Submaximal ADP‐stimulated respiration is impaired in ZDF rats and recovered by resveratrol

Smith, Brennan K.; Perry, Christopher G. R.; Herbst, Eric A.F.; Ritchie, Ian R. W.; Beaudoin, Marie-Soleil; Smith, Jeffrey C.; Neufer, P. Darrell; Wright, David C.; Holloway, Graham P.

doi:10.1113/jphysiol.2013.259226

Cited by 33 publications

(41 citation statements)

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“…Digitonin (8.1 μmol/L) was added to the chambers to permeabilize the cells, and the assay was initiated after a 5-min incubation period. Permeabilized skeletal muscle fibers and epididymal adipose tissue were prepared as previously described (31,32). BAT mitochondria were isolated, and respiration was performed similar to previous reports (33,34).…”

Section: Respiration Methodsmentioning

confidence: 99%

Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

et al. 2016

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Salsalate is a prodrug of salicylate that lowers blood glucose in patients with type 2 diabetes (T2D) and reduces nonalcoholic fatty liver disease (NAFLD) in animal models; however, the mechanism mediating these effects is unclear. Salicylate directly activates AMPK via the β1 subunit, but whether salsalate requires AMPK-β1 to improve T2D and NAFLD has not been examined. Therefore, wild-type (WT) and AMPK-β1-knockout (AMPK-β1KO) mice were treated with a salsalate dose resulting in clinically relevant serum salicylate concentrations (~1 mmol/L). Salsalate treatment increased VO 2 , lowered fasting glucose, improved glucose tolerance, and led to an ~55% reduction in liver lipid content. These effects were observed in both WT and AMPK-β1KO mice. To explain these AMPK-independent effects, we found that salicylate increases oligomycin-insensitive respiration (state 4o) and directly increases mitochondrial proton Corresponding author: Gregory R. Steinberg, gsteinberg@mcmaster.ca. Duality of Interest. No potential conflicts of interest relevant to this article were reported.Author Contributions. B.K.S. and G.R.S. designed research studies, analyzed data, and wrote the manuscript. B.K.S., R.J.F., E.M.D., A.E.G., M.C.H., V.P.H., E.A.D., K.M., J.D.C., E.P.M., and C.G.R.P. conducted experiments and analyzed data. B.K.S., R.J.F., E.M.D., A.E.G., V.P.H., E.A.D., K.M., J.D.C., E.P.M., B.E.K., M.A.T., and G.R.S. edited the manuscript. G.R.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0564/-/DC1. Diabetes. Author manuscript; available in PMC 2017 January 12.Published in final edited form as:Diabetes. 2016 November ; 65(11): 3352-3361. doi:10.2337/db16-0564. CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptconductance at clinical concentrations. This uncoupling effect is tightly correlated with the suppression of de novo lipogenesis. Salicylate is also able to stimulate brown adipose tissue respiration independent of uncoupling protein 1. These data indicate that the primary mechanism by which salsalate improves glucose homeostasis and NAFLD is via salicylate-driven mitochondrial uncoupling.Nonalcoholic fatty liver disease (NAFLD) is considered an important contributing factor to the development of insulin resistance and type 2 diabetes (T2D) (1). Despite the rising prevalence of NAFLD and importance for the development of T2D, there are currently no pharmacological approaches for the treatment of this disease (2).Salsalate is a prodrug of salicylate and is hydrolyzed in the small intestine to produce two molecules of salicylate (3,4). The circulating concentration of salicylate in humans administered salsalate in T2D clinical trials is ~1 mmol/L (5-8). Salsalate has also been shown to improve symptoms of NAFLD (9) and nonalcoholic steatohepatitis in...

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Section: Respiration Methodsmentioning

confidence: 99%

Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

et al. 2016

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“…) and a reduction in ANT protein has been associated with impairments in submaximal ADP sensitivity and oxidative stress (Smith et al . ).…”

Section: Introductionmentioning

confidence: 97%

Beetroot juice supplementation reduces whole body oxygen consumption but does not improve indices of mitochondrial efficiency in human skeletal muscle

