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Zhong Chen - One of the best experts on this subject based on the ideXlab platform.
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Protective effect of Carnosine on febrile seizures in immature mice.
Neuroscience letters, 2015Co-Authors: Yun-jian Dai, Hiroshi Ohtsu, Bo Feng, Wei-wei Hou, Zhong ChenAbstract:Febrile seizures (FSs) are the most common type of convulsions in childhood and complex FSs represent an increased risk for development of temporal lobe epilepsy. The aim of this study was to analyze the anticonvulsant effects of Carnosine, an endogenous dipeptide composed of alanine and histidine, on hyperthermia induced seizure in immature mice. Injection of Carnosine significantly increased the latency and decreased the duration of FSs in a dose-dependent manner. In addition, histidine had similar effects on FSs as Carnosine. The protective effect of Carnosine or histidine was completely abolished by α-fluoromethylhistidine (α-FMH), a selective and irreversible histidine decarboxylase inhibitor, or in histidine decarboxylase deficient (HDC-KO) mice. Peripheral Carnosine administration increased the level of Carnosine, histidine and histamine in the cortex and hippocampus of mice pups, but decreased glutamate contents in the cortex and hippocampus. These results indicate that Carnosine can protect against FSs in mice pups through its conversion to histamine, suggesting that it may serve as an efficient anti-FSs drug in the future.
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Carnosine Protects Against Aβ42-induced Neurotoxicity in Differentiated Rat PC12 Cells
Cellular and molecular neurobiology, 2007Co-Authors: Haibin Dai, Yan-ying Fan, Yao Shen, Weiping Zhang, Zhong ChenAbstract:(1) The present study was designed to investigate whether histamine is involved in the protective effect of Carnosine on Abeta42-induced impairment in differentiated PC12 cells. (2) PC12 cells were exposed to Abeta42 (5 muM) for 24 h after Carnosine (5 mM) applied for 18 h. Histamine receptor antagonists (diphenhydramine, zolantidine, thioperamide, clobenpropit) or histidine decarboxylase inhibitor (alpha-fluoromethylhistidine) were added 15 min before Carnosine. Cell viability, glutamate release or cell surface expression of NMDA receptor was examined. (3) Abeta42 caused a concentration-dependent reduction of viability in PC12 cells and pretreatment with Carnosine ameliorated this impairment. This amelioration was reversed by the H(3) receptor antagonists thioperamide and clobenpropit, but not by either the H(1) receptor antagonist diphenhydramine or the H(2) receptor antagonist zolantidine. Further, alpha-fluoromethylhistidine, an irreversible inhibitor of histidine decarboxylase, also had no effect. In the presence of Abeta42, Carnosine significantly decreased glutamate release and Carnosine increased the surface expression of NMDA receptor. (4) These results indicate that the mechanism by which Carnosine attenuates Abeta42-induced neurotoxicity is independent of the Carnosine-histidine-histamine pathway, but may act through regulation of glutamate release and NMDA receptor trafficking.
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Carnosine inhibits pentylenetetrazol induced seizures by histaminergic mechanisms in histidine decarboxylase knock out mice
Neuroscience Letters, 2007Co-Authors: Zhengbing Zhuge, Dengchang Wu, Shuang Wang, Hiroshi Ohtsu, Zhong ChenAbstract:Abstract In the present study, we used both histidine decarboxylase-deficient (HDC-KO) mice and wild-type (WT) mice to elucidate the possible role of Carnosine in pentylenetetrazol (PTZ)-induced seizures. In the acute PTZ challenge study, PTZ (75 mg/kg) was injected intraperitoneally (i.p.) to induce seizures. Carnosine (200, 500 or 1000 mg/kg, i.p.) significantly decreased seizure stage, and prolonged the latency for myoclonic jerks in WT mice in a dose-dependent manner. The effects of Carnosine (500 mg/kg) were time-dependent and reached a peak at 1 h. However, it had no significant effect on HDC-KO mice. Carnosine (500 mg/kg) also significantly elevated the thresholds in WT mice but not HDC-KO mice following intravenous (tail vein) administration of PTZ. We also found that α-fluoromethylhistidine substantially reversed the protective effects of Carnosine in WT mice. In addition, Carnosine pretreatment reduced the cortical EEG activity induced by PTZ (75 mg/kg, i.p.). These results indicate that Carnosine can protect against PTZ-induced seizures and its action is mainly through the Carnosine–histidine–histamine metabolic pathway. This suggests that Carnosine may be an endogenous anticonvulsant factor in the brain and may be used as a new antiepileptic drug in the future.
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Carnosine and diseases of central nervous system
Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences, 2007Co-Authors: Yao Shen, Zhong ChenAbstract:The naturally-occurring dipeptide Carnosine (beta-alanyl-L-histidine) is found exclusively in animal tissues, such as brain and skeletal muscle tissues. Carnosine is a potent hydrophilic antioxidant, antiglycating agent, reactive oxygen species scavenger and pH-buffer. Recent reports suggest that Carnosine has potential therapeutic applications in many diseases of central nervous system, such as Alzheimer's disease, Parkinson's disease and cerebral ischemic diseases. To investigate the relationship between Carnosine and diseases of central nervous system, and to research and develop Carnosine drugs will shed light on a new way for treatment of diseases of central nervous system.
