Serum levels of carnosine may be associated with the duration of MDD episodes.

BACKGROUND: Major depressive disorder (MDD) is a recurrent disorder that incurs a high societal burden. However, the etiology of MDD remains unclear. The functioning of several systems associated with the etiopathogenesis of MDD, such as inflammatory and stress systems, is partially modulated by the dipeptide carnosine. METHODS: The study comprised 99 MDD patients and 253 non-depressed controls aged 20-71 years. Fasting serum samples were analyzed using ultra-performance liquid chromatography coupled to mass spectrometry to determine the serum levels of carnosine and its constituent, histidine. We compared these metabolites in three different settings: 1) MDD patients vs. non-depressed controls and 2) remitted vs. non-remitted MDD patients, as well as 3) changes in the metabolite levels during the follow-up period within a) the remitted group and b) the non-remitted group. In addition, we assessed the possible effect of medications on the measured metabolites. RESULTS: We observed higher serum levels of carnosine in the MDD group compared to the control group at baseline (OR = 1.895, 95%CI = 1.223-2.937, p = 0.004). Elevated serum levels of carnosine were also associated with a longer duration of the depressive episode (Z = 0.406, p = 0.001). However, the use of any antipsychotic medication (n = 36) was associated with lowered carnosine levels (p = 0.010 for use vs. non-use). At the follow-up, remitted and non-remitted participants displayed no significant differences in their carnosine levels (Z = -0.14, p = 0.891) or histidine (Z = -1.39 p = 0.164). CONCLUSIONS: An increase in circulating carnosine may characterize depressive episodes and may represent a protective homeostatic reaction against MDD-related oxidative stress and inflammation.

Plasma Metabolomics Profile of "Insulin Sensitive" Male Hypogonadism after Testosterone Replacement Therapy.

Male hypogonadism is a disorder characterized by low levels of testosterone, but patients can either show normal insulin (insulin-sensitive (IS)) or over time they can become insulin-resistant (IR). Since the two groups showed different altered metabolisms, testosterone replacement therapy (TRT) could achieve different results. In this paper, we analyzed plasma from 20 IS patients with low testosterone (<8 nmol/L) and HOMAi < 2.5. The samples, pre- and post-treatment with testosterone for 60 days, were analyzed by UHPLC and mass spectrometry. Glycolysis was significantly upregulated, suggesting an improved glucose utilization. Conversely, the pentose phosphate pathway was reduced, while the Krebs cycle was not used. Branched amino acids and carnosine metabolism were positively influenced, while ß-oxidation of fatty acids (FFA) was not activated. Cholesterol, HDL, and lipid metabolism did not show any improvements at 60 days but did so later in the experimental period. Finally, both malate and glycerol shuttle were reduced. As a result, both NADH and ATP were significantly lower. Interestingly, a significant production of lactate was observed, which induced the activation of the Cori cycle between the liver and muscles, which became the main source of energy for these patients without involving alanine. Thus, the treatment must be integrated with chemicals which are not restored in order to reactivate energy production.

Efficacy of high-intensity interval- or continuous aerobic-training on insulin resistance and muscle function in adults with metabolic syndrome: a clinical trial.

