Nature. 2011 Oct 6;478(7367):127-31
references: 21979053
references: Biochem Biophys Res Commun. 2011 Dec 2;415(4):637-41
references: 22079630
references: EMBO J. 2003 Apr 15;22(8):1732-42
references: 12682006
references: Diabetologia. 2003 Jul;46(7):875-91
references: 12819907
references: Am J Physiol Cell Physiol. 2003 Dec;285(6):C1464-74
references: 12917105
references: J Physiol. 1988 Oct;404:71-82
references: 3253447
references: Am J Physiol. 1991 Dec;261(6 Pt 2):H1675-86
references: 1750525
references: J Physiol. 1994 Mar 15;475(3):495-507
references: 8006831
references: J Physiol. 1997 Mar 15;499 ( Pt 3):715-20
references: 9130167
references: Neuron. 1997 May;18(5):827-38
references: 9182806
references: Endocr Rev. 1999 Apr;20(2):101-35
references: 10204114
references: Physiol Genomics. 2005 Jul 14;22(2):204-12
references: 15914579
references: N Engl J Med. 2005 Nov 17;353(20):2111-20
references: 16291981
references: Hum Mol Genet. 2006 Aug 1;15(15):2285-97
references: 16782803
references: J Physiol. 2007 Jul 15;582(Pt 2):843-57
references: 17510189
references: Exp Physiol. 2008 Oct;93(10):1126-38
references: 18586858
references: Arch Intern Med. 2008 Oct 27;168(19):2070-80
references: 18955635
references: Biotechniques. 2008 Dec;45(6):613-4, 616, 618 passim
references: 19238792
references: Molecules. 2009;14(3):1304-23
references: 19325525
references: Mol Ther. 2009 May;17(5):864-71
references: 19277018
references: Mol Ther. 2010 Jan;18(1):198-205
references: 19844193
references: Cardiovasc Res. 2010 Feb 1;85(3):444-53
references: 19815563
references: JAMA. 2012 Feb 1;307(5):491-7
references: 22253363