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Neuroprotective effect of Carnosine on necrotic cell death in PC12 cells
Neuroscience letters, 2006Co-Authors: Yao Shen, Yan-ying Fan, Haibin Dai, Zhong ChenAbstract:The nervous tissue of many vertebrates, including humans, can synthesize beta-alanyl-L-histidine (Carnosine). The biological functions of Carnosine are still open to question, although several theories supported by strong experimental data have been proposed. The objective of this study was to examine the effects of Carnosine on neurotoxicity in differentiated rat pheochromocytoma (PC12) cells. Neurotoxicity was induced by N-methyl-D-aspartate (NMDA), which caused time- and concentration-dependent cell death as measured by MTT and LDH assays. Pretreatment with Carnosine significantly prevented the neurotoxicity in a concentration-dependent manner. The protective effect of Carnosine was antagonized by the H1 receptor antagonist pyrilamine, but not by the H2 receptor antagonist cimetidine. In addition, alpha-fluoromethylhistidine, a histidine decarboxylase inhibitor, slightly reversed the protective action of Carnosine. These results indicate that Carnosine can effectively protect against NMDA-induced necrosis in PC12 cells, and its protection may in part be due to the activation of the postsynaptic histamine H1 receptor. The study suggests that Carnosine may be an endogenous protective factor and calls for its further study as a new anti-excitotoxic agent.
Yao Shen - One of the best experts on this subject based on the ideXlab platform.
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profiling and targeting of cellular mitochondrial bioenergetics inhibition of human gastric cancer cell growth by Carnosine
Acta Pharmacologica Sinica, 2019Co-Authors: Jiaoyan Cheng, Jianbo Yang, Yuan Liu, Yuyan Huang, Jingjing Zhang, Pei Cao, Jianxin Lyu, Yao ShenAbstract:L -Carnosine (β-alanyl- L -histidine) is a naturally occurring dipeptide distributed in various organs of mammalians. We previously showed that Carnosine inhibited proliferation of human gastric cancer cells through targeting both mitochondrial bioenergetics and glycolysis pathway. But the mechanism underlying Carnosine action on mitochondrial bioenergetics of tumor cells remains unclear. In the current study we investigated the effect of Carnosine on the growth of human gastric cancer SGC-7901 cells in vitro and in vivo. We firstly showed that hydrolysis of Carnosine was not a prerequisite for its anti-gastric cancer effect. Treatment of SGC-7901 cells with Carnosine (20 mmol/L) significantly decreased the activities of mitochondrial respiratory chain complexes I–IV and mitochondrial ATP production, and downregulated 13 proteins involved in mitochondrial bioenergetics. Furthermore, Carnosine treatment significantly suppressed the phosphorylation of Akt, while inhibition of Akt activation with GSK690693 significantly reduced the localization of prohibitin-1 (PHB-1) in the mitochondria of SGC-7901 and BGC-823 cells. In addition, we showed that silencing of PHB-1 gene with shRNA markedly reduced the mitochondrial PHB-1 in SGC-7901 cells, and significantly decreased the colony formation capacity and growth rate of the cells. In SGC-7901 cell xenograft nude mice, administration of Carnosine (250 mg kg/d, ip, for 3 weeks) significantly inhibited the tumor growth and decreased the expression of mitochondrial PHB-1 in tumor tissue. Taken together, these results suggest that Carnosine may act on multiple mitochondrial proteins to down-regulate mitochondrial bioenergetics and then to inhibit the growth and proliferation of SGC-7901 and BGC-823 cells.
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Carnosine Protects Against Aβ42-induced Neurotoxicity in Differentiated Rat PC12 Cells
Cellular and molecular neurobiology, 2007Co-Authors: Haibin Dai, Yan-ying Fan, Yao Shen, Weiping Zhang, Zhong ChenAbstract:(1) The present study was designed to investigate whether histamine is involved in the protective effect of Carnosine on Abeta42-induced impairment in differentiated PC12 cells. (2) PC12 cells were exposed to Abeta42 (5 muM) for 24 h after Carnosine (5 mM) applied for 18 h. Histamine receptor antagonists (diphenhydramine, zolantidine, thioperamide, clobenpropit) or histidine decarboxylase inhibitor (alpha-fluoromethylhistidine) were added 15 min before Carnosine. Cell viability, glutamate release or cell surface expression of NMDA receptor was examined. (3) Abeta42 caused a concentration-dependent reduction of viability in PC12 cells and pretreatment with Carnosine ameliorated this impairment. This amelioration was reversed by the H(3) receptor antagonists thioperamide and clobenpropit, but not by either the H(1) receptor antagonist diphenhydramine or the H(2) receptor antagonist zolantidine. Further, alpha-fluoromethylhistidine, an irreversible inhibitor of histidine decarboxylase, also had no effect. In the presence of Abeta42, Carnosine significantly decreased glutamate release and Carnosine increased the surface expression of NMDA receptor. (4) These results indicate that the mechanism by which Carnosine attenuates Abeta42-induced neurotoxicity is independent of the Carnosine-histidine-histamine pathway, but may act through regulation of glutamate release and NMDA receptor trafficking.
