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Alfa ketoglutarate (AKG) inhibit osteoporoses development in postmenopausal women
... Thus, AKG and its derivatives can play a role as a Fe 2+ absorption enhancer both in rapidly growing animals and humans with Fe 2+ insufficiency (Dąbek et al., 2005). Furthermore, AKG, ascor-bate and Fe 2+ steer hydroxylation of peptide-bound proline to hydroxyproline via prolyl hydrolase, increasing the conversion of pro-collagen to collagen and bone matrix formation (Tocaj et al., 2003). Therefore, AKG is an important source of amino acids for collagen synthesis in the cell and organism. ...
... The similar influence of AKG administration on bone tissue was also observed in studies performed on humans (Tocaj et al., 2003;Fayh et al., 2007). It can facilitate muscle protein synthesis in post-operative patients (Wernerman et al., 1990), to improve amino acid metabolism in haemo-dialysed patients (Riedel et al., 1996), and to accelerate the transport of organic anions in the kidneys (Welborn et al., 1998), when AKG was given as a supplement. ...
... In clinical studies on septic, traumatic or surgical patients, AKG has been found to display beneficial effects by improving the body weight gain, nitrogen balance. A recent study has shown the potential usefulness of AKG treatment in preserving bone mass as well as lowering bone turnover in post-menopausal women (Tocaj et al., 2003). Results suggest a link between enteral AKG and an increase in oestrogen levels. ...
Alpha-ketoglutarate (AKG) is a key molecule in the Krebs cycle determining the overall rate of the citric acid cycle of the organism. It is a nitrogen scavenger and a source of glutamate and glutamine that stimulates protein synthesis and inhibits protein degradation in muscles. AKG as a precursor of glutamate and glutamine is a central metabolic fuel for cells of the gastrointestinal tract as well. AKG can decrease protein catabolism and increase protein synthesis to enhance bone tissue formation in the skeletal muscles and can be used in clinical applications. In addition to these health benefits, a recent study has shown that AKG can extend the lifespan of adult Caenorhabditis elegans by inhibiting ATP synthase and TOR. AKG not only extends lifespan, but also delays age-related disease. In this review, we will summarize the advances in AKG research field, in the content of its physiological functions and applications.
... There is preliminary evidence to show that the dietary supplementation of 2-oxoglutarate (2-Ox) counteracts the bone loss observed in ovariectomized or gastrectomized rats and in postmenopausal women [16][17][18]. 2-Ox is a precursor of glutamine that serves as an oxidative fuel for rapidly dividing cells such as lymphocytes and fibroblasts [19][20][21]. Glutamine plays an important role in the interorgan flow of nitrogen (in ammonia genesis) and carbon between carbohydrates and proteins [20]. ...
... However, the decrease in calcium absorption, caused by hypochlorhydria, has been posed as a possible mechanism by which PPIs increase the fracture risk [9]. Furthermore, it was assumed that some of the changes caused by omeprazole could be abolished by 2-oxoglutaric acid, which, in previous animal and human studies, has shown a protective effect on bones loss caused by gastrectomy, fundectomy, or inhibited osteoporosis development in postmenopausal women [16,18,23,35]. Moreover, these surgeries or hormonal disorders can be related to decreased calcium absorption [34]. ...
... The 2-oxoglutaric acid also had a protective effect on bones loss caused by the development of osteoporosis in postmenopausal women and ovariectomized rats and in rats with established osteopenia [17,18,35,44]. Moreover, 2-Ox showed a protective effect on the body, stomach, liver, and spleen weights of piglets after fundectomy and on gastrectomy-evoked impairment of the calvaria and trabecular bone of rats [16,45]. ...
Objective:
Proton-pump inhibitors, such as omeprazole, are widely used in the prevention and treatment of gastroesophageal diseases. However, an association between proton-pump inhibitors and the increased risk of bone fractures has been observed, especially in patients treated for extended periods. Conversely, 2-oxoglutarate, a precursor of hydroxyproline, the most abundant amino acid in bone collagen, counteracts the bone loss. The aim of the present study was to elucidate the influence of omeprazole on bone and investigate whether dietary 2-oxoglutarate supplementation could prevent the effects of omeprazole.
