Dietary α-ketoglutarate reduces gastrectomy-evoked loss of calvaria and trabecular bone in female rats

Dobrowolski, Piotr; Piersiak, Tomasz; Surve, Vikas; Kruszewska, D; Gawron, Antoni; Pacuska, Paulina; Håkanson, R.; Pierzynowski, Stefan

doi:10.1080/00365520701824951

Cited by 28 publications

(50 citation statements)

References 35 publications

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“…Several studies have shown that 2-oxoglutaric acid (2-Ox), the precursor to proline, hydroxyproline, glutamate, arginine and asparagine, has an effect on the growth of both human and animal bones. Dietary supplementation with 2-Ox also counteracted the bone loss observed in gastrectomised, fundectomised and ovariectomised animals, as well as in post-menopausal women ( 5 , 6 , 8 – 14 ) . 2-Ox affects the synthesis of amino acids and proteins, as well as improving their absorption from the gut ( 15 ) .…”

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confidence: 88%

The effect of dietary administration of 2-oxoglutaric acid on the cartilage and bone of growing rats

et al. 2013

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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 (P¼ 0·031). Femoral length (P¼ 0·045) and bone mineral density (P¼ 0·014), overall thickness of growth plate (femur P¼0·036 and tibia P¼0·026) 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.

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confidence: 88%

The effect of dietary administration of 2-oxoglutaric acid on the cartilage and bone of growing rats

et al. 2013

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“…Due to its broad roles in multiple biological processes, AKG has been a subject of interest for researchers in various fields [16]. AKG also influences several age-related processes, including stem cell proliferation [17,18] and osteoporosis [19]. To study its role in mammalian aging, animals received sustained CaAKG treatment starting at 18 months of age and determined its effect on 4 survival, as well as the onset of frailty.…”

Section: Introductionmentioning

confidence: 99%

Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice

Shahmirzadi

Edgar

Liao

et al. 2019

Preprint

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The decline in early life mortality since the 1950s has resulted in dramatic demographic shift towards aged population. Aging manifests as a decline in health, multiple organ dysfunction and increased vulnerability to diseases, which degrades quality of life. A verity of genetic and pharmacological interventions, mostly from non-vertebrate models, have been identified that can enhance lifespan. Whether these interventions extend healthspan, the disease free and functional period of life, has only sometimes been tested and is often a matter of debate. Human aging indices have been developed to assess elements of functional decline with aging (e.g. sarcopenia, cognitive function). However, corresponding comprehensive indices in mice are seldom applied to aging studies. To probe the relationship between healthspan and lifespan extension in mammals, we performed a series of longitudinal, clinically-relevant healthspan measurements.Metabolism and aging are tightly connected and specific perturbations of nutrient-sensing pathways can enhance longevity in laboratory animals. Here we show that alpha-ketoglutarate (delivered in the form of a Calcium salt, CaAKG), a key metabolite in tricarboxylic (TCA) cycle that is reported to extend lifespan in worms , can significantly extend lifespan and healthspan in mice. AKG is involved in various fundamental processes including collagen synthesis and epigenetic changes. Due to its broad roles in multiple biological processes, AKG has been a subject of interest for researchers in various fields. AKG also influences several age-related processes, including stem cell proliferation and osteoporosis. To determine its role in mammalian aging, we administered CaAKG in 18 months old mice and determined its effect on the onset of frailty and survival, discovering that the metabolite promotes longer, healthier life associated with a decrease in levels of inflammatory factors. Interestingly the reduction in frailty was more dramatic than the increase in lifespan, leading us to propose that CaAKG compresses morbidity.

