128 research outputs found
An update on carnosine and anserine research
No full textCarnosine belongs to a family of histidyl dipeptides, consisting of l-histidine and beta-alanine. It is more prevalent in the mammalian and human tissues, whereas its analogues such as anserine, which is methylated at the Nπ of imidazole, is present in birds and fish and balenine, methylated at the Nτ of histidine, is largely present in marine mammals and reptiles (Boldyrev et al. 2013). Despite their early discovery and their prominent concentrations in certain tissues, the exact role and potential of these dipeptides are still not fully understood. Carnosine is a multifunctional dipeptide. Based on its biochemical properties, it has been suggested to be involved in acid–base balance, antioxidant defense and scavenging of lipid peroxidation products. The latter functions of the dipeptide have generated various expectations as therapeutic interventions, e.g. for the pathologies associated with enhanced generation of lipid peroxidation products.
There is a growing interest from the broad scientific community to unravel the fundamental properties as well as the potential application spectrum of carnosine and related dipeptides. As to date (December 2018), over 3300 publications are found on Web of Science when searching for ‘carnosine’, and Fig. 1 displays the fundamental (panel A) and applied research areas (panel B) in which these papers are mostly situated. The majority of fundamental research is performed in the field of biochemistry/molecular biology, pharmacology and physiology (Fig. 1a). The major application fields are neurology, diabetes, cardiovascular disease and nutrition (Fig. 1b), although the interest and relevance are broad and extends all the way to agriculture, zoology, sports sciences, etc. The wide variety of disciplines of the manuscripts in this current Special Issue is a reflection hereof.No Full Tex
Physiology and pathophysiology of carnosine
No full textCarnosine (β-alanyl-l-histidine) was discovered in 1900 as an abundant non-protein nitrogen-containing compound of meat. The dipeptide is not only found in skeletal muscle, but also in other excitable tissues. Most animals, except humans, also possess a methylated variant of carnosine, either anserine or ophidine/balenine, collectively called the histidine-containing dipeptides. This review aims to decipher the physiological roles of carnosine, based on its biochemical properties. The latter include pH-buffering, metal-ion chelation, and antioxidant capacity as well as the capacity to protect against formation of advanced glycation and lipoxidation end-products. For these reasons, the therapeutic potential of carnosine supplementation has been tested in numerous diseases in which ischemic or oxidative stress are involved. For several pathologies, such as diabetes and its complications, ocular disease, aging, and neurological disorders, promising preclinical and clinical results have been obtained. Also the pathophysiological relevance of serum carnosinase, the enzyme actively degrading carnosine into l-histidine and β-alanine, is discussed. The carnosine system has evolved as a pluripotent solution to a number of homeostatic challenges. l-Histidine, and more specifically its imidazole moiety, appears to be the prime bioactive component, whereas β-alanine is mainly regulating the synthesis of the dipeptide. This paper summarizes a century of scientific exploration on the (patho)physiological role of carnosine and related compounds. However, far more experiments in the fields of physiology and related disciplines (biology, pharmacology, genetics, molecular biology, etc.) are required to gain a full understanding of the function and applications of this intriguing molecule
Correction to: An update on carnosine and anserine research
No full textThe original version of this article unfortunately contained a mistake. The author “Shahid Baba” would like to include the middle name “P” in the online published article.No Full Tex
Predicting and testing bioavailability of magnesium supplements
No full textDespite the presumption of the beneficial effects of magnesium supplementation, little is known about the pharmacokinetics of different magnesium formulations. We aimed to investigate the value of two in vitro approaches to predict bioavailability of magnesium and to validate this in subsequent in vivo testing. In vitro assessment of 15 commercially available magnesium formulations was performed by means of a Simulator of the Human Intestinal Microbial Ecosystem (SHIME (R)) and by dissolution tests. Two magnesium formulations with contrasting bioavailability prediction from both in vitro tests (best vs. worst) were selected for in vivo testing in 30 subjects. In vivo bioavailability was compared following one acute ingestion by monitoring blood magnesium concentrations up to 6 h following intake. The in vitro tests showed a very wide variation in absorption and dissolution of the 15 magnesium products. In the in vivo testing, a significant different serum magnesium absorption profile was found up to 4 h following supplement ingestion for the two supplements with opposing in vitro test results. Moreover, maximal serum magnesium increase and total area under the curve were significantly different for both supplements (+6.2% vs. +4.6% and 6.87 vs. 0.31 mM.min, respectively). Collectively, poor bioaccessibility and bioavailability in the SHIME model clearly translated into poor dissolution and poor bioavailability in vivo. This provides a valid methodology for the prediction of in vivo bioavailability and effectiveness of micronutrients by specific in vitro approaches
Muscle carnosine is associated with cardiometabolic risk factors in humans
No full textBACKGROUND: Carnosine is a naturally present dipeptide abundant in skeletal muscle and an over-the counter food additive. Animal data suggest a role of carnosine supplementation in the prevention and treatment of obesity, insulin resistance, type 2 diabetes and cardiovascular disease but only limited human data exists.
