Abstract
Aims/hypothesisTreatment 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.MethodsMPs 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.ResultsD-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/interpretationThese 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
Highlights
An estimated 463 million people are currently living with diabetes mellitus [1], a major risk factor for cardiovascular disease [2, 3]
Muscle pericytes (MPs)-like cells isolated from diabetic patients presenting with critical limb ischaemia (CLI) (D-MPs), together with non-diabetic control participants (ND-MPs), were screened for a combination of pericyteassociated markers
While the presence of diabetic MPs (D-MPs) did not alter endothelial cells (ECs) permeability or the ability of ECs to undergo tubulogenesis, D-MPs did demonstrate a reduction in their proliferative behaviour, reduced propensity to differentiate down the myogenic lineage, and reduced interaction with ECs
Summary
An estimated 463 million people are currently living with diabetes mellitus [1], a major risk factor for cardiovascular disease [2, 3]. This number is projected to rise over the decade [1]. We reported a reduction in number and function of supporting MP-like cells of diabetes patients presenting with critical limb ischaemia (CLI) [9]. These diabetic MPs (D-MPs) had elevated levels of reactive oxygen species (ROS) and exerted adverse effects on ECs
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