Methods:
Eighteen male Sprague-Dawley rats were used. Rats received omeprazole in the diet and 2-oxoglutarate in the drinking water. Body and organ weights and serum concentrations of cholecystokinin and gastrin were measured. The femurs, tibias, and calvarias were collected. Histomorphometric analysis of bone and cartilage tissues was conducted. Bone densitometric and peripheral quantitative computed tomographic analyses of the femur and tibia were performed.
Results:
Omeprazole decreased the femur and tibia weights, the mechanical properties of the femur, the volumetric bone density and content, the trabecular and cortical bone mineral content, the total, trabecular, and cortical bone areas, the mean cortical thickness, and the periosteal circumference of the femur. Omeprazole had a minor effect on the examined bone morphology and exerted negligible effects on the cartilage. 2-Oxoglutarate lowered the gastrin concentration.
Conclusions:
Omeprazole treatment exerts its effects mostly on bone mineralization and cancellous bone, adversely affecting bone properties. This adverse effect of omeprazole was not markedly abolished by 2-oxoglutaric acid, which acted as an anti-hypergastrinemic agent.
... The main components of collagen are hydroxyproline and proline, which are synthesized in the gastrointestinal tract from a-ketoglutarate (AKG), proline in turn being converted into hydroxyproline in the presence of vitamin C and Fe 2' [28]. There is preliminary evidence to show that dietary AKG counteracts the bone loss observed in ovariectomized rats [29] and in postmenopausal women [30]. The purpose of this study was to investigate whether AKG can counteract the Gx-induced bone impairment in rats. ...
... Recent observations suggest that dietary supplementation with AKG has unexpected effects on growth and performance [35,36], including stimulatory effects on bone [29,30,37]. The purpose of this study was to evaluate the effect of dietary AKG on Gx-evoked bone impairment in rats. ...
... The results of our study indicate that dietary AKG is capable of counteracting the Gx-evoked impairment of calvarial and trabecular bone in rats (but not the loss of femoral/tibial BMC and BMD, representing mainly changes in cortical bone and cortical bone minerals). Our results are in line with earlier observations, suggesting that AKG counteracts the development of osteopenia in ovariectomized rats [29] and in postmenopausal women [30]. Our results, moreover, suggest that AKG has an effect on trabecular and not on cortical bone and that the calcium content of cortical bone is not affected. ...
Surgical removal of the stomach (gastrectomy, Gx) leads to osteopenia in animals and in humans. In the rat, Gx adversely affects calvaria and trabecular bone. alpha-Ketoglutarate (AKG) is a precursor of hydroxyproline--the most abundant amino acid in bone collagen. The purpose of this study was to investigate the effects of dietary AKG on Gx-induced osteopenia.
Twenty female Sprague-Dawley rats were subjected to Gx and divided between two groups: Gx+AKG in the drinking water and Gx+Vehicle (i.e. drinking water without AKG). Another 20 rats were sham-operated and divided between two groups: Sham+AKG and Sham+Vehicle. The daily dose of AKG was 0.43 g per 100 g rat. All the rats were killed 8 weeks later and the calvariae, femora and tibiae were collected. The integrity of the calvariae was analysed planimetrically, following transillumination and photography. The bone mineral content (BMC) and bone mineral density (BMD) were measured in the right femorae and tibiae (bone densitometry), leaving the left femorae and tibiae to be analysed histomorphometrically (measurement of trabecular bone volume and trabecular fractal dimension).
Gx caused calvarial bone degradation, reduced trabecular bone (femur and tibia) and impaired trabecular architecture. In addition, Gx lowered the femoral/tibial BMC and BMD (mainly cortical bone). Dietary AKG counteracted the Gx-evoked impairment of calvaria and trabecular bone but failed to affect the BMC and the BMD in either sham- operated or Gx rats.