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Carnosine and diseases of central nervous system
Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences, 2007Co-Authors: Yao Shen, Zhong ChenAbstract:The naturally-occurring dipeptide Carnosine (beta-alanyl-L-histidine) is found exclusively in animal tissues, such as brain and skeletal muscle tissues. Carnosine is a potent hydrophilic antioxidant, antiglycating agent, reactive oxygen species scavenger and pH-buffer. Recent reports suggest that Carnosine has potential therapeutic applications in many diseases of central nervous system, such as Alzheimer's disease, Parkinson's disease and cerebral ischemic diseases. To investigate the relationship between Carnosine and diseases of central nervous system, and to research and develop Carnosine drugs will shed light on a new way for treatment of diseases of central nervous system.
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Neuroprotective effect of Carnosine on necrotic cell death in PC12 cells
Neuroscience letters, 2006Co-Authors: Yao Shen, Yan-ying Fan, Haibin Dai, Zhong ChenAbstract:The nervous tissue of many vertebrates, including humans, can synthesize beta-alanyl-L-histidine (Carnosine). The biological functions of Carnosine are still open to question, although several theories supported by strong experimental data have been proposed. The objective of this study was to examine the effects of Carnosine on neurotoxicity in differentiated rat pheochromocytoma (PC12) cells. Neurotoxicity was induced by N-methyl-D-aspartate (NMDA), which caused time- and concentration-dependent cell death as measured by MTT and LDH assays. Pretreatment with Carnosine significantly prevented the neurotoxicity in a concentration-dependent manner. The protective effect of Carnosine was antagonized by the H1 receptor antagonist pyrilamine, but not by the H2 receptor antagonist cimetidine. In addition, alpha-fluoromethylhistidine, a histidine decarboxylase inhibitor, slightly reversed the protective action of Carnosine. These results indicate that Carnosine can effectively protect against NMDA-induced necrosis in PC12 cells, and its protection may in part be due to the activation of the postsynaptic histamine H1 receptor. The study suggests that Carnosine may be an endogenous protective factor and calls for its further study as a new anti-excitotoxic agent.
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Carnosine protects against NMDA-induced neurotoxicity in differentiated rat PC12 cells through Carnosine-histidine-histamine pathway and H1/H3 receptors
Biochemical pharmacology, 2006Co-Authors: Yao Shen, Jianhong Luo, Erqing Wei, Yan-yin Fan, Hai-bing Dai, Zhong ChenAbstract:Since the histidine-containing dipeptide Carnosine (beta-alanyl-L-histidine) is believed to have many physiological functions in the brain, we investigated the neuroprotective effects of Carnosine and its mechanisms of action in an in vitro model of neurotoxicity induced by N-methyl-d-aspartate (NMDA) in differentiated PC12 cells. Pretreatment with Carnosine increased the viability and decreased the number of apoptotic and necrotic cells measured by MTT and Hoechst 33342 and propidium iodide (PI) double staining assays. Carnosine also can inhibit the glutamate release and increase HDC activity and the intracellular and extracellular contents of Carnosine, histidine and histamine detected by high-performance liquid chromatography (HPLC). The protection by Carnosine was reversed by alpha- fluoromethylhistidine, a selective and irreversible inhibitor of histidine decarboxylase (HDC). Pyrilamine and thioperamide, selective central histamine H(1) and H(3) antagonists also significantly reversed the protection of Carnosine. Further, the inhibition of glutamate release by Carnosine was reversed by thioperamide. Therefore, the protective mechanism of Carnosine may not only involve the Carnosine-histidine-histamine pathway, but also H(1)/H(3) receptors and the effective inhibition of glutamate release. This study indicates that Carnosine may be an endogenous protective factor and calls for its further study as a new antiexcitotoxic agent.
Guilherme Giannini Artioli - One of the best experts on this subject based on the ideXlab platform.