Whitfield

Ludzki

Heigenhauser

et al. 2015

The Journal of Physiology

110

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Key pointsr Oral consumption of nitrate (NO 3 − ) in beetroot juice has been shown to decrease the oxygen cost of submaximal exercise; however, the mechanism of action remains unresolved.r We supplemented recreationally active males with beetroot juice to determine if this altered mitochondrial bioenergetics.r Despite reduced submaximal exercise oxygen consumption, measures of mitochondrial coupling and respiratory efficiency were not altered in muscle.r In contrast, rates of mitochondrial hydrogen peroxide (H 2 O 2 ) emission were increased in the absence of markers of lipid or protein oxidative damage.r These results suggest that improvements in mitochondrial oxidative metabolism are not the cause of beetroot juice-mediated improvements in whole body oxygen consumption. Abstract Ingestion of sodium nitrate (NO 3− ) simultaneously reduces whole body oxygen consumption (V O 2 ) during submaximal exercise while improving mitochondrial efficiency, suggesting a causal link. Consumption of beetroot juice (BRJ) elicits similar decreases inV O 2 but potential effects on the mitochondria remain unknown. Therefore we examined the effects of 7-day supplementation with BRJ (280 ml day −1 , ß26 mmol NO 3 − ) in young active males (n = 10) who had muscle biopsies taken before and after supplementation for assessments of mitochondrial bioenergetics. Subjects performed 20 min of cycling (10 min at 50% and 70% V O 2 peak ) 48 h before 'Pre' (baseline) and 'Post' (day 5 of supplementation) biopsies. Whole bodẏ V O 2 decreased (P < 0.05) by ß3% at 70%V O 2 peak following supplementation. Mitochondrial respiration in permeabilized muscle fibres showed no change in leak respiration, the content of proteins associated with uncoupling (UCP3, ANT1, ANT2), maximal substrate-supported respiration, or ADP sensitivity (apparent K m ). In addition, isolated subsarcolemmal and intermyofibrillar mitochondria showed unaltered assessments of mitochondrial efficiency, including ADP consumed/oxygen consumed (P/O ratio), respiratory control ratios and membrane potential determined fluorometrically using Safranine-O. In contrast, rates of mitochondrial hydrogen peroxide (H 2 O 2 ) emission were increased following BRJ. Therefore, in contrast to sodium nitrate, BRJ supplementation does not alter key parameters of mitochondrial efficiency. This occurred despite a decrease in exerciseV O 2 , suggesting that the ergogenic effects of BRJ ingestion are not due to a change in mitochondrial coupling or efficiency. It remains to be determined if increased mitochondrial H 2 O 2 contributes to this response.

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“…Comparable behaviour was reported for mitochondria isolated from the hearts of STZ-induced diabetic rats by Pierce and Dhalla [63]. Since those early studies, functional impairment of diabetic cardiac mitochondria has been reported in a variety of animal models: genetically diabetic mice [64], STZ-induced type 1 diabetic rats [65], insulin-resistant and obese mice [43,44] and Zucker Diabetic Fatty rats at submaximal rates of ADP-stimulated respiration [66], even prior to the development of symptoms of diabetic cardiomyopathy [67]. Our recent (unpublished) results (Figure 3) are in general accord.…”

Section: Evidence From the Literaturementioning

confidence: 70%

Assessing the Efficiency of the Diabetic Heart at Subcellular, Tissue and Organ Level

Han¹

2014

J Gen Pract

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In this review, we focus on the diabetic heart rather than the vascular complications of diabetes. Focus is further narrowed to a specific, but widely used, animal model: the diabetic rat heart in which diabetes has been induced by a single injection of streptozotocin. Our experimental approach is primarily biophysical and ranges from measurements made in isolated working whole-hearts, to those made from isolated left-ventricular tissues and mitochondria. Our interest is on the effect of severe diabetes on cardiac energetics, in terms of efficiency of cardiac work performance, ATP synthesis and oxygen consumption. By designing experiments to test the energetic performance of the heart and its trabeculae across a wide range of protocols, we have revealed the dependence of efficiency on afterload. This has allowed us to clarify a long-standing uncertainty in the literature; whereas the diabetic heart is unable to work against high afterloads, it nevertheless retains normal peak efficiency. But a further anomaly has been revealed. Whereas there is no evidence that the diabetic myocardium loses peak mechanical efficiency, its mitochondria demonstrate a decreased P:O ratio -i.e., a decreased bioenergetic efficiency. This decrease is consistent with an increase in the rate of production of reactive oxygen species, together with elevated proton leakage across the inner mitochondrial membrane at near maximal phosphorylating respiration states.Keywords: Cardiac oxygen consumption; Pressure-volume work; Myocardial heat production, Force-length work, Mitochondrial efficiency PreambleReaders of the Journal of General Practice will scarcely need to be reminded that diabetes is a leading cause of death in both the 'developed' and 'developing' world [1]. New Zealand is no exception. We do have something of a unique situation, however, since the burden falls disproportionately on the Maori & Polynesian populations, with both the prevalence and the death rates approaching double those of Pakeha (http://www.maoridiabetes.co.nz/). Given the strong link between obesity and diabetes, the high rates of obesity in New Zealand (31% of adults in 2013) is of increasing concern (http:// www.health.govt.nz/our-work/diseases-and-conditions/obesity/ obesity-key-facts-and-statistics).There have been a number of excellent reviews on the subject of diabetes [2][3][4][5], surely the most unique of which is that authored by Gottlieb [6], dealing with clinical and epidemiological issues. Since we are neither clinicians nor epidemiologists but rather, physiologists, biophysicists and bioengineers, we offer a different point-of-view. Our motivation commences from the knowledge that upwards of 80% of overall morbidity and mortality associated with diabetes is attributable to cardiovascular disease, involving both the arterial/arteriolar system and the myocardium per se. Specifically, we focus on the 'diabetic heart' first described by Rubler et al. [7] from four diabetic patients who had died of diabetic glomerulosclerosis and whose hearts w...

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Submaximal ADP‐stimulated respiration is impaired in ZDF rats and recovered by resveratrol

Cited by 33 publications

References 53 publications

Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

Beetroot juice supplementation reduces whole body oxygen consumption but does not improve indices of mitochondrial efficiency in human skeletal muscle

Assessing the Efficiency of the Diabetic Heart at Subcellular, Tissue and Organ Level

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