METHODS AND RESULTS: Samples of vastus lateralis muscle were obtained by needle biopsy. We measured muscle carnosine levels (high-performance liquid chromatography), % body fat (bioimpedance), abdominal subcutaneous and visceral adiposity (magnetic resonance imaging), insulin sensitivity (euglycaemic hyperinsulinemic clamp), resting energy expenditure (REE, indirect calorimetry), free-living ambulatory physical activity (accelerometers) and lipid profile in 36 sedentary non-vegetarian middle aged men (45±7 years) with varying degrees of adiposity and glucose tolerance. Muscle carnosine content was positively related to % body fat (r = 0.35, p = 0.04) and subcutaneous (r = 0.38, p = 0.02) but not visceral fat (r = 0.17, p = 0.33). Muscle carnosine content was inversely associated with insulin sensitivity (r = -0.44, p = 0.008), REE (r = -0.58, p<0.001) and HDL-cholesterol levels (r = -0.34, p = 0.048). Insulin sensitivity and physical activity were the best predictors of muscle carnosine content after adjustment for adiposity.
CONCLUSION: Our data shows that higher carnosine content in human skeletal muscle is positively associated with insulin resistance and fasting metabolic preference for glucose. Moreover, it is negatively associated with HDL-cholesterol and basal energy expenditure. Intervention studies targeting insulin resistance, metabolic and cardiovascular disease risk factors are necessary to evaluate its putative role in the prevention and management of type 2 diabetes and cardiovascular disease
Personalized sport and exercise nutrition
No full textPersonalized nutrition is an approach that is currently attracting increasing interest in the area of sport and exercise. The prospect of individually tailored, and therefore more effective, sport and exercise nutrition sounds appealing, but research in this area is still in its infancy. To compliment traditional analysis of group mean response, studies are trying to describe the totality of responses by providing individual performance and health data to an intervention which often show large inter-individual variability. Emerging evidence indicates that sport nutrition strategies may work in some individuals or under certain conditions, yet not in others, likely due to a myriad of environmental and genetic factors, highlighting the necessity in providing a more thorough examination of results. The current Research Topic aimed to provide a platform for original data and reviews on novel strategies for personalized sport and exercise nutrition.Full Tex
Development and validation of a sensitive LC–MS/MS assay for the quantification of anserine in human plasma and urine and its application to pharmacokinetic study
No full textCarnosine (beta-alanyl-l-histidine) and its methylated analogue anserine are present in relevant concentrations in the omnivore human diet. Several studies reported promising therapeutic potential for carnosine in various rodent models of oxidative stress and inflammation-related chronic diseases. Nevertheless, the poor serum stability of carnosine in humans makes the translation of rodent models hard. Even though anserine and carnosine have similar biochemical properties, anserine has better serum stability. Despite this interesting profile, the research on anserine is scarce. The aim of this study was to explore the bioavailability and stability of synthesized anserine by (1) performing in vitro stability experiments in human plasma and molecular modelling studies and by (2) evaluating the plasma and urinary pharmacokinetic profile in healthy volunteers following different doses of anserine (4–10–20 mg/kg body weight). A bio-analytical method for measuring anserine levels was developed and validated using liquid chromatography-electrospray mass spectrometry. Both plasma (CMAX: 0.54–1.10–3.12 μM) and urinary (CMAX: 0.09–0.41–0.72 mg/mg creatinine) anserine increased dose-dependently following ingestion of 4–10–20 anserine mg/kg BW, respectively. The inter-individual variation in plasma anserine was mainly explained by the activity (R2 = 0.75) and content (R2 = 0.77) of the enzyme serum carnosinase-1. Compared to carnosine, a lower interaction energy of anserine with carnosinase-1 was suggested by molecular modelling studies. Conversely, the two dipeptides seems to have similar interaction with the PEPT1 transporter. It can be concluded that nutritionally relevant doses of synthesized anserine are well-absorbed and that its degradation by serum carnosinase-1 is less pronounced compared to carnosine. This makes anserine a good candidate as a more stable carnosine-analogue to attenuate chronic diseases in humans
Dietary carnosine intake improves outcomes in Experimental Autoimmune Encephalomyelitis