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magnetic resonance spectroscopy as a non invasive method to quantify muscle Carnosine in humans a comprehensive validity assessment
Scientific Reports, 2020Co-Authors: Vinicius Da Eira Silva, Vitor De Salles Painelli, Samuel Katsuyuki Shinjo, Eduardo Maffud Cilli, Craig Sale, Bruno Gualano, Maria Concepcion Garcia Otaduy, Wagner Ribeiro Pereira, Guilherme Giannini ArtioliAbstract:Carnosine is a dipeptide abundantly found in human skeletal muscle, cardiac muscle and neuronal cells having numerous properties that confers performance enhancing effects, as well as a wide-range of potential therapeutic applications. A reliable and valid method for tissue Carnosine quantification is crucial for advancing the knowledge on biological processes involved with Carnosine metabolism. In this regard, proton magnetic resonance spectroscopy (1H-MRS) has been used as a non-invasive alternative to quantify Carnosine in human skeletal muscle. However, Carnosine quantification by 1H-MRS has some potential limitations that warrant a thorough experimental examination of its validity. The present investigation examined the reliability, accuracy and sensitivity for the determination of muscle Carnosine in humans using in vitro and in vivo experiments and comparing it to reference method for Carnosine quantification (high-performance liquid chromatography – HPLC). We used in vitro 1H-MRS to verify signal linearity and possible noise sources. Carnosine was determined in the m. gastrocnemius by 1H-MRS and HPLC to compare signal quality and convergent validity. 1H-MRS showed adequate discriminant validity, but limited reliability and poor agreement with a reference method. Low signal amplitude, low signal-to-noise ratio, and voxel repositioning are major sources of error.
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is proton magnetic resonance spectroscopy a valid method to quantify muscle Carnosine in humans
bioRxiv, 2019Co-Authors: Vinicius Da Eira Silva, Vitor De Salles Painelli, Samuel Katsuyuki Shinjo, Eduardo Maffud Cilli, Craig Sale, Bruno Gualano, Maria Concepcion Garcia Otaduy, Guilherme Giannini ArtioliAbstract:Abstract We aimed to examine the validity and reliability of Proton Magnetic Resonance Spectroscopy (1H-MRS) to quantify Carnosine in human muscle. Phantoms containing different concentrations of pure Carnosine, imidazole, histidine and protein (bovine serum albumin) were analyzed by 1H-MRS to verify signal linearity, and the influence of other sources of imidazole to Carnosine signal. Carnosine was determined in the m. gastrocnemius by 1H-MRS and high-performance liquid chromatography (HPLC, reference method) in muscle biopsy samples. Signal quality was compared between in vivo and in vitro assessments. Test-retest reliability was determined with (n=10) and without (n=5) voxel repositioning and re-shimming. Convergent validity (n=16) was determined by comparing Carnosine values obtained with 1H-MRS vs. HPLC. Discriminant validity (n=14) was determined by measuring Carnosine before and after β-alanine supplementation. Carnosine signal showed excellent linearity within the physiological concentration range (2.5 to 50 mmol·L−1). A clear loss of quality was shown when Carnosine was measured in vivo. Histidine and imidazole, but not protein, emitted quantifiable signals in the same chemical shift of Carnosine. 1H-MRS coefficient of variation without repositioning voxel was 6.6% (ICC=0.924) and 16.9% (ICC=0.775) with voxel repositioning. 1H-MRS was able to detect a significant increase in muscle Carnosine after β-alanine supplementation (p=0.04), but individual data analyses showed a substantial disagreement with HPLC. Comparison of 1H-MRS with HPLC showed poor convergent validity for 1H-MRS. In conclusion, 1H-MRS showed adequate discriminant validity, but limited reliability and poor agreement with a reference method. Low signal amplitude, low signal-to-noise ratio, and voxel repositioning are major sources of error. New & noteworthy Although most of the Carnosine research relies on muscle Carnosine determination by 1H-MRS, its validity remains unknown. We showed loss of signal quality and amplitude when Carnosine is measured in vivo vs. pure Carnosine, and poor test-retest reliability when voxel is repositioned. Although 1H-MRS was sensitive to detect mean group changes in muscle Carnosine, poor agreement with a reference method was shown. 1H-MRS showed poor validity, suggesting that existing Carnosine literature might need further re-examination.