Gx resulted in loss of calvarial, trabecular and cortical bone in the rat. AKG counteracted the effect of Gx on calvaria and trabecular bone but not on cortical bone.
... a-Ketoglutarate (AKG) has been given to pigs, sheep and turkeys as well as humans with effects on the skeletal system and protein synthesis (Hammarqvist et al., 1991;Tocaj et al., 2003;Harrison et al., 2004;Kowalik et al., 2005b;Tatara et al., 2005aTatara et al., , 2007. Endogenous AKG is generated in the tricarboxylic acid (TCA)-cycle taking place in the mitochondrial matrix and by the deamination of both glutamine and glutamate. ...
... Despite the low portal uptake of AKG and its short systemic half-life ($5 min) (Dabek et al., 2005), AKG increases bone mineral density and mechanical strength, when given orally to turkeys , pigs (Kowalik et al., 2005b) and lambs (Harrison et al., 2004;Tatara et al., 2007). Whilst the question of whether AKG supplements, given postnatally, have a permanent effect on bone mineralisation in pigs has yet to been resolved, a recent study has shown the potential usefulness of AKG treatment in preserving bone mass as well as lowering bone turnover in post-menopausal women (Tocaj et al., 2003), results which suggest a link between enteral AKG and an increase in oestrogen levels. ...
The long-term effect of alpha-ketoglutarate (AKG) given for 21-24 days post-partum, on the skeleton of commercial pigs, was investigated. In experiment A, 12 pigs were given AKG [0.1 g/kg of body weight (b.w.) per day per os], while 12 controls were administered vehicle. At day 169, the left and right femur, humerus and sixth ribs were analysed for mechanical and geometrical properties and quantitative computed tomography. In experiment B, 32 piglets were divided equally into an AKG group (0.3 g/kg of b.w. per day) or a control group. Blood, taken at days 24 and 53 was analysed for plasma 17 beta-oestradiol. The main bone effect of AKG was to increase bone length in the sixth rib (7.3%, p < 0.01), ultimate strength (23%, p < 0.05), Young s modulus (52%, p < 0.001) and maximum elastic strength (31%, p = 0.056) compared with controls. In both experiments, AKG preferentially increased the growth of female piglets, whilst for male piglets AKG had the opposite effect. In addition, AKG elevated plasma 17 beta-oestradiol levels compared to those of controls at the end of the period of treatment (20%, p = 0.002). It is concluded that AKG has long-term effects on rib properties when given early in postnatal life whilst it elevates plasma 17 beta-oestradiol levels only so long as it is being administered.
... However, metabolites of digestion and compounds synthesized in the intestine can be very important factors in the synthesis of collagen [13]. Indeed, digestive processes are influenced by enteral alpha-ketoglutarate (AKG), which acts as an energy donor and as a substrate for the synthesis of amino acids (AA), principally proline [31], where improved proline synthesis, regulated by AKG, ascorbate, and Fe 2+ , leads to increased collagen formation. ...
... Due to increased proline synthesis and its further hydroxylation to hydroxyproline, the major constituent of collagen, enteral AKG administration is believed to enhance bone tissue formation. Moreover, the conversion of pro-collagen to collagen is dependent on the hydroxylation of peptide-bound proline to hydroxyproline via prolyl hydrolase that is regulated by AKG, ascorbate, and Fe 2+ [31]. In contrast to the enteral effect of AKG, oral administration of glutamate or glutamine results in their metabolization to CO 2 during their first pass through the enterocytes [27]. ...
This study has investigated the long-term effect on skeletal development of a short postnatal period of oral alpha-ketoglutarate (AKG) administration, a compound known to regulate the synthesis of proline, which in turn is important for collagen production. Male lambs born to Shropshire ewes were used in this study. Lambs were randomly assigned to either an AKG-treated group or a control group receiving an equal volume of distilled water. AKG-treated lambs received 0.1 g/kg body weight orally from the first 14 days of postnatal life. Lambs were slaughtered at approximately 130 day of life and a body weight of 43-49 kg. Plasma samples, collected from lambs at days 14 and 130, were analyzed for IGF-1 concentration using sheep-specific RIA kits. Bone development was determined on the femur in terms of geometrical and mechanical properties and quantitative computed tomography (QCT). Trabecular bone density, cortical bone density, and the mechanical properties of the bones were significantly higher for AKG-treated compared with control lambs. However, neither plasma IGF-1 concentration nor the geometrical properties of the bones were significantly influenced by AKG treatment. It is concluded that early postnatal treatment of lambs with AKG positively affects bone strength, an effect that does not appear to be mediated by an increased plasma IGF-1 concentration.