No full textBackground: Carnosine (C9H14N4O3) is a naturally occurring dipeptide synthetized from histidine and β-alanine that is mainly found in excitable tissues such as skeletal muscle and the central nervous system (CNS). Here, carnosine serves versatile functions to protect the CNS and preserve homeostasis (e.g. antioxidant, antiglycation, reactive aldehyde quenching). We investigated the effect of carnosine treatment in Experimental Autoimmune Encephalomyelitis (EAE), an animal model for neuroinflammation and demyelination that mimics multiple sclerosis (MS). Methods: To induce EAE, female C57/BL6 mice were actively immunized with MOG35-55 followed by i.p. injection with pertussis toxin. Mice receiving carnosine (0.3%, 1.5%, or 3%) in their drinking water were compared with mice receiving normal tap water. All mice were sacrificed 56 days post immunization. Results: Dietary carnosine intake (3%) reduced clinical EAE severity compared to controls, 0.3% carnosine and 1.5% carnosine. Immunohistochemistry revealed a reduced number of T lymphocytes (CD3+ ) and microglia/macrophages (F4/80+ ) in the spinal cord. TNF-α mRNA abundance decreased and brain-derived neurotrophic factor (BDNF) increased in animals treated with 3% carnosine. Conclusion: Carnosine treatment effectively reduced clinical EAE severity, which was paralleled by changes in bio- and histochemical analyses. Future research is warranted to unravel the underlying mechanisms of carnosine treatment for neuroinflammatory and demyelinating disorders.No Full Tex
Effect of beta-alanine and histidine supplementation on muscle carnosine loading
No full textCarnosine (β-alanyl-L-histidine) occurs in high concentrations in human skeletal muscle where it works as a proton buffer (Derave et al, 2010). Studies on different animal species reported that beta-alanine and/or L-histidine supplementation are able to increase muscle carnosine and/or anserine content (Tamaki et al., 1977; Dunnett and Harris (1999) and Park et al., 2013). In humans, Harris et al (2006) showed that chronic oral beta-alanine supplementation can elevate muscle carnosine content. However, the effect of L-histidine was never established. Therefore, the aims of this study were to investigate the effect of beta-alanine and L-histidine supplementation, alone and combined, on human muscle carnosine loading.
15 male and 15 female participants (age: 20.0 ± 2.4 yr, body weight: 66.0 ± 10.6 kg) were divided in three groups (n=10). Each group was supplemented with either pure beta-alanine (BA) (6g/day), L-histidine hydrochloride monohydrate (HIS) (4.7g/day) or both amino acids (BA+HIS). Before and after 23 days of supplementation, carnosine content was evaluated in soleus and gastrocnemius medialis muscles by 1H-MRS.
Both BA and BA+HIS groups showed significantly increased carnosine concentrations after 23 days of supplementation (BA: soleus p<0.001 (+57.2%), gastrocnemius p=0.002 (+34.6%). BA+HIS: soleus p<0.001 (+54.0%), gastrocnemius p=0.004 (+33.1%)), in contrast to the HIS group of which the carnosine concentration remained constant during the supplementation period (soleus p=0.894 (+5.0%), gastrocnemius p=0.528 (+4.0%)).
This is the first study to investigate the effect of L-histidine supplementation on muscle carnosine content. In contrast to the animal data, histidine supplementation does not induce carnosine loading in human muscles. Furthermore, combined supplementation with beta-alanine and L-histidine has no additional effect compared to beta-alanine supplementation alone. Collectively, these data confirm that beta-alanine is the rate-limiting factor for carnosine synthesis in humans.
References
Derave W et al (2010). Sports medicine 40: 247–63.
Tamaki N et al (1977). Journal of Nutritional Science and Vitaminology 23: 331-340.
Dunnett and Harris (1999). Equine Vet J (Suppl.) 30: 499-504
Park SW et al (2013). Japan Poultry Science 50: 251-256.
Harris RC et al (2006). Amino Acids 30(3): 279–289
Human skeletal muscle atrophy in amyotrophic lateral sclerosis reveals a reduction in Akt and an increase in atrogin-1
No full textThe molecular mechanisms influencing muscle atrophy in humans are poorly understood. Atrogin-1 and MuRF1, two ubiquitin E3-ligases, mediate rodent and cell muscle atrophy and are suggested to be regulated by an Akt/Forkhead (FKHR) signaling pathway. Here we investigated the expression of atrogin-1, MuRF1, and the activity of Akt and its catabolic (FKHR and FKHRL1) and anabolic (p70(s6k) and GSK-3beta) targets in human skeletal muscle atrophy. The muscle atrophy model used was amyotrophic lateral sclerosis (ALS). All measurements were performed in biopsies from 22 ALS patients and 16 healthy controls as well as in G93A ALS mice. ALS patients had a significant increase in atrogin-1 mRNA and protein content, which was associated with a decrease in Akt activity. There was no difference in the mRNA and protein content of FKHR, FKHRL1, p70(s6k), and GSK-3beta. Similar observations were made in the G93A ALS mice. Human skeletal muscle atrophy, as seen in the ALS model, is associated with an increase in atrogin-1 and a decrease in Akt. The transcriptional regulation of human atrogin-1 may be controlled by an Akt-mediated transcription factor other than FKHR or via another signaling pathway
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