PURPOSE: We carried out a randomized, clinical trial in adults of both sexes with metabolic syndrome (MS) to assess the efficacy of high-intensity, low-volume interval training (HIIT) compared to moderate-intensity continuous training (MICT) on insulin resistance (IR), muscle mass, muscle activation, and serum musclin. METHODS: Fasting glycemia, insulinemia, and glycated haemoglobin were determined by conventional methods, IR by Homeostatic model assessment (HOMA), lean mass by Dual-Energy X-ray Absorptiometry, muscle activation through carnosine by Proton Magnetic Resonance Spectroscopy, and musclin by Enzyme-Linked ImmunoSorbent Assay before and after a supervised, three-times/week, 12-week treadmill programme. HIIT (n = 29) consisted of six intervals with one-minute, high-intensity phases at 90% of peak oxygen consumption (VO2peak). MICT (n = 31) trained at 60% of VO2peak for 30 min. RESULTS: Patients had a mean age of 50.8 ± 6.0 years, body mass index of 30.6 ± 4.0 kg/m2, and VO2peak of 29.0 ± 6.3 mL.kg-1.min-1. Compared to MICT, HIIT was not superior at reducing Ln HOMA-IR (adjusted mean difference: 0.083 [95%CI - 0.092 to 0.257]), carnosine or musclin or at increasing thigh lean mass. HIIT increased carnosine by 0.66 mmol/kg.ww (95% CI 0.08-1.24) after intervention. Both interventions reduced IR, body fat percentage and increased total lean mass/height2 and VO2peak. Musclin showed a non-significant reduction with a small effect size after both interventions. CONCLUSION: Compared to MICT, HIIT is not superior at reducing IR, carnosine or musclin or at increasing skeletal muscle mass in adults with MS. Both training types improved IR, muscle mass and body composition. NCT03087721, March 22nd, 2017. TRIAL REGISTRATION NUMBER: NCT03087721. Registered March 22nd, 2017.

Ergogenic effect of pre-exercise chicken broth ingestion on a high-intensity cycling time-trial.

BACKGROUND: chicken meat extract is a popular functional food in Asia. It is rich in the bioactive compounds carnosine and anserine, two histidine-containing dipeptides (HCD). Studies suggest that acute pre-exercise ingestion of chicken extracts has important applications towards exercise performance and fatigue control, but the evidence is equivocal. This study aimed to evaluate the ergogenic potential of the pre-exercise ingestion of a homemade chicken broth (CB) vs a placebo soup on a short-lasting, high-intensity cycling exercise. METHODS: fourteen men participated in this double-blind, placebo-controlled, crossover intervention study. Subjects ingested either CB, thereby receiving 46.4 mg/kg body weight of HCD, or a placebo soup (similar in taste without HCD) 40 min before an 8 min cycling time trial (TT) was performed. Venous blood samples were collected at arrival (fasted), before exercise and at 5 min recovery. Plasma HCD were measured with UPLC-MS/MS and glutathione (in red blood cells) was measured through HPLC. Capillary blood samples were collected at different timepoints before and after exercise. RESULTS: a significant improvement (p = 0.033; 5.2%) of the 8 min TT mean power was observed after CB supplementation compared to placebo. Post-exercise plasma carnosine (p <  0.05) and anserine (p <  0.001) was significantly increased after CB supplementation and not following placebo. No significant effect of CB supplementation was observed either on blood glutathione levels, nor on capillary blood analysis. CONCLUSIONS: oral CB supplementation improved the 8 min TT performance albeit it did not affect the acid-base balance or oxidative status parameters. Further research should unravel the potential role and mechanisms of HCD, present in CB, in this ergogenic approach.

The free amino acid profiles and metabolic biomarkers of predicting the chemotherapeutic response in advanced sarcoma patients.

PURPOSE: Metabolomics is an emerging field in cancer research. Plasma free amino acid profiles (PFAAs) have shown different features in various cancers, but the characteristic in advanced sarcoma remains unclear. We aimed to uncover the specific PFAAs in advanced sarcoma and to find the relationship between the altering of PFAAs and response to chemotherapy. PATIENTS AND METHODS: We analyzed the differences in PFAAs between 23 sarcoma patients and 30 healthy subjects basing on liquid chromatography-tandem mass spectrometry (LC-MS/MS). Then, we compared the dynamics of PFAAs after chemotherapy between improvement group and deterioration group. RESULTS: We identified seven biological differential amino acids and four pathways which were perturbed in the sarcoma patients compared with healthy subjects. After one cycle chemotherapy, the levels of γ-aminobutyric acid (GABA) and carnosine (Car) decreased significantly in the improvement group but not in deterioration group. The levels of α-aminobutyric acid (Abu) increased significantly in the deterioration group but not in the improvement group. CONCLUSION: Our study suggests the potential specific PFAAs in sarcoma patients. The unusual amino acids and metabolic pathways may provide ideas for clinical drugs targeting therapy. Three amino acids including Car, GABA and Abu may be metabolic biomarkers playing a role in dynamic monitoring of the therapeutic effect.

