Carnosine Supplementation Enhances Post Ischemic Hind Limb Revascularization

Abstract

High (millimolar) concentrations of the histidine containing dipeptide – carnosine (β-alanine-L-histidine) are present in the skeletal muscle. The dipeptide has been shown to buffer intracellular pH, chelate transition metals, and scavenge lipid peroxidation products; however, its role in protecting against tissue injury remains unclear. In this study, we tested the hypothesis that carnosine protects against post ischemia by augmenting HIF-1α angiogenic signaling by Fe 2+ chelation. We found that wild type (WT) C57BL/6 mice, subjected to hind limb ischemia (HLI) and supplemented with carnosine (1g/L) in drinking water, had improved blood flow recovery and limb function, enhanced revascularization and regeneration of myocytes compared with HLI mice placed on water alone. Carnosine supplementation enhanced the bioavailability of carnosine in the ischemic limb, which was accompanied by increased expression of proton-coupled oligopeptide transporters. Consistent with our hypothesis, carnosine supplementation augmented HIF-1α and VEGF expression in the ischemic limb and the mobilization of proangiogenic Flk-1 + /Sca-1 + cells into circulation. Pretreatment of murine myoblast (C2C12) cells with octyl-D-carnosine or carnosine enhanced HIF-1α protein expression, VEGF mRNA levels and VEGF release under hypoxic conditions. Similarly pretreatment of WT C57/Bl6 mice with carnosine showed enhanced blood flow in the ischemic limb following HLI surgery. In contrast, pretreatment of hypoxic C2C12 cells with methylcarcinine, a carnosine analog, lacking Fe 2+ chelating capacity, had no effect on HIF-1α levels and VEGF release. Collectively, these data suggest that carnosine promotes post ischemic revascularization via augmentation of pro-angiogenic HIF-1α/VEGF signaling, possibly by Fe 2+ chelation.

Space Flight Diet-Induced Deficiency and Response to Gravity-Free Resistive Exercise

“…We must reject the current study’s hypothesis that daily omega-3 fatty acid, β-alanine, and carnosine intakes would correlate with significant amounts of total work variance. Current results, in comparison to positive outcomes seen in related studies [ 6 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 25 ], were unexpected. Throughout the 14-day dietary period, the current study participants were not administered a structured exercise intervention or ingested supplements for the three nutrients under investigation, either of which would have increased the concentrations of those same nutrients [ 6 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 25 ].…”

“…Throughout the 14-day dietary period, the current study participants were not administered a structured exercise intervention or ingested supplements for the three nutrients under investigation, either of which would have increased the concentrations of those same nutrients [ 6 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 25 ]. Yet, in relation to the studies that saw positive outcomes [ 6 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 25 ], the inclusion of current study data suggests that the totality of evidence on this topic makes a strong case for dietary supplementation, and the 55% carbohydrate, 30% fat, and 15% protein macronutrient ratio while on an isocaloric diet may not offer enough omega-3 fatty acid, β-alanine, and carnosine for long-term manned space missions.…”

“…In addition to omega-3 fatty acids, the common food constituent carnosine (β-alanine-histidine) improves immune function [ 17 , 18 ]. Carnosine is a dipeptide mostly found in glycolytically active tissues such as the heart, brain, and skeletal muscle.…”

The Role of GSH in Intracellular Iron Trafficking

“…Carnosine ( 6 ) is a well-established chelating molecule, capable of binding transition metals [ 61 ]. Indeed, it has been suggested that carnosine can compete for iron(II) with hypoxia-inducible factor 1 alpha (H1F-1α), an iron-dependent proline hydroxylase [ 62 ]. Furthermore, carnosine has previously been demonstrated to form mixed transition metal complexes with glutathione [ 63 ].…”

“…There is no doubt that the presence of carnosine is important for muscle contraction, including that of cardiac muscle [ 59 ]. Recently, it has been suggested that carnosine protects muscle against post ischemia by augmenting HIF-1α angiogenic signalling by iron chelation [ 62 ]. Significantly, methylcarcinine ( Scheme 3 ), a carnosine analogue, lacking iron(II)-chelating capacity, was found to have no effect on HIF-1α activity or the release of vascular endothelial growth factor in complete contrast to carnosine [ 62 ].…”