Carnosine protects stimulus-secretion coupling through prevention of protein carbonyl adduction events in cells under metabolic stress

Lavilla, Charlie; Billacura, Merell P.; Hanna, Katie; Boocock, David J.; Coveney, Clare; Miles, Amanda K.; Foulds, Gemma A.; Murphy, Alice; Tan, Arnold; Jackisch, Laura; Sayers, Sophie; Caton, Paul; Doig, Craig; McTernan, Philip; Colombo, Sergio; Sale, Craig; Turner, Martha

doi:10.1016/j.freeradbiomed.2021.08.233

Cited by 12 publications

(11 citation statements)

References 74 publications

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“…By buffering these metal ions, carnosine may also act as an AGE inhibitor, preventing AGE formation and glycoxidation ( 36 , 84 ). Indeed, carnosine has recently been shown to prevent 65–90% of AGE and advanced lipid end product (ALE) protein adduct formation in skeletal muscle cells under metabolic stress ( 85 ), suggesting the potential for a similar role in cardiomyocytes.…”

Section: Physiological Roles Of Carnosine In Myocardial Tissuementioning

confidence: 99%

Physiological Roles of Carnosine in Myocardial Function and Health

Creighton

Gonçalves

Artioli

et al. 2022

Advances in Nutrition

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Carnosine is a pleiotropic histidine-containing dipeptide synthesized from β-alanine and l-histidine, with the intact dipeptide and constituent amino acids being available from the diet. The therapeutic application of carnosine in myocardial tissue is promising, with carnosine playing a potentially beneficial role in both healthy and diseased myocardial models. This narrative review discusses the role of carnosine in myocardial function and health, including an overview of the metabolic pathway of carnosine in the myocardial tissue, the roles carnosine may play in the myocardium, and a critical analysis of the literature, focusing on the effect of exogenous carnosine and its precursors on myocardial function. By so doing, we aim to identify current gaps in the literature, thereby identifying considerations for future research.

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Section: Physiological Roles Of Carnosine In Myocardial Tissuementioning

confidence: 99%

Physiological Roles of Carnosine in Myocardial Function and Health

Creighton

Gonçalves

Artioli

et al. 2022

Advances in Nutrition

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“…A plethora of in vitro studies have shown the various protective activities of carnosine in multiple heterogeneous cell types, such as macrophages/microglia [ 21 , 60 , 61 , 62 ], myocytes [ 63 ], skeletal muscle myoblasts [ 64 ], podocytes [ 65 ], endothelial cells [ 66 ], pancreatic β-cells [ 67 ], chondrocytes [ 68 ], fibroblasts [ 69 ], hepatic cells [ 70 ], lymphocytes [ 71 ], erythrocytes [ 72 ], astrocytes [ 30 , 73 ], neuron-like cells [ 74 , 75 ], and stem cells [ 76 ]. The “coverage” of the very wide range of cell types demonstrated in vitro, representative of different body districts, strengthens the idea that carnosine has the potential to exert therapeutic effects in a broad spectrum of pathological conditions.…”

Section: The Multimodal Mechanism Of Action Of Carnosine: Contributio...mentioning

confidence: 99%

Unveiling the Hidden Therapeutic Potential of Carnosine, a Molecule with a Multimodal Mechanism of Action: A Position Paper

Caruso

2022

Molecules

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Carnosine (β-alanyl-L-histidine) is a naturally occurring endogenous dipeptide and an over-the-counter food supplement with a well-demonstrated multimodal mechanism of action that includes the detoxification of reactive oxygen and nitrogen species, the down-regulation of the production of pro-inflammatory mediators, the inhibition of aberrant protein formation, and the modulation of cells in the peripheral (macrophages) and brain (microglia) immune systems. Since its discovery more than 100 years ago, a plethora of in vivo preclinical studies have been carried out; however, there is still substantial heterogeneity regarding the route of administration, the dosage, the duration of the treatment, and the animal model selected, underlining the urgent need for “coordinated/aligned” preclinical studies laying the foundations for well-defined future clinical trials. The main aim of the present position paper is to critically and concisely consider these key points and open a discussion on the possible “alignment” for future studies, with the goal of validating the full therapeutic potential of this intriguing molecule.