Laboratory predictors of death from coronavirus disease 2019 (COVID-19) in the area of Valcamonica, Italy.

Background Comprehensive information has been published on laboratory tests which may predict worse outcome in Asian populations with coronavirus disease 2019 (COVID-19). The aim of this study is to describe laboratory findings in a group of Italian COVID-19 patients in the area of Valcamonica, and correlate abnormalities with disease severity. Methods The final study population consisted of 144 patients diagnosed with COVID-19 (70 who died during hospital stay and 74 who survived and could be discharged) between March 1 and 30, 2020, in Valcamonica Hospital. Demographical, clinical and laboratory data were collected upon hospital admission and were then correlated with outcome (i.e. in-hospital death vs. discharge). Results Compared to patients who could be finally discharged, those who died during hospital stay displayed significantly higher values of serum glucose, aspartate aminotransferase (AST), creatine kinase (CK), lactate dehydrogenase (LDH), urea, creatinine, high-sensitivity cardiac troponin I (hscTnI), prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (APTT), D-dimer, C reactive protein (CRP), ferritin and leukocytes (especially neutrophils), whilst values of albumin, hemoglobin and lymphocytes were significantly decreased. In multiple regression analysis, LDH, CRP, neutrophils, lymphocytes, albumin, APTT and age remained significant predictors of in-hospital death. A regression model incorporating these variables explained 80% of overall variance of in-hospital death. Conclusions The most important laboratory abnormalities described here in a subset of European COVID-19 patients residing in Valcamonica are highly predictive of in-hospital death and may be useful for guiding risk assessment and clinical decision-making.

Comparison of zinc acetate hydrate and polaprezinc for zinc deficiency in patients on maintenance hemodialysis: A single-center, open-label, prospective randomized study.

The efficacy and safety of zinc acetate hydrate (ZAH) for zinc supplementation in patients on maintenance hemodialysis (MHD) remains unknown. In this prospective, single-center, open-label, parallel-group trial for MHD patients with serum zinc level <70 µg/dL, we compared ZAH (zinc; 50 mg/day) and polaprezinc (PPZ; zinc; 34 mg/day) beyond 6-month administration in a 1:1 randomization manner. The ZAH and PPZ groups had 44 and 47 patients, respectively. At 3 months, the change rate of serum zinc levels in the ZAH group was significantly higher than that in the PPZ group. Three months after the study, serum copper levels significantly decreased in the ZAH group, but not in the PPZ group. No significant differences were noted in anemia management in either group. ZAH was superior to PPZ in increasing serum zinc levels. Clinicians should note the stronger decline in serum copper levels when using ZAH for MHD patients.

Identification and characterisation of carnostatine (SAN9812), a potent and selective carnosinase (CN1) inhibitor with in vivo activity.

Carnosinase 1 (CN1) has been postulated to be a susceptibility factor for developing diabetic nephropathy (DN). Although its major substrate, carnosine, is beneficial in rodent models of DN, translation of these findings to humans has been hampered by high CN1 activity in human serum resulting in rapid degradation of carnosine. To overcome this hurdle, we screened a protease-directed small-molecule library for inhibitors of human recombinant CN1. We identified SAN9812 as a potent and highly selective inhibitor of CN1 activity with a Ki of 11 nM. It also inhibited CN1 activity in human serum and serum of transgenic mice-overexpressing human CN1. Subcutaneous administration of 30 mg/kg SAN9812 led to a sustained reduction in circulating CN1 activity in human CN1 transgenic (TG) mice. Simultaneous administration of carnosine and SAN9812 increased carnosine levels in plasma and kidney by up to 100-fold compared to treatment-naïve CN1-overexpressing mice. To our knowledge, this is the first study reporting on a potent and selective CN1 inhibitor with in vivo activity. SAN9812, also called carnostatine, may be used to increase renal carnosine concentration as a potential therapeutic modality for renal diseases linked to glycoxidative conditions.