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comparison between proton magnetic resonance spectroscopy and high performance liquid chromatography to quantify muscle Carnosine in humans
bioRxiv, 2019Co-Authors: Vinicius Da Eira Silva, Vitor De Salles Painelli, Samuel Katsuyuki Shinjo, Eduardo Maffud Cilli, Craig Sale, Bruno Gualano, Maria Concepcion Garcia Otaduy, Guilherme Giannini ArtioliAbstract:Proton magnetic resonance spectroscopy (1H-MRS) has been used as a non-invasive alternative to quantify Carnosine in human muscle. It is unclear whether 1H-MRS is a valid and reliable method. 1H-MRS validity and reliability was examined in a series of in vitro and in vivo studies. In the in vitro study, phantoms containing different concentrations of Carnosine, imidazole, histidine and bovine serum albumin (BSA) were submitted to 1H-MRS to verify: 1) signal linearity; 2) whether other sources of imidazole could contribute to Carnosine signal. In the in vivo study, Carnosine was determined in the m. gastrocnemius by 1H-MRS and by high-performance liquid chromatography (HPLC, a reference method) in muscle biopsy samples from 16 young men. Test-retest reliability was determined with (n=10) and without (n=5) voxel repositioning and re-shimming. Convergent validity (n=16) was determined by comparing Carnosine values obtained with 1H-MRS vs. HPLC. Discriminant validity (n=14) was determined by measuring Carnosine before and after 4 weeks of {beta}-alanine supplementation. In vitro Carnosine signal showed excellent linearity (Pearson correlation: r=0.999). Histidine and imidazole, but not BSA, emitted quantifiable signals in the same chemical shift of Carnosine. A clear loss in signal quality was shown in the signal obtained in vivo. 1H-MRS coefficient of variation without repositioning voxel was 6.6% and increased to 16.9% with voxel repositioning. 1H-MRS was able to detect a significant increase in muscle Carnosine after {beta}-alanine supplementation, both a substantial disagreement with HPLC was shown. 1H-MRS showed adequate discriminant validity, but limited reliability and poor agreement with the reference method.nnKey points summaryO_LIAlthough proton magnetic resonance spectroscopy (1H-MRS) was developed to quantify Carnosine in human muscle as a non-invasive alternative method to high-performance liquid chromatography (HPLC) in extracts from human muscle biopsy, a thorough assessment of 1H-MRS validity is lacking. Thus, we examined signal linearity in vitro, matrix effect in vivo, as well as reliability, convergent validity and discriminant validity of in vivo 1H-MRS for the determination of Carnosine in human muscle using in vitro and in vivo experiments.nC_LIO_LIAn excellent 1H-MRS in vitro signal linearity was shown for Carnosine across the physiological range, although broadening and signal losses were observed when 1H-MRS was performed in vivo.nC_LIO_LIFree histidine and imidazole also emitted quantifiable signals at the same chemical shift of Carnosine, which could constitute a source of error in Carnosine quantification. Large protein (e.g., bovine serum albumin) did not emitted signal, thereby indicating they do not constitute a source of error.nC_LIO_LI1H-MRS can detect and quantify muscle Carnosine in vivo, and it is sensitive to detect increases in muscle Carnosine brought about by {beta}-alanine supplementation.nC_LIO_LIDespite being sensitivity, 1H-MRS showed poor test-retest reliability, especially due to voxel repositioning and re-shimming.nC_LIO_LIA poor agreement was shown for muscle Carnosine determination between 1H-MRS and HPLC performed in muscle biopsies taken at the closest possible site (m. gastrocnemius).nC_LIO_LICaution should be exercised when interpreting muscle Carnosine data obtained with 1H-MRS.nC_LI
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Carnosine in health and disease
European journal of sport science, 2018Co-Authors: Guilherme Giannini Artioli, Craig Sale, Rebecca Louise JonesAbstract:Carnosine was originally discovered in skeletal muscle, where it exists in larger amounts than in other tissues. The majority of research into the physiological roles of Carnosine have been conducted on skeletal muscle. Given this and the potential for muscle Carnosine content to be increased with supplementation, there is now a large body of research examining the ergogenic effects (or otherwise) of Carnosine. More recent research, however, points towards a potential for Carnosine to exert a wider range of physiological effects in other tissues, including the brain, heart, pancreas, kidney and cancer cells. Taken together, this is suggestive of a potential for Carnosine to have therapeutic benefits in health and disease, although this is by no means without complication. Herein, we will provide a review of the current literature relating to the potential therapeutic effects of Carnosine in health and disease.
Wim Derave - One of the best experts on this subject based on the ideXlab platform.
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gene expression of Carnosine related enzymes and transporters in skeletal muscle
European Journal of Applied Physiology, 2013Co-Authors: Inge Everaert, Youri Taes, Helene De Naeyer, Wim DeraveAbstract:Chronic oral beta-alanine supplementation can elevate muscle Carnosine (beta-alanyl-l-histidine) content and improve high-intensity exercise performance. However, the regulation of muscle Carnosine levels is poorly understood. The uptake of the rate-limiting precursor beta-alanine and the enzyme catalyzing the dipeptide synthesis are thought to be key steps. The aims of this study were to investigate the expression of possible Carnosine-related enzymes and transporters in both human and mouse skeletal muscle in response to Carnosine-altering stimuli. Human gastrocnemius lateralis and mouse tibialis anterior muscle samples were subjected to HPLC and qPCR analysis. Mice were subjected to chronic oral supplementation of beta-alanine and Carnosine or to orchidectomy (7 and 30 days, with or without testosterone replacement), stimuli known to, respectively, increase and decrease muscle Carnosine and anserine. The following Carnosine-related enzymes and transporters were expressed in human and/or mouse muscles: Carnosine synthase (CARNS), carnosinase-2 (CNDP2), the Carnosine/histidine transporters PHT1 and PHT2, the beta-alanine transporters TauT and PAT1, beta-alanine transaminase (ABAT) and histidine decarboxylase (HDC). Six of these genes showed altered expression in the investigated interventions. Orchidectomy led to decreased muscle Carnosine content, which was paralleled with decreased TauT expression, whereas CARNS expression was surprisingly increased. Beta-alanine supplementation increased both muscle Carnosine content and TauT, CARNS and ABAT expression, suggesting that muscles increase beta-alanine utilization through both dipeptide synthesis (CARNS) and deamination (ABAT) and further oxidation, in conditions of excess availability. Collectively, these data show that muscle Carnosine homeostasis is regulated by nutritional and hormonal stimuli in a complex interplay between related transporters and enzymes.
