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Supplemental Oxygen Improves In Vivo Mitochondrial Oxidative Phosphorylation Flux in Sedentary Obese Adults With Type 2 Diabetes.

ABSTRACT: Type 2 diabetes is associated with impaired exercise capacity. Alterations in both muscle perfusion and mitochondrial function can contribute to exercise impairment. We hypothesized that impaired muscle mitochondrial function in type 2 diabetes is mediated, in part, by decreased tissue oxygen delivery and would improve with oxygen supplementation. Ex vivo muscle mitochondrial content and respiration assessed from biopsy samples demonstrated expected differences in obese individuals with (n = 18) and without (n = 17) diabetes. Similarly, in vivo mitochondrial oxidative phosphorylation capacity measured in the gastrocnemius muscle via ³¹P-MRS indicated an impairment in the rate of ADP depletion with rest (27 ± 6 s [diabetes], 21 ± 7 s [control subjects]; P = 0.008) and oxidative phosphorylation (P = 0.046) in type 2 diabetes after isometric calf exercise compared with control subjects. Importantly, the in vivo impairment in oxidative capacity resolved with oxygen supplementation in adults with diabetes (ADP depletion rate 5.0 s faster, P = 0.012; oxidative phosphorylation 0.046 ± 0.079 mmol/L/s faster, P = 0.027). Multiple in vivo mitochondrial measures related to HbA_1c These data suggest that oxygen availability is rate limiting for in vivo mitochondrial oxidative exercise recovery measured with ³¹P-MRS in individuals with uncomplicated diabetes. Targeting muscle oxygenation could improve exercise function in type 2 diabetes.

SUBMITTER: Cree-Green M

PROVIDER: S-EPMC6463751 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Supplemental Oxygen Improves In Vivo Mitochondrial Oxidative Phosphorylation Flux in Sedentary Obese Adults With Type 2 Diabetes.

Cree-Green Melanie M Scalzo Rebecca L RL Harrall Kylie K Newcomer Bradley R BR Schauer Irene E IE Huebschmann Amy G AG McMillin Shawna S Brown Mark S MS Orlicky David D Knaub Leslie L Nadeau Kristen J KJ McClatchey P Mason PM Bauer Timothy A TA Regensteiner Judith G JG Reusch Jane E B JEB

Diabetes 20180411 7

Type 2 diabetes is associated with impaired exercise capacity. Alterations in both muscle perfusion and mitochondrial function can contribute to exercise impairment. We hypothesized that impaired muscle mitochondrial function in type 2 diabetes is mediated, in part, by decreased tissue oxygen delivery and would improve with oxygen supplementation. Ex vivo muscle mitochondrial content and respiration assessed from biopsy samples demonstrated expected differences in obese individuals with (<i>n</i ...[more]

PMID: 29643061

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Project description:Aims: Catecholamine metabolism via monoamine oxidase (MAO) contributes to cardiac injury in models of ischemia and diabetes, but the pathogenic mechanisms involved are unclear. MAO deaminates norepinephrine (NE) and dopamine to produce H2O2 and highly reactive "catecholaldehydes," which may be toxic to mitochondria due to the localization of MAO to the outer mitochondrial membrane. We performed a comprehensive analysis of catecholamine metabolism and its impact on mitochondrial energetics in atrial myocardium obtained from patients with and without type 2 diabetes. Results: Content and maximal activity of MAO-A and MAO-B were higher in the myocardium of patients with diabetes and they were associated with body mass index. Metabolomic analysis of atrial tissue from these patients showed decreased catecholamine levels in the myocardium, supporting an increased flux through MAOs. Catecholaldehyde-modified protein adducts were more abundant in myocardial tissue extracts from patients with diabetes and were confirmed to be MAO dependent. NE treatment suppressed mitochondrial ATP production in permeabilized myofibers from patients with diabetes in an MAO-dependent manner. Aldehyde dehydrogenase (ALDH) activity was substantially decreased in atrial myocardium from these patients, and metabolomics confirmed lower levels of ALDH-catalyzed catecholamine metabolites. Proteomic analysis of catechol-modified proteins in isolated cardiac mitochondria from these patients identified >300 mitochondrial proteins to be potential targets of these unique carbonyls. Innovation and Conclusion: These findings illustrate a unique form of carbonyl toxicity driven by MAO-mediated metabolism of catecholamines, and they reveal pathogenic factors underlying cardiometabolic disease. Importantly, they suggest that pharmacotherapies targeting aldehyde stress and catecholamine metabolism in heart may be beneficial in patients with diabetes and cardiac disease. Antioxid. Redox Signal. 35, 235-251.

Dataset Information

Supplemental Oxygen Improves In Vivo Mitochondrial Oxidative Phosphorylation Flux in Sedentary Obese Adults With Type 2 Diabetes.

Publications

Supplemental Oxygen Improves In Vivo Mitochondrial Oxidative Phosphorylation Flux in Sedentary Obese Adults With Type 2 Diabetes.

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