Plasma concentrations of anserine, carnosine and pi-methylhistidine as biomarkers of habitual meat consumption.

BACKGROUND/OBJECTIVES: Dietary intake of red and processed meat has been associated with disease risk. Since dietary intake assessment methods are prone to measurement errors, identifying biomarkers of meat intake in bio-samples could provide more valid intake estimates. We examined associations of habitual red and processed meat, poultry, fish, and dairy products consumption with plasma concentrations of anserine, carnosine, pi-methylhistidine (Π-MH), tau-methylhistidine (T-MH), and the ratio of T-MH to Π-MH in a cross-sectional study. SUBJECTS/METHODS: Plasma anserine, carnosine, Π-MH, and T-MH concentrations were measured using ion-pair LC-MS/MS in 294 participants in the second Bavarian Food Consumption Survey (BVS II). Habitual food consumption was assessed using three 24-h dietary recalls. Associations between plasma metabolites concentrations and meat, fish, eggs, and dairy products consumption were assessed by fitting generalized linear model, adjusted for age, sex, and BMI. RESULTS: Total meat intake was associated with plasma concentrations of anserine, carnosine, Π-MH and, the ratio of T-MH to Π-MH. Red meat intake was related to carnosine (p-trend = 0.0028) and Π-MH plasma levels (p-trend = 0.0493). Poultry (p-trend = 0.0006) and chicken (p-trend = 0.0003) intake were associated with Π-MH. The highest anserine concentrations were observed in individuals consuming processed meat or turkey. For T-MH we did not observe any association with meat intake. CONCLUSIONS: Our results indicate an association between habitual meat consumption and plasma concentrations of anserine, carnosine, Π-MH and the ratio of T-MH to Π-MH. Intervention studies should clarify whether the analyzed plasma metabolites are indicative for a specific type of meat before proposing them as biomarkers of habitual meat intake in epidemiologic studies.

Appearance of Di- and Tripeptides in Human Plasma after a Protein Meal Does Not Correlate with PEPT1 Substrate Selectivity.

SCOPE: Peptide transporter 1 (PEPT1) function is well understood, yet little is known about its contribution toward the absorption of dietary amino acids in the form of di- and tripeptides. In the present human study, changes in plasma concentrations of a representative oligopeptide panel are investigated after meat intake. METHODS AND RESULTS: Based on a method for quantitative analysis of a panel of selected di- and tripeptides in biological samples, the kinetics of plasma changes of peptides derived from a widely accessible dietary protein source are described. The findings demonstrate postprandial changes of a whole spectrum of dipeptides of different size, charge, and polarity in peripheral blood in a dose-dependent manner after consumption of chicken breast in healthy human volunteers. Although the substrate specificity of PEPT1 is well known, the spectrum of peptides appearing in blood cannot be matched to the affinity to PEPT1. Stability against hydrolysis by exo- and endopeptidases appears to be another factor influencing their presence in blood. In addition, the study shows that dipeptides, including gamma-glutamyl-peptides, as well as tripeptides are common components present in human plasma. CONCLUSION: Besides amino acids, human peripheral blood contains numerous di- and tripeptides. The dietary source determines their abundance and composition.

Antioxidant status of turkey breast meat and blood after feeding a diet enriched with histidine.

The objective of this study was to investigate the effects of 1) spray dried blood cells rich in histidine and 2) pure histidine added to feed on the antioxidant status and concentration of carnosine related components in the blood and breast meat of female turkeys. The experiment was performed on 168 Big7 turkey females randomly assigned to 3 dietary treatments: control; control with the addition of 0.18% L-histidine (His); and control with the addition of spray dried blood cells (SDBC). Birds were raised for 103 d on a floor with sawdust litter, with drinking water and feed ad libitum. The antioxidant status of blood plasma and breast muscle was analyzed by ferric reducing ability (FRAP) and by 2,2-Azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radicals scavenging ability. The activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) was analyzed in the blood and breast meat, with the content of carnosine and anserine quantified by HPLC. Proximate analysis as well as amino acid profiling were carried out for the feed and breast muscles. Growth performance parameters also were calculated. Histidine supplementation of the turkey diet resulted in increased DPPH radical scavenging capacity in the breast muscles and blood, but did not result in higher histidine dipeptide concentrations. The enzymatic antioxidant system of turkey blood was affected by the diet with SDBC. In the plasma, the SDBC addition increased both SOD and GPx activity, and decreased GPx activity in the erythrocytes. Feeding turkeys with an SDBC containing diet increased BW and the content of isoleucine and valine in breast muscles.

