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Glutathione administration reduces mitochondrial damage and shifts cell death from necrosis to apoptosis in ageing diabetic mice hearts during exercise.

ABSTRACT: The effect of antioxidants on ageing type 2 diabetic (T2D) hearts during exercise is unclear. We hypothesized that GSH therapy during exercise reduces mitochondrial oxidative stress (mOXS) and cell death in ageing db/db mice hearts.The effect of GSH on cardiac mOXS and cell death was evaluated both in vivo and in vitro.During exercise, GSH treatment protected db/db hearts from exaggerated mOXS without reducing total cell death. Despite similar cell death, investigations on apoptosis-specific single-stranded DNA breaks and necrosis-specific damage provided the first in vivo evidence of a shift from necrosis to apoptosis, with reduced fibrosis following GSH administration in exercised db/db hearts. Further support for a GSH-regulated 'switch' in death phenotypes came from NIH-3T3 fibroblasts and H9c2 cardiomyocytes treated with H2 O2 , a reactive oxygen species (ROS). Similar to in vivo findings, augmenting GSH by overexpressing glutamyl cysteine ligase (GCLc) protected fibroblasts and cardiomyocytes from necrosis induced by H2 O2 , but elevated caspase-3 and apoptosis instead. Similar to in vivo findings, where GSH therapy in normoglycaemic mice suppressed endogenous antioxidants and augmented caspase-3 activity, GCLc overexpression during staurosporine-induced death, which was not characterized by ROS, increased GSH efflux and aggravated death in fibroblasts and cardiomyocytes, confirming that oxidative stress is required for GSH-mediated cytoprotection.While GSH treatment is useful for reducing mOXS and attenuating necrosis and fibrosis in ageing T2D hearts during exercise, such antioxidant treatment could be counterproductive in the healthy heart during exercise.

SUBMITTER: Golbidi S

PROVIDER: S-EPMC4294044 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Glutathione administration reduces mitochondrial damage and shifts cell death from necrosis to apoptosis in ageing diabetic mice hearts during exercise.

Golbidi S S Botta A A Gottfred S S Nusrat A A Laher I I Ghosh S S

British journal of pharmacology 20141201 23

<h4>Background and purpose</h4>The effect of antioxidants on ageing type 2 diabetic (T2D) hearts during exercise is unclear. We hypothesized that GSH therapy during exercise reduces mitochondrial oxidative stress (mOXS) and cell death in ageing db/db mice hearts.<h4>Experimental approach</h4>The effect of GSH on cardiac mOXS and cell death was evaluated both in vivo and in vitro.<h4>Key results</h4>During exercise, GSH treatment protected db/db hearts from exaggerated mOXS without reducing total ...[more]

PMID: 25039894

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Project description:BackgroundHigh glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control.ObjectivesWe investigated the possible effects of GlycACE2 on the anti-remodeling pathways of the RAS inhibitors by evaluating the levels of Angiotensin (Ang) 1-9, Ang 1-7, and Mas receptor (MasR), Nuclear-factor of activated T-cells (NFAT), and fibrosis in human hearts.MethodsWe evaluated 197 first HTX recipients (107 non-T2DM, 90 T2DM). All patients were treated with angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at hospital discharge. Patients underwent clinical evaluation (metabolic status, echocardiography, coronary CT-angiography, and endomyocardial biopsies). Biopsies were used to evaluate ACE2, GlycACE2, Ang 1-9, Ang 1-7, MasR, NAFT, and fibrosis.ResultsGlycACE2 was higher in T2DM compared tonon-T2DM cardiomyocytes. Moreover, reduced expressions of Ang 1-9, Ang 1-7, and MasR were observed, suggesting impaired effects of RAS-inhibition in diabetic hearts. Accordingly, biopsies from T2DM recipients showed higher fibrosis than those from non-T2DM recipients. Notably, the expression of GlycACE2 in heart biopsies was strongly dependent on glycemic control, as reflected by the correlation between mean plasma HbA1c, evaluated quarterly during the 12-month follow-up, and GlycACE2 expression.ConclusionPoor glycemic control, favoring GlycACE2, may attenuate the cardioprotective effects of RAS-inhibition. However, the achievement of tight glycemic control normalizes the anti-remodeling effects of RAS-inhibition.Trial registrationhttps://clinicaltrials.gov/ NCT03546062.

Project description:Objective. Probiotics have been reported to support healthy digestive and immune function, aid in protein absorption, and decrease inflammation. Further, a trend to increase vertical jump power has been observed following co-administration of protein and probiotics in resistance-trained subjects. However, to date the potential beneficial effect of probiotics on recovery from high intensity resistance exercise have yet to be explored. Therefore, this study examined the effect of co-administration of protein and probiotics on muscle damage, recovery and performance following a damaging exercise bout. Design. Twenty nine (n = 29) recreationally-trained males (mean ± SD; 21.5 ± 2.8 years; 89.7 ± 28.2 kg; 177.4 ± 8.0 cm) were assigned to consume either 20 g of casein (PRO) or 20 g of casein plus probiotic (1 billion CFU Bacillus coagulans GBI-30, 6086, PROBC) in a crossover, diet-controlled design. After two weeks of supplementation, perceptional measures, athletic performance, and muscle damage were analyzed following a damaging exercise bout. Results. The damaging exercise bout significantly increased muscle soreness, and reduced perceived recovery; however, PROBC significantly increased recovery at 24 and 72 h, and decreased soreness at 72 h post exercise in comparison to PRO. Perceptual measures were confirmed by increases in CK (PRO: +266.8%, p = 0.0002; PROBC: +137.7%, p = 0.01), with PROBC showing a trend towards reduced muscle damage (p = 0.08). The muscle-damaging exercise resulted in significantly increased muscle swelling and Blood Urea Nitrogen levels in both conditions with no difference between groups. The strenuous exercise significantly reduced athletic performance in PRO (Wingate Peak Power; PRO: (-39.8 watts, -5.3%, p = 0.03)), whereas PROBC maintained performance (+10.1 watts, +1.7%). Conclusions. The results provide evidence that probiotic supplementation in combination with protein tended to reduce indices of muscle damage, improves recovery, and maintains physical performance subsequent to damaging exercise.

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Glutathione administration reduces mitochondrial damage and shifts cell death from necrosis to apoptosis in ageing diabetic mice hearts during exercise.

Publications

Glutathione administration reduces mitochondrial damage and shifts cell death from necrosis to apoptosis in ageing diabetic mice hearts during exercise.

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