Absence of endogenous carnosine synthesis does not increase protein carbonylation and advanced lipoxidation end products in brain, kidney or muscle

Abstract

Carnosine and other histidine-containing dipeptides are expected to be important anti-oxidants in vertebrates based on various in vitro and in vivo studies with exogenously administered carnosine or its precursor β-alanine. To examine a possible anti-oxidant role of endogenous carnosine, mice lacking carnosine synthase (Carns1−/−) had been generated and were examined further in the present study. Protein carbonylation increased significantly between old (18 months) and aged (24 months) mice in brain and kidney but this was independent of the Carns1 genotype. Lipoxidation end products were not increased in 18-month-old Carns1−/− mice compared to controls. We also found no evidence for compensatory increase of anti-oxidant enzymes in Carns1−/− mice. To explore the effect of carnosine deficiency in a mouse model known to suffer from increased oxidative stress, Carns1 also was deleted in the type II diabetes model Leprdb/db mouse. In line with previous studies, malondialdehyde adducts were elevated in Leprdb/db mouse kidney, but there was no further increase by additional deficiency in Carns1. Furthermore, Leprdb/db mice lacking Carns1 were indistinguishable from conventional Leprdb/db mice with respect to fasting blood glucose and insulin levels. Taken together, Carns1 deficiency appears not to reinforce oxidative stress in old mice and there was no evidence for a compensatory upregulation of anti-oxidant enzymes. We conclude that the significance of the anti-oxidant activity of endogenously synthesized HCDs is limited in mice, suggesting that other functions of HCDs play a more important role.

Extensive profiling of histidine-containing dipeptides reveals species- and tissue-specific distribution and metabolism in mice, rats and humans

“…All mouse tissues were obtained from an in-house breeding of Carns1 -KO and WT mice with a C57/BL6 background, kindly provided by Prof. M. Eckhardt ( 14, 57 ). Genotypes of the offspring from heterozygous parents were determined in toe samples using a previously published protocol ( 14 ).…”

Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis

“…This is in line with the fact that healthy Carns1-KO mice do not display any phenotype, i.e. they exhibit normal postnatal (CNS) development [32,41]. Augmenting carnosine levels is not an effective strategy to boost OPC differentiation and remyelination.…”

“…The lack of endogenous carnosine in Carns1-KO mice resulted in a decreased ability to protect against acroleinprotein adduct formation. It is interesting to note that Wang-Eckhardt et al did not observe an increase in carbonyl-protein adducts in the CNS of healthy aged Carns1-KO mice [41], implying that the dependence on HCDs to counter carbonyl overload only manifests under more challenging (pathological) conditions such as EAE. That oligodendrocytes and OPCs are particularly vulnerable to oxidative and carbonyl stress [11] suggests that a vicious cycle may emerge, in which carbonyl overload causes oligodendroglial injury, diminished CARNS1 expression and reduced HCD production; culminating in a weakened protection of the CNS against carbonyl stress, inflammation, demyelination, and neurodegeneration.…”

Extensive profiling of histidine‐containing dipeptides reveals species‐ and tissue‐specific distribution and metabolism in mice, rats, and humans

“…All mouse tissues were obtained from an in-house breeding of Carns1-KO and WT mice with a C57/BL6 background, kindly provided by Prof. M. Eckhardt. 14,65 Genotypes of the offspring from heterozygous parents were determined in toe samples using a previously published protocol. 14 Wistar rats were supplied by Envigo (The Netherlands).…”