Plasma carnosine, but not muscle carnosine, attenuates high-fat diet-induced metabolic stress.

There is growing in vivo evidence that the dipeptide carnosine has protective effects in metabolic diseases. A critical unanswered question is whether its site of action is tissues or plasma. This was investigated using oral carnosine versus ß-alanine supplementation in a high-fat diet rat model. Thirty-six male Sprague-Dawley rats received a control diet (CON), a high-fat diet (HF; 60% of energy from fat), the HF diet with 1.8% carnosine (HFcar), or the HF diet with 1% ß-alanine (HFba), as ß-alanine can increase muscle carnosine without increasing plasma carnosine. Insulin sensitivity, inflammatory signaling, and lipoxidative stress were determined in skeletal muscle and blood. In a pilot study, urine was collected. The 3 HF groups were significantly heavier than the CON group. Muscle carnosine concentrations increased equally in the HFcar and HFba groups, while elevated plasma carnosine levels and carnosine-4-hydroxy-2-nonenal adducts were detected only in the HFcar group. Elevated plasma and urine N(ε)-(carboxymethyl)lysine in HF rats was reduced by ∼50% in the HFcar group but not in the HFba group. Likewise, inducible nitric oxide synthase mRNA was decreased by 47% (p < 0.05) in the HFcar group, but not in the HFba group, compared with HF rats. We conclude that plasma carnosine, but not muscle carnosine, is involved in preventing early-stage lipoxidation in the circulation and inflammatory signaling in the muscle of rats.

Zinc supplementation influences genomic stability biomarkers, antioxidant activity, and zinc transporter genes in an elderly Australian population with low zinc status.

SCOPE: An increased intake of Zinc (Zn) may reduce the risk of degenerative diseases but may prove to be toxic if taken in excess. This study aimed to investigate whether zinc carnosine supplement can improve Zn status, genome stability events, and Zn transporter gene expression in an elderly (65-85 years) South Australian cohort with low plasma Zn levels. METHODS AND RESULTS: A 12-week placebo-controlled intervention trial was performed with 84 volunteers completing the study, (placebo, n = 42) and (Zn group, n = 42). Plasma Zn was significantly increased (p < 0.05) by 5.69% in the Zn supplemented group after 12 weeks. A significant (p < 0.05) decrease in the micronucleus frequency (-24.18%) was observed for the Zn supplemented cohort relative to baseline compared to the placebo group. Reductions of -7.09% for tail moment and -8.76% for tail intensity were observed for the Zn group (relative to baseline) (p < 0.05). Telomere base damage was found to be also significantly decreased in the Zn group (p < 0.05). Both MT1A and ZIP1 expression showed a significant increase in the Zn supplemented group (p < 0.05). CONCLUSION: Zn supplementation may have a beneficial effect in an elderly population with low Zn levels by improving Zn status, antioxidant profile, and lowering DNA damage.

The effects of beta-alanine supplementation on performance: a systematic review of the literature.