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vegetarianism female gender and increasing age but not cndp1 genotype are associated with reduced muscle Carnosine levels in humans
Amino Acids, 2011Co-Authors: Inge Everaert, A L Mooyaart, Audrey Baguet, Ana Zutinic, Hans J Baelde, Eric Achten, Youri Taes, Emile De Heer, Wim DeraveAbstract:Carnosine is found in high concentrations in skeletal muscles, where it is involved in several physiological functions. The muscle Carnosine content measured within a population can vary by a factor 4. The aim of this study was to further characterize suggested determinants of the muscle Carnosine content (diet, gender and age) and to identify new determinants (plasma carnosinase activity and testosterone). We investigated a group of 149 healthy subjects, which consisted of 94 men (12 vegetarians) and 55 women. Muscle Carnosine was quantified in M. soleus, gastrocnemius and tibialis anterior using magnetic resonance proton spectroscopy and blood samples were collected to determine CNDP1 genotype, plasma carnosinase activity and testosterone concentrations. Compared to women, men have 36, 28 and 82% higher Carnosine concentrations in M. soleus, gastrocnemius and tibialis anterior muscle, respectively, whereas circulating testosterone concentrations were unrelated to muscle Carnosine levels in healthy men. The Carnosine content of the M. soleus is negatively related to the subjects’ age. Vegetarians have a lower Carnosine content of 26% in gastrocnemius compared to omnivores. In contrast, there is no difference in muscle Carnosine content between omnivores with a high or low ingestion of β-alanine. Muscle Carnosine levels are not related to the polymorphism of the CNDP1 gene or to the enzymatic activity of the plasma carnosinase. In conclusion, neither CNDP1 genotype nor the normal variation in circulating testosterone levels affects the muscular Carnosine content, whereas vegetarianism, female gender and increasing age are the factors associated with reduced muscle Carnosine stores.
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muscle Carnosine metabolism and β alanine supplementation in relation to exercise and training
Sports Medicine, 2010Co-Authors: Wim Derave, Inge Everaert, Sam Beeckman, Audrey BaguetAbstract:Carnosine is a dipeptide with a high concentration in mammalian skeletal muscle. It is synthesized by Carnosine synthase from the amino acids L-histidine and β-alanine, of which the latter is the rate-limiting precursor, and degraded by carnosinase. Recent studies have shown that the chronic oral ingestion of β-alanine can substantially elevate (up to 80%) the Carnosine content of human skeletal muscle. Interestingly, muscle Carnosine loading leads to improved performance in high-intensity exercise in both untrained and trained individuals. Although Carnosine is not involved in the classic adenosine triphosphate-generating metabolic pathways, this suggests an important role of the dipeptide in the homeostasis of contracting muscle cells, especially during high rates of anaerobic energy delivery. Carnosine may attenuate acidosis by acting as a pH buffer, but improved contractile performance may also be obtained by improved excitation-contraction coupling and defence against reactive oxygen species. High Carnosine concentrations are found in individuals with a high proportion of fast-twitch fibres, because these fibres are enriched with the dipeptide. Muscle Carnosine content is lower in women, declines with age and is probably lower in vegetarians, whose diets are deprived of β-alanine. Sprint-trained athletes display markedly high muscular Carnosine, but the acute effect of several weeks of training on muscle Carnosine is limited. High Carnosine levels in elite sprinters are therefore either an important genetically determined talent selection criterion or a result of slow adaptation to years of training. β-alanine is rapidly developing as a popular ergogenic nutritional supplement for athletes worldwide, and the currently available scientific literature suggests that its use is evidence based. However, many aspects of the supplement, such as the potential side effects and the mechanism of action, require additional and thorough investigation by the sports science community.
Craig Sale - One of the best experts on this subject based on the ideXlab platform.
