title: Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice.
abstract: By sensing intracellular energy levels, ATP-sensitive potassium (K(ATP)) channels help regulate vascular tone, glucose metabolism, and cardioprotection. SUR2 mutant mice lack full-length K(ATP) channels in striated and smooth muscle and display a complex phenotype of hypertension and coronary vasospasm. SUR2 mutant mice also display baseline cardioprotection and can withstand acute sympathetic stress better than normal mice. We now studied response to a form of chronic stress, namely that induced by 4 wk of daily exercise on SUR2 mutant mice. Control mice increased exercise capacity by 400% over the training period, while SUR2 mutant mice showed little increase in exercise capacity. Unexercised SUR2 mutant showed necrotic and regenerating fibers in multiple muscle skeletal muscles, including quadriceps, tibialis anterior, and diaphragm muscles. Unlike exercised control animals, SUR2 mutant mice did not lose weight, presumably due to less overall exertion. Unexercised SUR2 mutant mice showed a trend of mildly reduced cardiac function, measured by fractional shortening, (46 +/- 4% vs. 57 +/- 7% for SUR2 mutant and control, respectively), and this decrease was not exacerbated by chronic exercise exposure. Despite an improved response to acute sympathetic stress and baseline cardioprotection, exercise intolerance results from lack of SUR2 K(ATP) channels in mice.
authors.affiliation: Committee on Cellular and Molecular Physiology, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Stoller
authors.forename: Peter
authors.initials: P
authors.lastname: Pytel
authors.forename: Sophie
authors.initials: S
authors.lastname: Katz
authors.forename: Judy U
authors.initials: JU
authors.lastname: Earley
authors.forename: Keith
authors.initials: K
authors.lastname: Collins
authors.forename: Jamie
authors.initials: J
authors.lastname: Metcalfe
authors.forename: Roberto M
authors.initials: RM
authors.lastname: Lang
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: McNally
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D017079:Exercise Tolerance / Q000235:genetics; D005260:Female; D005838:Genotype; D006706:Homeostasis; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D009200:Myocardial Contraction; D009336:Necrosis; D010641:Phenotype; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D012508:Sarcolemma / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics; D064233:Sulfonylurea Receptors; D013997:Time Factors; D015431:Weight Loss
chemical_list: D018528:ATP-Binding Cassette Transporters; D001786:Blood Glucose; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors
references.citation: Physiol Genomics. 2005 Jul 14;22(2):204-12
references.pmid: 15914579
references.citation: Am J Physiol Endocrinol Metab. 2002 Dec;283(6):E1178-84
references.pmid: 12388128
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13278-83
references.pmid: 12271142
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11760-4
references.pmid: 11562480
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10402-6
references.pmid: 9724715
references.citation: Am J Physiol Cell Physiol. 2003 Dec;285(6):C1464-74
references.pmid: 12917105
references.citation: Med Sci Sports Exerc. 2004 Aug;36(8):1321-7
references.pmid: 15292739
references.citation: J Mol Cell Cardiol. 2008 Jan;44(1):188-200
references.pmid: 18001767
references.citation: J Mol Cell Cardiol. 2007 Oct;43(4):445-54
references.pmid: 17765261
references.citation: J Mol Cell Cardiol. 2005 Jun;38(6):937-43
references.pmid: 15910878
references.citation: Circ Res. 2006 Mar 17;98(5):682-9
references.pmid: 16456098
references.citation: Am J Physiol Regul Integr Comp Physiol. 2006 Nov;291(5):R1344-8
references.pmid: 16778069
references.citation: Acta Physiol Scand. 2000 Apr;168(4):489-503
references.pmid: 10759586
references.citation: J Clin Invest. 1997 Jun 1;99(11):2602-9
references.pmid: 9169489
references.citation: J Clin Invest. 2002 Feb;109(4):509-16
references.pmid: 11854323
references.citation: Prog Biophys Mol Biol. 2003 Feb;81(2):133-76
references.pmid: 12565699
references.citation: Exp Physiol. 2008 Oct;93(10):1126-38
references.pmid: 18586858
references.citation: J Physiol. 2006 Dec 15;577(Pt 3):1053-65
references.pmid: 17038430
references.citation: Hum Mol Genet. 2006 Aug 1;15(15):2285-97
references.pmid: 16782803
references.citation: Am J Physiol Cell Physiol. 2000 Nov;279(5):C1351-8
references.pmid: 11029282
references.citation: Am J Physiol Heart Circ Physiol. 2006 Jun;290(6):H2644-47
references.pmid: 16473955
references.citation: J Physiol. 2007 Jul 15;582(Pt 2):843-57
references.pmid: 17510189
references.citation: J Clin Invest. 2002 Jul;110(2):203-8
references.pmid: 12122112
references.citation: Diabetes. 2004 Dec;53 Suppl 3:S169-75
references.pmid: 15561907
references.citation: J Mol Cell Cardiol. 2005 Jun;38(6):917-25
references.pmid: 15910876
references.citation: Biol Pharm Bull. 2006 Oct;29(10):2106-10
references.pmid: 17015959