PURPOSE: To critically review the methodological quality and synthesize information from systematic reviews and high quality studies on the effects of beta alanine (BA) on exercise and athletic performance. METHODS: A search strategy was developed in accordance with the standards for the reporting of scientific literature via systematic reviews. Five databases were thoroughly searched from inception to November 2012. Inclusion criteria were English language, human studies, used BA to increase exercise or athletic performance, systematic reviews or randomized controlled trials and were published in a peer-reviewed journal. Included studies were systematically graded for their methodological quality by rotating pairs of reviewers and the results were qualitatively synthesized. RESULTS: One systematic review and 19 randomized trials were included in this review. There is one systematic review with several methodological weaknesses that limit the confidence in its results. There are moderate to high quality studies that appear to support that BA may increase power output and working capacity, decrease the feeling of fatigue and exhaustion, and have of positive effect on body composition and carnosine content. The reporting of side effects from BA supplementation in the athletic population was generally under-reported. CONCLUSIONS: There appears to be some evidence from this review that supplementation with BA may increase athletic performance. However, there is insufficient evidence examining the safety of BA supplementation and its side effects. It is therefore recommended to err on the side of caution in using BA as an ergogenic aid until there is sufficient evidence confirming its safety.

[Carnosine, carnosinase and kidney diseases]. / Karnozyna i karnozynaza a choroby nerek.

 Carnosine (beta-alanyl-L-histidine) is an endogenously synthesized dipeptide which is present in different human tissues, including the kidney. Carnosine is hydrolyzed by the enzyme carnosinase. There are two carnosinase homologues: serum secreted carnosinase and non-specific cytosolic dipeptidase, encoded by the genes CNDP1 and CNDP2 respectively and located on chromosome 18q22.3. Carnosine functions as a radical oxygen species scavenger and as a natural angiotensin converting enzyme inhibitor. Carnosine inhibits advanced glycation end product formation and reduces the synthesis of matrix proteins such as fibronectin and collagen type VI of podocytes and mesangial cells. In experimental studies it was shown that carnosine reduces the level of proinflammatory and profibrotic cytokines. It is suggested that carnosine is a naturally occurring anti-aging substance in human organisms with a beneficial effect on the cardiovascular system. This paper reports the results of studies concerning carnosine's role in kidney diseases, particularly in ischemia/reperfusion induced acute renal failure, diabetic nephropathy, gentamicin-induced nephrotoxicity and also in blood pressure regulation. The correlations between serum carnosine and serum carnosinase activity and polymorphism in the CNDP1 gene are analyzed. The role of CNDP1 gene polymorphism in the development of diabetic nephropathy and non-diabetic chronic kidney disease is discussed. Carnosine is engaged in different metabolic pathways. It has nephroprotective features. Further studies of carnosine metabolism and its biological properties, particularly those concerning the human organism, are required.

Carnosine analogues containing NO-donor substructures: synthesis, physico-chemical characterization and preliminary pharmacological profile.

The synthesis, physico-chemical, and biological characterisation of a short series of carnosine amides bearing NO-donor nitrooxy functionalities are described. The NO-donor carnosine analogues and their des-NO derivatives display carnosine-like properties, differing from the lead for their high serum stability. The newly-synthesised compounds are able to complex Cu(2+) ions at physiological pH, displaying significant copper ion sequestering ability, and protect LDL from oxidation catalysed by Cu(2+) ions. All products show moderately-potent HNE quenching activity. The NO-donor compounds 7c-f relaxed rat aorta strips via an NO-dependent mechanism. In vivo evaluation of organ protection in a model of cerebral ischaemia/reperfusion injury, using the selected NO-donor 7e and its des-NO analogue 7a, showed that both derivatives protect from hypoxia-induced brain damage, at lower concentrations than carnosine; 7e also decreased serum TNF-α levels. This class of NO-donor carnosine amides is worthy of further study as potential tools for treating a wide range of chronic vascular and neurodegenerative diseases in which NO-bioavailability is reduced.

Carnosine and cancer: a perspective.

The application of carnosine in medicine has been discussed since several years, but many claims of therapeutic effects have not been substantiated by rigorous experimental examination. In the present perspective, a possible use of carnosine as an anti-neoplastic therapeutic, especially for the treatment of malignant brain tumours such as glioblastoma is discussed. Possible mechanisms by which carnosine may perform its anti-tumourigenic effects are outlined and its expected bioavailability and possible negative and positive side effects are considered. Finally, alternative strategies are examined such as treatment with other dipeptides or ß-alanine.

Optimizing human in vivo dosing and delivery of ß-alanine supplements for muscle carnosine synthesis.