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magnetic resonance spectroscopy as a non invasive method to quantify muscle Carnosine in humans a comprehensive validity assessment
Scientific Reports, 2020Co-Authors: Vinicius Da Eira Silva, Vitor De Salles Painelli, Samuel Katsuyuki Shinjo, Eduardo Maffud Cilli, Craig Sale, Bruno Gualano, Maria Concepcion Garcia Otaduy, Wagner Ribeiro Pereira, Guilherme Giannini ArtioliAbstract:Carnosine is a dipeptide abundantly found in human skeletal muscle, cardiac muscle and neuronal cells having numerous properties that confers performance enhancing effects, as well as a wide-range of potential therapeutic applications. A reliable and valid method for tissue Carnosine quantification is crucial for advancing the knowledge on biological processes involved with Carnosine metabolism. In this regard, proton magnetic resonance spectroscopy (1H-MRS) has been used as a non-invasive alternative to quantify Carnosine in human skeletal muscle. However, Carnosine quantification by 1H-MRS has some potential limitations that warrant a thorough experimental examination of its validity. The present investigation examined the reliability, accuracy and sensitivity for the determination of muscle Carnosine in humans using in vitro and in vivo experiments and comparing it to reference method for Carnosine quantification (high-performance liquid chromatography – HPLC). We used in vitro 1H-MRS to verify signal linearity and possible noise sources. Carnosine was determined in the m. gastrocnemius by 1H-MRS and HPLC to compare signal quality and convergent validity. 1H-MRS showed adequate discriminant validity, but limited reliability and poor agreement with a reference method. Low signal amplitude, low signal-to-noise ratio, and voxel repositioning are major sources of error.
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is proton magnetic resonance spectroscopy a valid method to quantify muscle Carnosine in humans
bioRxiv, 2019Co-Authors: Vinicius Da Eira Silva, Vitor De Salles Painelli, Samuel Katsuyuki Shinjo, Eduardo Maffud Cilli, Craig Sale, Bruno Gualano, Maria Concepcion Garcia Otaduy, Guilherme Giannini ArtioliAbstract:Abstract We aimed to examine the validity and reliability of Proton Magnetic Resonance Spectroscopy (1H-MRS) to quantify Carnosine in human muscle. Phantoms containing different concentrations of pure Carnosine, imidazole, histidine and protein (bovine serum albumin) were analyzed by 1H-MRS to verify signal linearity, and the influence of other sources of imidazole to Carnosine signal. Carnosine was determined in the m. gastrocnemius by 1H-MRS and high-performance liquid chromatography (HPLC, reference method) in muscle biopsy samples. Signal quality was compared between in vivo and in vitro assessments. Test-retest reliability was determined with (n=10) and without (n=5) voxel repositioning and re-shimming. Convergent validity (n=16) was determined by comparing Carnosine values obtained with 1H-MRS vs. HPLC. Discriminant validity (n=14) was determined by measuring Carnosine before and after β-alanine supplementation. Carnosine signal showed excellent linearity within the physiological concentration range (2.5 to 50 mmol·L−1). A clear loss of quality was shown when Carnosine was measured in vivo. Histidine and imidazole, but not protein, emitted quantifiable signals in the same chemical shift of Carnosine. 1H-MRS coefficient of variation without repositioning voxel was 6.6% (ICC=0.924) and 16.9% (ICC=0.775) with voxel repositioning. 1H-MRS was able to detect a significant increase in muscle Carnosine after β-alanine supplementation (p=0.04), but individual data analyses showed a substantial disagreement with HPLC. Comparison of 1H-MRS with HPLC showed poor convergent validity for 1H-MRS. In conclusion, 1H-MRS showed adequate discriminant validity, but limited reliability and poor agreement with a reference method. Low signal amplitude, low signal-to-noise ratio, and voxel repositioning are major sources of error. New & noteworthy Although most of the Carnosine research relies on muscle Carnosine determination by 1H-MRS, its validity remains unknown. We showed loss of signal quality and amplitude when Carnosine is measured in vivo vs. pure Carnosine, and poor test-retest reliability when voxel is repositioned. Although 1H-MRS was sensitive to detect mean group changes in muscle Carnosine, poor agreement with a reference method was shown. 1H-MRS showed poor validity, suggesting that existing Carnosine literature might need further re-examination.