... Overall, the results of these studies show a beneficial effect of AKG on bone metabolism, justifying its possible application in the treatment of bone loss. For example, positive influence of AKG administration on the skeletal system has been observed in stomach-removed rats (Dobrowolski et al. 2008), in ovariectomized rats (Radzki et al. 2002Bieńko et al. 2003), and in postmenopausal women (Tocaj et al. 2003). Future studies should focus on the suitable additive amount of AKG in different stages of different animals. ...
l-Glutamine is a nutritionally semi-essential amino acid for proper growth in most cells and tissues, and plays an important role in the determination and guarding of the normal metabolic processes of the cells. With the help of transport systems, extracellular l-glutamine crosses the plasma membrane and is converted into alpha-ketoglutarate (AKG) through two pathways, namely, the glutaminase (GLS) I and II pathway. Reversely, AKG can be converted into glutamine by glutamate dehydrogenase (GDH) and glutamine synthetase (GS), or be converted into CO2 via the tricarboxylic acid (TCA) cycle and provide energy for the cells. Different steps of glutamine metabolism (the glutamine-AKG axis) are regulated by several factors, rendering the glutamine-AKG axis a potential target to counteract cancer. Moreover, intracellular glutamine plays an important role in cellular homeostasis not only as a precursor for protein synthesis, but also for its nutritional roles in cell growth, lipid metabolism, insulin secretion, and so on. The main objective of this review is to highlight the metabolic pathways of glutamine to AKG, with special emphasis on nutritional and therapeutic use of glutamine-AKG axis to improve the health and well-being of animals and humans.
... Metabolization of glutamate post mortem has been documented by Yi et al. (2015). Glutamate probably metabolizes to 2-oxoglutarate to have its desirable effect on redox states, and 2-oxoglutarate, as a food additive, has a different health image from glutamate (Tocaj et al., 2003). ...
... reduced and eradicated destructive effects of gastrectomy on bone and cartilage collagen in rats) (24). Moreover, AKG treatment cured osteoporosis in humans (25,26). Radzki et al. (28) clearly showed that the administration of enteral AKG decreased body weight and reduced both plasma LDL and cholesterol concentrations in cholesteremic rats and humans. ...
The fact that men and women are living longer than they have ever done before is something in which we can all rejoice. However, the process of ageing is associated with changes in skeletal, muscular, gastrointestinal, neural hormonal and metabolic processes that seriously affect an individual's performance and quality of life. Indeed, such changes can be contributory to a loss of independence in the elderly. This state-of-the art address highlights the main changes found to occur with ageing whilst simultaneously reporting findings of in vivo and in vitro studies designed to elucidate the potential of the Krebs cycle intermediate - alpha-ketoglutaric acid (AKG) in protecting elderly body systems from failing and degradation. The topics of paramount importance include impaired bone structure and strength, amino acid and mineral absorption, muscle performance, as well as highlighting the role of Krebs cycle intermediates in the debilitating changes that occur with end-stage renal failure and the regulation of the lipid metabolism. Finally, focus will be given to the role of 2-oxoglutarate as a potent protective factor in connection with the development of malignant cells in the body.