Interest into the effects of carnosine on cellular metabolism is rapidly expanding. The first study to demonstrate in humans that chronic ß-alanine (BA) supplementation (~3-6 g BA/day for ~4 weeks) can result in significantly augmented muscle carnosine concentrations (>50%) was only recently published. BA supplementation is potentially poised for application beyond the niche exercise and performance-enhancement field and into other more clinical populations. When examining all BA supplementation studies that directly measure muscle carnosine (n=8), there is a significant linear correlation between total grams of BA consumed (of daily intake ranges of 1.6-6.4 g BA/day) versus both the relative and absolute increases in muscle carnosine. Supporting this, a recent dose-response study demonstrated a large linear dependency (R2=0.921) based on the total grams of BA consumed over 8 weeks. The pre-supplementation baseline carnosine or individual subjects' body weight (from 65 to 90 kg) does not appear to impact on subsequent carnosine synthesis from BA consumption. Once muscle carnosine is augmented, the washout is very slow (~2%/week). Recently, a slow-release BA tablet supplement has been developed showing a smaller peak plasma BA concentration and delayed time to peak, with no difference in the area under the curve compared to pure BA in solution. Further, this slow-release profile resulted in a reduced urinary BA loss and improved retention, while at the same time, eliciting minimal paraesthesia symptoms. However, our complete understanding of optimizing in vivo delivery and dosing of BA is still in its infancy. Thus, this review will clarify our current knowledge of BA supplementation to augment muscle carnosine as well as highlight future research questions on the regulatory points of control for muscle carnosine synthesis.

Determinants of muscle carnosine content.

The main determinant of muscle carnosine (M-Carn) content is undoubtedly species, with, for example, aerobically trained female vegetarian athletes [with circa 13 mmol/kg dry muscle (dm)] having just 1/10th of that found in trained thoroughbred horses. Muscle fibre type is another key determinant, as type II fibres have a higher M-Carn or muscle histidine containing dipeptide (M-HCD) content than type I fibres. In vegetarians, M-Carn is limited by hepatic synthesis of ß-alanine, whereas in omnivores this is augmented by the hydrolysis of dietary supplied HCD's resulting in muscle levels two or more times higher. ß-alanine supplementation will increase M-Carn. The same increase in M-Carn occurs with administration of an equal molar quantity of carnosine as an alternative source of ß-alanine. Following the cessation of supplementation, M-Carn returns to pre-supplementation levels, with an estimated t1/2 of 5-9 weeks. Higher than normal M-Carn contents have been noted in some chronically weight-trained subjects, but it is unclear if this is due to the training per se, or secondary to changes in muscle fibre composition, an increase in ß-alanine intake or even anabolic steroid use. There is no measureable loss of M-Carn with acute exercise, although exercise-induced muscle damage may result in raised plasma concentrations in equines. Animal studies indicate effects of gender and age, but human studies lack sufficient control of the effects of diet and changes in muscle fibre composition.

Reduced muscle carnosine content in type 2, but not in type 1 diabetic patients.

Carnosine is present in high concentrations in skeletal muscle where it contributes to acid buffering and functions also as a natural protector against oxidative and carbonyl stress. Animal studies have shown an anti-diabetic effect of carnosine supplementation. High carnosinase activity, the carnosine degrading enzyme in serum, is a risk factor for diabetic complications in humans. The aim of the present study was to compare the muscle carnosine concentration in diabetic subjects to the level in non-diabetics. Type 1 and 2 diabetic patients and matched healthy controls (total n=58) were included in the study. Muscle carnosine content was evaluated by proton magnetic resonance spectroscopy (3 Tesla) in soleus and gastrocnemius. Significantly lower carnosine content (-45%) in gastrocnemius muscle, but not in soleus, was shown in type 2 diabetic patients compared with controls. No differences were observed in type 1 diabetic patients. Type II diabetic patients display a reduced muscular carnosine content. A reduction in muscle carnosine concentration may be partially associated with defective mechanisms against oxidative, glycative and carbonyl stress in muscle.