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“…Differences between letters mean significant differences with P < 0.05. appears to be even more effective in preserving bone structure and mineralization in GCs induced rather than in gastrectomy-induced osteopenia, since there was no improvement in femoral and tibial BMD and BMC of gastrectomized rats receiving even higher dose of 2-Ox in our previous study. 21 The ability to withstand the mechanical forces acting upon a bone and to resist fractures is related to its geometry, mineralization, and quality of structural components such as shape, microarchitecture of trabecular bone, the turnover, collagen and cells regularly spaced throughout the mineralized matrix. 19,28 There are several possible mechanisms of GIO presented in literature: inhibition of bone formation by suppression of genesis and activity of osteoblasts with accelerated osteocyte and osteoblasts apoptosis as well as acceleration of bone resorption by extension of osteoclasts life span.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, for the trabecular bone, the number of osseous lacunae per square millimeter of trabeculae, the total area of osseous lacunae per square millimeter of trabeculae, and the mean cross-sectional area of osseous lacunae were assessed as previously described. 18,21,23 Blood sample collection and analysis Blood samples collection and analysis were carried out as described previously. 15,24 Briefly, blood of not fasted piglets was collected from subclavian vein.…”

Section: Histomorphometrymentioning

confidence: 99%

Dietary 2-oxoglutarate prevents bone loss caused by neonatal treatment with maximal dexamethasone dose

Dobrowolski

Tomaszewska

Muszyński

et al. 2017

Exp Biol Med (Maywood)

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Synthetic glucocorticoids (GCs) are widely used in the variety of dosages for treatment of premature infants with chronic lung disease, respiratory distress syndrome, allergies, asthma, and other inflammatory and autoimmune conditions. Yet, adverse effects such as glucocorticoid-induced osteoporosis and growth retardation are recognized. Conversely, 2-oxoglutarate (2-Ox), a precursor of glutamine, glutamate, and collagen amino acids, exerts protective effects on bone development. Our aim was to elucidate the effect of dietary administered 2-Ox on bone loss caused by neonatal treatment with clinically relevant maximal therapeutic dexamethasone (Dex) dose. Long bones of neonatal female piglets receiving Dex, Dex+2-Ox, or untreated were examined through measurements of mechanical properties, density, mineralization, geometry, histomorphometry, and histology. Selected hormones, bone turnover, and growth markers were also analyzed. Neonatal administration of clinically relevant maximal dose of Dex alone led to over 30% decrease in bone mass and the ultimate strength ( P < 0.001 for all). The length (13 and 7% for femur and humerus, respectively) and other geometrical parameters (13-45%) decreased compared to the control ( P < 0.001 for all). Dex impaired bone growth and caused hormonal imbalance. Dietary 2-Ox prevented Dex influence and vast majority of assessed bone parameters were restored almost to the control level. Piglets receiving 2-Ox had heavier, denser, and stronger bones; higher levels of growth hormone and osteocalcin concentration; and preserved microarchitecture of trabecular bone compared to the Dex group. 2-Ox administered postnatally had a potential to maintain bone structure of animals simultaneously treated with maximal therapeutic doses of Dex, which, in our opinion, may open up a new opportunity in developing combined treatment for children treated with GCs. Impact statement The present study has showed, for the first time, that dietary 2-oxoglutarate (2-Ox) administered postnatally has a potential to improve/maintain bone structure of animals simultaneously treated with maximal therapeutic doses of dexamethasone (Dex). It may open the new direction in searching and developing combined treatment for children treated with glucocorticoids (GCs) since growing group of children is exposed to synthetic GCs and adverse effects such as glucocorticoid-induced osteoporosis and growth retardation are recognized. Currently proposed combined therapies have numerous side effects. Thus, this study proposed a new direction in combined therapies utilizing dietary supplementation with glutamine derivative. Impairment caused by Dex in presented long bones animal model was prevented by dietary supplementation with 2-Ox and vast majority of assessed bone parameters were restored almost to the control level. These results support previous thesis on the regulatory mechanism of nutrient utilization regulated by glutamine derivatives and enrich the nutritional science.

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Dietary α-ketoglutarate reduces gastrectomy-evoked loss of calvaria and trabecular bone in female rats

Abstract: 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.

Cited by 28 publications

References 35 publications

The effect of dietary administration of 2-oxoglutaric acid on the cartilage and bone of growing rats

The effect of dietary administration of 2-oxoglutaric acid on the cartilage and bone of growing rats

Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice

Dietary 2-oxoglutarate prevents bone loss caused by neonatal treatment with maximal dexamethasone dose

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