Osteoclasts (OCs) have been well-known involved in the exacerbation of bone-related diseases. However, the role of metabolites on osteoclastogenesis has not been well characterized. Herein, we found osteoclastogenesis was negatively regulated by α-ketoglutarate (αKG) in vitro and in vivo (C57BL/6 mouse). Kinetic transcriptome analysis revealed the upregulation of solute carrier family 7 member 11 (Slc7a11), a subunit of the cysteine/glutamate antiporter, as well as the downregulation of typical OC maker genes through αKG treatment. Given that Slc7a11 could control ROS level through glutathione import, we measured intracellular ROS, then RANKL-induced ROS production was inhibited by αKG. Notably, we highlight that αKG plays an epigenetic co-factor at the Slc7a11 promoter by demethylating repressive histone H3K9 methylation and simultaneously increasing the nuclear factor erythroid 2-related factor (Nrf2) binding, a critical transcription factor through chromatin immunoprecipitation (ChIP) analysis. Together, we suggested that αKG could be a therapeutic strategy for OC activated diseases.
The a-ketoglutarate has a positive effects on phosphorus metabolism and bone synthesis and is expected to decrease the phosphorus requirement of fish, so as to reduce phosphorus pollution in aquaculture. The effects of AKG supplementation in low phosphorous (P) diets on the growth, P metabolism and skeletal development of juvenile songpu mirror carp (Cyprinus carpio) were studied. Triplicate groups of mirror carp (6.67 ± 0.08 g) were fed diets containing a total phosphorous of 0.96% (adequate P, AP) and 0.82% (low P, LP), with graded levels 0 (LP-0), 0.2% (LP-0.2), 0.4% (LP-0.4), 0.6% (LP-0.6), 0.8% (LP-0.8) and 1.0% (LP-1.0) of AKG added to diets; fish were fed to satiation for 8 weeks. The results are as follows: Compared with the AP group, the weight gain rate (WGR) and the specific growth rate (SGR) were significantly lower and the feed coefficient rate (FCR) was significantly higher (P < 0.05); the content of crude lipid (EE) was significantly higher; the contents of Ca and P of the vertebra were significantly decreased (P < 0.05); and the activity of alkaline phosphatase (ALP) in plasma were significantly decreased in the LP-0 group (P < 0.05). Compared with the LP-0 group, the WGR, SGR, PER, HI, CF, content of P in the vertebra and P deposition rate (PDR)were significantly increased; the FCR was significantly decreased in the LP-0.6 group (P < 0.05); the ALP was significantly increased in the AKG supplementation groups (P < 0.05); and the content of collagen in the vertebra was significantly increased with the 0.6–1.0% AKG supplementation (P < 0.05). The expression of NaPi-IIb mRNA in the foregut, midgut and hindgut, kidney and vertebra were similar between the AP and LP-0 groups (P > 0.05), but the expression of NaPi-IIb mRNA in the foregut and hindgut were significantly decreased in the AKG supplementation group (P < 0.05); and the IGF-I mRNA significantly increased by 0.4–1.0% in the AKG supplementation groups (P < 0.05). This study confirmed that the supplementation of AKG can promote growth performance, P metabolism, and the synthesis of collagen in vertebra.
The aim of this study was to determine the influence of alpha-ketoglutarate (AKG) on volumetric bone density, geometrical and mechanical properties of femur and tibia in farm turkeys. All animals were kept under standard rearing conditions with constant access to water and appropriate feed, supplied in accordance with the stage of production cycle. Bone samples were collected 14 weeks after beginning of the experiment. To the first group belonged control turkeys. The second group of animals consisted of turkeys that were administered AKG from the 22nd to 110th d of life. Using Quantitative Computed Tomography (QCT) method, volumetric bone density of femur and tibia were estimated for trabecular and cortical bone. Both the mechanical and geometrical properties of femur and tibia were assessed according to Ferretti's method. The obtained results indicate positive influence of enterai AKG administration on skeletal system quality in turkeys.
