Nutritional Intervention Restores Muscle but Not Kidney Phenotypes in Adult Calcineurin Aα Null Mice

• Type of Material: Article
• Authors: Kirsten Madsen, Emory University; Ramesh N. Reddy, Emory University; Russ Price, Emory University; Clintoria Williams, Emory University; Jennifer Gooch, Emory University
• Language: English
• Date: 2013-04-30
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0062503
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 8
• Issue: 4
• Start Page: 1
• End Page: 8
• Grant/Funding Information: Funding for this research was provided by the Department of Veterans Affairs, Presidential Early Career Award for Scientists and Engineers (JLG), and National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases DK50740 and DK95610 (SRP).; In addition, the authors thank the Danish Heart Foundation, the Lundbeck Foundation, the Hoerslev Foundation and the Danish Medical Foundation for financial support (KM).
• Research Categories: Health Sciences, General; Health Sciences, Nutrition

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.