2. Academic Validation
  3. Dimethyl-2-oxoglutarate improves redox balance and mitochondrial function in muscle pericytes of individuals with diabetes mellitus

Dimethyl-2-oxoglutarate improves redox balance and mitochondrial function in muscle pericytes of individuals with diabetes mellitus

  • Diabetologia. 2020 Oct;63(10):2205-2217. doi: 10.1007/s00125-020-05230-4.
Ashton Faulkner 1 2,  Anita Tamiato 3,  William Cathery 3,  Andrea Rampin 4,  Carlo Maria Caravaggi 4,  Eva Jover 3,  Steve Allen 5,  Harry Mellor 6,  David Hauton 7,  Lisa C Heather 8,  Gaia Spinetti 4,  Paolo Madeddu 9
Affiliations

Affiliations

  • 1 Bristol Medical School, Translational Health Sciences, University of Bristol, Upper Maudlin Street, Bristol, BS2 8HW, UK. ashton.faulkner@bristol.ac.uk.
  • 2 School of Biochemistry, University of Bristol, University Walk, Bristol, BS8 1TD, UK. ashton.faulkner@bristol.ac.uk.
  • 3 Bristol Medical School, Translational Health Sciences, University of Bristol, Upper Maudlin Street, Bristol, BS2 8HW, UK.
  • 4 IRCCS, MultiMedica, Milan, Italy.
  • 5 Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK.
  • 6 School of Biochemistry, University of Bristol, University Walk, Bristol, BS8 1TD, UK.
  • 7 Department of Chemistry, University of Oxford, Oxford, UK.
  • 8 Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, UK.
  • 9 Bristol Medical School, Translational Health Sciences, University of Bristol, Upper Maudlin Street, Bristol, BS2 8HW, UK. mdprm@bristol.ac.uk.
PMID: 32728894 DOI: 10.1007/s00125-020-05230-4
Abstract

Aims/hypothesis: Treatment of vascular complications of diabetes remains inadequate. We reported that muscle pericytes (MPs) from limb muscles of vascular patients with diabetes mellitus display elevated levels of oxidative stress causing a dysfunctional phenotype. Here, we investigated whether treatment with dimethyl-2-oxoglutarate (DM-2OG), a tricarboxylic acid cycle metabolite with antioxidant properties, can restore a healthy metabolic and functional phenotype.

Methods: MPs were isolated from limb muscles of diabetes patients with vascular disease (D-MPs) and from non-diabetic control participants (ND-MPs). Metabolic status was assessed in untreated and DM-2OG-treated (1 mmol/l) cells using an extracellular flux analyser and anion-exchange chromatography-mass spectrometry (IC-MS/MS). Redox status was measured using commercial kits and IC-MS/MS, with antioxidant and metabolic Enzyme expression assessed by quantitative RT-PCR and western blotting. Myogenic differentiation and proliferation and pericyte-endothelial interaction were assessed as functional readouts.

Results: D-MPs showed mitochondrial dysfunction, suppressed glycolytic activity and reduced reactive oxygen species-buffering capacity, but no suppression of antioxidant systems when compared with ND-MP controls. DM-2OG supplementation improved redox balance and mitochondrial function, without affecting glycolysis or antioxidant systems. Nonetheless, this was not enough for treated D-MPs to regain the level of proliferation and myogenic differentiation of ND-MPs. Interestingly, DM-2OG exerted a positive effect on pericyte-endothelial cell interaction in the co-culture angiogenesis assay, independent of the diabetic status.

Conclusions/interpretation: These novel findings support the concept of using DM-2OG supplementation to improve pericyte redox balance and mitochondrial function, while concurrently allowing for enhanced pericyte-endothelial crosstalk. Such effects may help to prevent or slow down vasculopathy in skeletal muscles of people with diabetes. Graphical abstract.

Keywords

2-Oxoglutarate; Diabetes mellitus; Mitochondria; Pericytes; Redox; Vascular protection.

Figures
Products