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.

Compensatory renal hypertrophy following uninephrectomy is calcineurin‐independent

“…Figure shows that, similar to WT, kidneys from UNX CnAα−/− and CnAβ−/− mice are significantly larger than Sham‐operated controls within each group ( P < 0.05, two‐way anova ). The kidney mass of CnAα−/− Sham mice are smaller than WT as previously reported ( P < 0.05, anova ) . In addition, inhibition of both isoforms by administration of CsA also failed to block hypertrophy.…”

Global Transcriptomic Profiling of Cardiac Hypertrophy and Fatty Heart Induced by Long-Term High-Energy Diet in Bama Miniature Pigs

“…ATF4, a transcription factor, is widely expressed and is one of the DNA binding proteins that are involved in cell differentiation and proliferation [ 25 ]. PPP3CA encodes a multi-subunit phosphatase, and PPP3CA−/− mice exhibit changes in the brain consistent with hyperphosphorylation of the cytoskeletal protein substrate tau, along with memory impairment and susceptibility to immune suppression [ 26 ]. HSP27 is a heat shock protein, and it has important roles in cellular stress, atherosclerosis, oxidative stress, inflammation, and the production of cytokine and toll-like receptors [ 27 ].…”

The Ca2+/Calmodulin-dependent Calcineurin/NFAT Signaling Pathway in the Pathogenesis of Insulin Resistance in Skeletal Muscle

“…It is related to skeletal muscle remodeling from fast-twitch to slow-twitch fi bers via activation of CaN. In their study, Madsen et al [ 40 ] focused on mice lacking the α isoform of the catalytic subunit of CaN (CnAα). Through their investigation into the role of this crucial enzyme in cellular signaling, the researchers sought to elucidate its eff ects on biological pathways linked to insulin sensitivity and its potential signifi cance in skeletal muscle.…”