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comparison between proton magnetic resonance spectroscopy and high performance liquid chromatography to quantify muscle Carnosine in humans
bioRxiv, 2019Co-Authors: Vinicius Da Eira Silva, Vitor De Salles Painelli, Samuel Katsuyuki Shinjo, Eduardo Maffud Cilli, Craig Sale, Bruno Gualano, Maria Concepcion Garcia Otaduy, Guilherme Giannini ArtioliAbstract:Proton magnetic resonance spectroscopy (1H-MRS) has been used as a non-invasive alternative to quantify Carnosine in human muscle. It is unclear whether 1H-MRS is a valid and reliable method. 1H-MRS validity and reliability was examined in a series of in vitro and in vivo studies. In the in vitro study, phantoms containing different concentrations of Carnosine, imidazole, histidine and bovine serum albumin (BSA) were submitted to 1H-MRS to verify: 1) signal linearity; 2) whether other sources of imidazole could contribute to Carnosine signal. In the in vivo study, Carnosine was determined in the m. gastrocnemius by 1H-MRS and by high-performance liquid chromatography (HPLC, a reference method) in muscle biopsy samples from 16 young men. Test-retest reliability was determined with (n=10) and without (n=5) voxel repositioning and re-shimming. Convergent validity (n=16) was determined by comparing Carnosine values obtained with 1H-MRS vs. HPLC. Discriminant validity (n=14) was determined by measuring Carnosine before and after 4 weeks of {beta}-alanine supplementation. In vitro Carnosine signal showed excellent linearity (Pearson correlation: r=0.999). Histidine and imidazole, but not BSA, emitted quantifiable signals in the same chemical shift of Carnosine. A clear loss in signal quality was shown in the signal obtained in vivo. 1H-MRS coefficient of variation without repositioning voxel was 6.6% and increased to 16.9% with voxel repositioning. 1H-MRS was able to detect a significant increase in muscle Carnosine after {beta}-alanine supplementation, both a substantial disagreement with HPLC was shown. 1H-MRS showed adequate discriminant validity, but limited reliability and poor agreement with the reference method.nnKey points summaryO_LIAlthough proton magnetic resonance spectroscopy (1H-MRS) was developed to quantify Carnosine in human muscle as a non-invasive alternative method to high-performance liquid chromatography (HPLC) in extracts from human muscle biopsy, a thorough assessment of 1H-MRS validity is lacking. Thus, we examined signal linearity in vitro, matrix effect in vivo, as well as reliability, convergent validity and discriminant validity of in vivo 1H-MRS for the determination of Carnosine in human muscle using in vitro and in vivo experiments.nC_LIO_LIAn excellent 1H-MRS in vitro signal linearity was shown for Carnosine across the physiological range, although broadening and signal losses were observed when 1H-MRS was performed in vivo.nC_LIO_LIFree histidine and imidazole also emitted quantifiable signals at the same chemical shift of Carnosine, which could constitute a source of error in Carnosine quantification. Large protein (e.g., bovine serum albumin) did not emitted signal, thereby indicating they do not constitute a source of error.nC_LIO_LI1H-MRS can detect and quantify muscle Carnosine in vivo, and it is sensitive to detect increases in muscle Carnosine brought about by {beta}-alanine supplementation.nC_LIO_LIDespite being sensitivity, 1H-MRS showed poor test-retest reliability, especially due to voxel repositioning and re-shimming.nC_LIO_LIA poor agreement was shown for muscle Carnosine determination between 1H-MRS and HPLC performed in muscle biopsies taken at the closest possible site (m. gastrocnemius).nC_LIO_LICaution should be exercised when interpreting muscle Carnosine data obtained with 1H-MRS.nC_LI
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Carnosine in health and disease
European journal of sport science, 2018Co-Authors: Guilherme Giannini Artioli, Craig Sale, Rebecca Louise JonesAbstract:Carnosine was originally discovered in skeletal muscle, where it exists in larger amounts than in other tissues. The majority of research into the physiological roles of Carnosine have been conducted on skeletal muscle. Given this and the potential for muscle Carnosine content to be increased with supplementation, there is now a large body of research examining the ergogenic effects (or otherwise) of Carnosine. More recent research, however, points towards a potential for Carnosine to exert a wider range of physiological effects in other tissues, including the brain, heart, pancreas, kidney and cancer cells. Taken together, this is suggestive of a potential for Carnosine to have therapeutic benefits in health and disease, although this is by no means without complication. Herein, we will provide a review of the current literature relating to the potential therapeutic effects of Carnosine in health and disease.
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Effect of beta-alanine supplementation on muscle Carnosine concentrations and exercise performance
Amino Acids, 2010Co-Authors: Craig Sale, Bryan Saunders, Roger C. HarrisAbstract:High-intensity exercise results in reduced substrate levels and accumulation of metabolites in the skeletal muscle. The accumulation of these metabolites (e.g. ADP, Pi and H^+) can have deleterious effects on skeletal muscle function and force generation, thus contributing to fatigue. Clearly this is a challenge to sport and exercise performance and, as such, any intervention capable of reducing the negative impact of these metabolites would be of use. Carnosine (β-alanyl- l -histidine) is a cytoplasmic dipeptide found in high concentrations in the skeletal muscle of both vertebrates and non-vertebrates and is formed by bonding histidine and β-alanine in a reaction catalysed by Carnosine synthase. Due to the pKa of its imidazole ring (6.83) and its location within skeletal muscle, Carnosine has a key role to play in intracellular pH buffering over the physiological pH range, although other physiological roles for Carnosine have also been suggested. The concentration of histidine in muscle and plasma is high relative to its K _m with muscle Carnosine synthase, whereas β-alanine exists in low concentration in muscle and has a higher K _m with muscle Carnosine synthase, which indicates that it is the availability of β-alanine that is limiting to the synthesis of Carnosine in skeletal muscle. Thus, the elevation of muscle Carnosine concentrations through the dietary intake of Carnosine, or chemically related dipeptides that release β-alanine on absorption, or supplementation with β-alanine directly could provide a method of increasing intracellular buffering capacity during exercise, which could provide a means of increasing high-intensity exercise capacity and performance. This paper reviews the available evidence relating to the effects of β-alanine supplementation on muscle Carnosine synthesis and the subsequent effects on exercise performance. In addition, the effects of training, with or without β-alanine supplementation, on muscle Carnosine concentrations are also reviewed.