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“…DMEM:F12 was supplemented with 2% fatty acid free bovine serum albumin (BSA); stock solutions of 100 mM palmitic acid, dissolved in 100% ethanol, and 100 mM sodium oleate, dissolved in 50% ethanol, were heated to 60 °C and added directly to the BSA (Sigma-Aldrich, UK). The media was then incubated at 37 °C for 1 h to allow fatty acid conjugation, before being sterile filtered through 0.2 µm membrane filters (Lavilla et al 2021 ; Marshall et al 2007 ).…”

Section: Methodsmentioning

confidence: 99%

“…In both studies, treatment with 10 mM carnosine led to a partial recovery of glucose uptake and GLUT4 translocation, a near full recovery of cellular respiration, and normalisation of ROS (Cripps et al 2017 ; Lavilla et al 2021 ). Consistent with its role as a scavenger of reactive species, carnosine prevented 90% and 80% of 4-HNE protein adduction in C2C12 and human skeletal muscle cells (Lavilla et al 2021 ). It is also possible that carnosine acts indirectly by activating endogenous anti-carbonylation, e.g., glyoxalase 1 (GLO1) defence systems (Aldini et al 2021 ), or by increasing the expression of metabolic proteins involved in regulating mitochondrial health e.g., NAD-dependent deacetylase sirtuins 1/3 (Sirt1, Sirt3) or peroxisome proliferator-activated receptor gamma coactivator a-alpha (PCG-1α), which have been linked to improvements in insulin signalling and oxidative stress (Jing et al 2011 ; Pagel-Langenickel et al 2008 ).…”

Section: Introductionmentioning

confidence: 99%

“…Mechanistic research from our group showed that C2C12 skeletal muscle cells cultured under glucolipotoxic (GLT) conditions (a model of metabolic stress) had reduced glucose uptake and higher reactive oxygen species (ROS) (Cripps et al 2017 ), as well as a suppression of GLUT4 translocation and cellular respiration (ATP-linked and maximal O 2 consumption) (Lavilla et al 2021 ). In both studies, treatment with 10 mM carnosine led to a partial recovery of glucose uptake and GLUT4 translocation, a near full recovery of cellular respiration, and normalisation of ROS (Cripps et al 2017 ; Lavilla et al 2021 ). Consistent with its role as a scavenger of reactive species, carnosine prevented 90% and 80% of 4-HNE protein adduction in C2C12 and human skeletal muscle cells (Lavilla et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Carnosine increases insulin-stimulated glucose uptake and reduces methylglyoxal-modified proteins in type-2 diabetic human skeletal muscle cells

et al. 2023

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Type-2 diabetes (T2D) is characterised by a dysregulation of metabolism, including skeletal muscle insulin resistance, mitochondrial dysfunction, and oxidative stress. Reactive species, such as methylglyoxal (MGO) and 4-hydroxynonenal (4-HNE), positively associate with T2D disease severity and can directly interfere with insulin signalling and glucose uptake in skeletal muscle by modifying cellular proteins. The multifunctional dipeptide carnosine, and its rate-limiting precursor β-alanine, have recently been shown to improve glycaemic control in humans and rodents with diabetes. However, the precise mechanisms are unclear and research in human skeletal muscle is limited. Herein, we present novel findings in primary human T2D and lean healthy control (LHC) skeletal muscle cells. Cells were differentiated to myotubes, and treated with 10 mM carnosine, 10 mM β-alanine, or control for 4-days. T2D cells had reduced ATP-linked and maximal respiration compared with LHC cells (p = 0.016 and p = 0.005). Treatment with 10 mM carnosine significantly increased insulin-stimulated glucose uptake in T2D cells (p = 0.047); with no effect in LHC cells. Insulin-stimulation increased MGO-modified proteins in T2D cells by 47%; treatment with carnosine attenuated this increase to 9.7% (p = 0.011). There was no effect treatment on cell viability or expression of other proteins. These findings suggest that the beneficial effects of carnosine on glycaemic control may be explained by its scavenging actions in human skeletal muscle.

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Carnosine protects stimulus-secretion coupling through prevention of protein carbonyl adduction events in cells under metabolic stress

Cited by 12 publications

References 74 publications

Physiological Roles of Carnosine in Myocardial Function and Health

Physiological Roles of Carnosine in Myocardial Function and Health

Unveiling the Hidden Therapeutic Potential of Carnosine, a Molecule with a Multimodal Mechanism of Action: A Position Paper

Carnosine increases insulin-stimulated glucose uptake and reduces methylglyoxal-modified proteins in type-2 diabetic human skeletal muscle cells

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