The aim of this study was to estimate an influence of alpha-ketoglutarate (AKG) on volumetric bone density and geometrical and mechanical properties of the humerus in farm turkeys. All birds were kept under standard rearing conditions with constant access to water and appropriate feed, supplied in accordance with the stage of production cycle. Bone samples were collected 14 weeks after beginning of the experiment. To the first group belonged the control turkeys. The second group of animals consisted of turkeys that were treated with AKG from the 22nd to 110th d of life. Using Quantitative Computed Tomography (QCT) method, volumetric bone density of the cortical bone in the humerus was estimated. Both the mechanical and geometrical properties of the bone were assessed according to Ferretti method. The obtained results showed anabolic influence of enteral AKG administration on cortical bone density, geometrical properties and mechanical endurance of the humerus. Moreover, the humerus in turkey may be utilised as a model of cortical bone for further investigations of factors conditioning skeletal homeostasis.
2-Oxoglutaric acid (2-Ox), a precursor to hydroxyproline - the most abundant amino acid in bone collagen, exerts protective effects on bone development during different stages of organism development; however, little is known about the action of 2-Ox on cartilage. The aim of the present study was to elucidate the influence of dietary 2-Ox supplementation on the growth plate, articular cartilage and bone of growing rats. A total of twelve male Sprague-Dawley rats were used in the study. Half of the rats received 2-oxoglutarate at a dose of 0·75 g/kg body weight per d in their drinking-water. Body and organ weights were measured. Histomorphometric analyses of the cartilage and bone tissue of the femora and tibiae were conducted, as well as bone densitometry and peripheral quantitative computed tomography (pQCT). Rats receiving 2-Ox had an increased body mass (P< 0·001) and absolute liver weight (P= 0·031). Femoral length (P= 0·045) and bone mineral density (P= 0·014), overall thickness of growth plate (femur P= 0·036 and tibia P= 0·026) and the thickness of femoral articular cartilage (P< 0·001) were also increased. 2-Ox administration had no effect on the mechanical properties or on any of the measured pQCT parameters for both bones analysed. There were also no significant differences in histomorphometric parameters of tibial articular cartilage and autofluorescence of femoral and tibial growth plate cartilage. Dietary supplementation with 2-Ox to growing rats exerts its effects mainly on cartilage tissue, having only a slight influence on bone. The effect of 2-Ox administration was selective, depending on the particular bone and type of cartilage analysed.
The purpose of this study was to determine the influence of daily administration of alpha-ketoglutarate (AKG) on mineral density and geometrical, mechanical and morphometrical parameters of the femur during postnatal life in piglets. The experiment was conducted from the 1 st d of neonatal life to the 70 th d of postnatal life. Experimental piglets were given AKG in the dosage of 0.4 g/kg b.w./d per os, while control piglets were treated per os with physiological saline in the dosage of 2 ml/kg b.w./ d. The piglets from both groups were divided into 6 age subgroups, namely 3, 14, 21, 35, 56 and 70 d. At the end of the experiment the animals were euthanised and right femora were isolated and frozen at –25 o C until further analyses. Using quantitative computed tomography (QCT) method, volumetric bone density of the cortical bone compartment was estimated. Moreover, geometrical, mechanical and morphometrical parameters of the bones were determined. The obtained results indicate that daily administration of AKG increased the cortical bone density, geometrical and mechanical properties of the femur and whole bone morphometry.
The objective of the study was to evaluate the effect of denervation and alpha-ketoglutarate (AKG) administration on the development of osteopenia in the turkey radius. At 22 d of age, all turkeys were subjected to neurectomy of the right radius. Control turkeys were given a saline solution into the crop each day for 97 d. Experimental turkeys were given 0.4 g of AKG/kg of BW into the crop each day. After 98 d, BW was not affected by the AKG treatment. Volumetric bone mineral density of the radius was measured by quantitative computed tomography. Mechanical properties were tested using a 3-point bending test. Cross-sectional area, second moment of inertia, and mean relative wall thickness were measured as well. Amino acid concentrations were assessed with the use of ion-exchange chromatography. Denervation had a negative effect on all bone characteristics that were measured except bone length. The AKG had a positive effect on all bone characteristics except bone length. Plasma concentrations of proline and leucine were increased by AKG, whereas concentrations of taurine and glutamine were decreased. The turkey radius appears to be a good model for studying osteopenia because its development can be affected by treatments such as denervation and AKG administration.
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