title: Nutritional intervention restores muscle but not kidney phenotypes in adult calcineurin Aα null mice.
abstract: Mice lacking the α isoform of the catalytic subunit of calcineurin (CnAα) were first reported in 1996 and have been an important model to understand the role of calcineurin in the brain, immune system, bones, muscle, and kidney. Research using the mice has been limited, however, by failure to thrive and early lethality of most null pups. Work in our laboratory led to the rescue of CnAα-/- mice by supplemental feeding to compensate for a defect in salivary enzyme secretion. The data revealed that, without intervention, knockout mice suffer from severe caloric restriction. Since nutritional deprivation is known to significantly alter development, it is imperative that previous conclusions based on CnAα-/- mice are revisited to determine which aspects of the phenotype were attributable to caloric restriction versus a direct role for CnAα. In this study, we find that defects in renal development and function persist in adult CnAα-/- mice including a significant decrease in glomerular filtration rate and an increase in blood urea nitrogen levels. These data indicate that impaired renal development we previously reported was not due to caloric restriction but rather a specific role for CnAα in renal development and function. In contrast, we find that rather than being hypoglycemic, rescued mice are mildly hyperglycemic and insulin resistant. Examination of muscle fiber types shows that previously reported reductions in type I muscle fibers are no longer evident in rescued null mice. Rather, loss of CnAα likely alters insulin response due to a reduction in insulin receptor substrate-2 (IRS2) expression and signaling in muscle. This study illustrates the importance of re-examining the phenotypes of CnAα-/- mice and the advances that are now possible with the use of adult, rescued knockout animals.
authors: Department of Medicine/Division of Nephrology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors: Kirsten
authors: K
authors: Madsen
authors: Ramesh N
authors: RN
authors: Reddy
authors: S Russ
authors: SR
authors: Price
authors: Clintoria R
authors: CR
authors: Williams
authors: Jennifer L
authors: JL
authors: Gooch
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000032:analysis / Q000235:genetics*; D031204:Caloric Restriction; D017353:Gene Deletion; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D007668:Kidney / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D010641:Phenotype; D015398:Signal Transduction
chemical_list: D007328:Insulin; D019703:Calcineurin
references: Exp Dermatol. 2010 Jun;19(6):501-10
references: 19703225
references: J Biol Chem. 2003 Nov 7;278(45):44298-304
references: 12941959
references: Am J Physiol Renal Physiol. 2003 Jan;284(1):F144-54
references: 12388427
references: J Cell Sci. 2006 Jun 15;119(Pt 12):2468-76
references: 16735444
references: Naunyn Schmiedebergs Arch Pharmacol. 1993 Dec;348(6):679-83
references: 8133911
references: Am J Physiol Renal Physiol. 2009 Mar;296(3):F512-20
references: 19129256
references: Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4586-91
references: 11904392
references: Mol Cell Biol. 2003 Jun;23(12):4331-43
references: 12773574
references: Am J Physiol Renal Physiol. 2006 Nov;291(5):F1104-7
references: 16774903
references: Neuropharmacology. 2008 Jul;55(1):71-9
references: 18538359
references: Kidney Int. 2008 Jul;74(2):187-95
references: 18432184
references: Ann N Y Acad Sci. 2007 Nov;1116:216-26
references: 17872390
references: Physiol Rev. 2000 Oct;80(4):1483-521
references: 11015619
references: Proc Natl Acad Sci U S A. 2002 Jul 9;99(14):9398-403
references: 12091710
references: Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4650-5
references: 10200317
references: Transplantation. 2007 Feb 27;83(4):439-47
references: 17318077
references: Am J Physiol Renal Physiol. 2006 Apr;290(4):F769-76
references: 16527922
references: Am J Pathol. 2004 Nov;165(5):1755-65
references: 15509543
references: J Clin Invest. 1996 Mar 15;97(6):1447-53
references: 8617877
references: J Exp Med. 1996 Feb 1;183(2):413-20
references: 8627154
references: Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17130-5
references: 16286645
references: Am J Pathol. 2011 Apr;178(4):1605-13
references: 21435446
references: J Biol Chem. 2004 Jun 18;279(25):26192-200
references: 15082723
references: Kidney Int. 2000 Dec;58(6):2291-300
references: 11115063
references: Kidney Int. 2000 Feb;57(2):414-22
references: 10652018
references: J Invest Dermatol. 2010 Jan;130(1):135-40
references: 19626032
references: J Biol Chem. 2004 Dec 31;279(53):55455-64
references: 15466861
references: J Neurochem. 1997 Apr;68(4):1668-78
references: 9084440
references: J Am Soc Nephrol. 2006 May;17(5):1388-94
references: 16611720