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Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with poorly understood pathogenesis and unmet medical needs. Here, we examine the role of interferon γ (IFNγ) using NOD female mice deficient in the inducible T cell co-stimulator (Icos), which have previously been shown to develop spontaneous IFNγ-driven myositis mimicking human disease. Using muscle proteomic and spatial transcriptomic analyses we reveal profound myofiber metabolic dysregulation in these mice. In addition, we report muscle mitochondrial abnormalities and oxidative stress in diseased mice. Supporting a pathogenic role for oxidative stress, treatment with a reactive oxygen species (ROS) buffer compound alleviated myositis, preserved muscle mitochondrial ultrastructure and respiration, and reduced inflammation. Mitochondrial anomalies and oxidative stress were diminished following anti-IFNγ treatment. Further transcriptomic analysis in IIMs patients and human myoblast in vitro studies supported the link between IFNγ and mitochondrial dysfunction observed in mice. These results suggest that mitochondrial dysfunction, ROS and inflammation are interconnected in a self-maintenance loop, opening perspectives for mitochondria therapy and/or ROS targeting drugs in myositis., (© 2024. The Author(s).)

Objectives: The current study was performed in order to determine the influence of hypercholesterolaemia on critical limb ischaemia (CLI) and whether targeting oxidative stress by antioxidant therapies such as N-acetyl cysteine (NAC), considered to be a direct scavenger of reactive oxygen species, could confer muscle protection., Methods: Apolipoprotein E (ApoE)-/- mice (n = 9, 29 weeks old) and their genetic controls ApoE+/+ mice (n = 9, 29 weeks old) were submitted to sequential right femoral and iliac ligations; the left limb served as control. ApoE+/+ mice were divided into two groups: Group 1 (n = 4) and Group 2 (n = 5); as well as ApoE-/- mice: Group 3 (n = 3), and Group 4 (n = 6). NAC treatment was administered to Groups 2 and 4 in drinking water. Mice were sacrificed on Day 40 and gastrocnemius muscles were harvested to study mitochondrial respiration by oxygraphy, calcium retention capacity by spectrofluorometry, and production of reactive oxygen species by electron paramagnetic resonance., Results: CLI associated with ApoE deficiency resulted in more severe mitochondrial dysfunction: maximum oxidative capacity and calcium retention capacity were decreased (-42.9% vs. -25.1%, p = .010; and -73.1% vs. -40.3%, p = .003 respectively) and production of reactive oxygen species was enhanced (+63.6% vs. +41.4%, p = .03) in ApoE-/- mice compared with ApoE+/+ mice respectively. Antioxidant treatment restored oxidative capacity, calcium retention capacity and decreased production of reactive oxygen species in both mice strands., Conclusions: In this small murine study, hypercholesterolaemia exacerbated mitochondrial dysfunction, as clinically expected; but antioxidant therapy appeared protective, which is counter to clinical experience. Further work is clearly needed., (Copyright © 2019 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Objective/background: The aim of this study was to investigate whether antioxidant therapy might decrease oxidative stress related deleterious effects in the setting of critical limb ischaemia (CLI)., Methods: Twenty Swiss mice were submitted to sequential right femoral and iliac ligatures; the left limb served as control. The mice were assigned to two groups: in the first group (no-treatment group, n = 10) no treatment was administered; in the second group (N-acetyl cysteine [NAC] group, n = 10) NAC was administered by dissolution in drinking water for 4 weeks, starting on day 7, when CLI was effective. Clinical and functional scores were assessed by two blinded investigators. Mice were killed on day 40 and mitochondrial respiratory chain complex activities, calcium retention capacity, oxidative stress, and histological analysis were analysed., Results: Ischaemic muscles in the no-treatment group showed significantly impaired mitochondrial respiration and calcium retention capacity, with increased production of reactive oxygen species; but no statistical difference was noticed when comparing ischaemic muscles in the NAC group (n = 10) to contralateral muscles (n = 10) and to control muscles in the no-treatment group (n = 10). Ischaemic muscles in the no-treatment group exhibited myopathic features such as wider range in fibre size, rounded shape, centrally located nuclei, and smaller cross sectional areas, but none of these features were observed in contralateral muscles or in NAC-group muscles (ischaemic or controls)., Conclusion: Targeting inhibition of oxidative stress may be a potential therapeutic strategy for muscle protection in CLI and might be considered as potential adjunctive therapy to revascularisation procedures., (Copyright © 2018 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Osmoregulating decapods such as the Mediterranean green crab Carcinus aestuarii possess two groups of spatially segregated gills: anterior gills serve mainly respiratory purposes, while posterior gills contain osmoregulatory structures. The co-existence of similar tissues serving different functions allows the study of differential adaptation, in terms of free radical metabolism, upon salinity change. Crabs were immersed for 2 weeks in seawater (SW, 37 ppt), diluted SW (dSW, 10 ppt) and concentrated SW (cSW, 45 ppt). Exposure to dSW was the most challenging condition, elevating respiration rates of whole animals and free radical formation in hemolymph (assessed fluorometrically using C-H2DFFDA). Further analyses considered anterior and posterior gills separately, and the results showed that posterior gills are the main tissues fueling osmoregulatory-related processes because their respiration rates in dSW were 3.2-fold higher than those of anterior gills, and this was accompanied by an increase in mitochondrial density (citrate synthase activity) and increased levels of reactive oxygen species (ROS) formation (1.4-fold greater, measured through electron paramagnetic resonance). Paradoxically, these posterior gills showed undisturbed caspase 3/7 activity, used here as a marker for apoptosis. This may only be due to the high antioxidant protection that posterior gills benefit from [superoxide dismutase (SOD) in posterior gills was over 6 times higher than in anterior gills]. In conclusion, osmoregulating posterior gills are better adapted to dSW exposure than respiratory anterior gills because they are capable of controlling the deleterious effects of the ROS production resulting from this salinity-induced stress., (© 2016. Published by The Company of Biologists Ltd.)

Cannabis has potential therapeutic use but tetrahydrocannabinol (THC), its main psychoactive component, appears as a risk factor for ischemic stroke in young adults. We therefore evaluate the effects of THC on brain mitochondrial function and oxidative stress, key factors involved in stroke. Maximal oxidative capacities V max (complexes I, III, and IV activities), V succ (complexes II, III, and IV activities), V tmpd (complex IV activity), together with mitochondrial coupling (V max/V 0), were determined in control conditions and after exposure to THC in isolated mitochondria extracted from rat brain, using differential centrifugations. Oxidative stress was also assessed through hydrogen peroxide (H2O2) production, measured with Amplex Red. THC significantly decreased V max (-71%; P < 0.0001), V succ (-65%; P < 0.0001), and V tmpd (-3.5%; P < 0.001). Mitochondrial coupling (V max/V 0) was also significantly decreased after THC exposure (1.8±0.2 versus 6.3±0.7; P < 0.001). Furthermore, THC significantly enhanced H2O2 production by cerebral mitochondria (+171%; P < 0.05) and mitochondrial free radical leak was increased from 0.01±0.01 to 0.10±0.01% (P < 0.001). Thus, THC increases oxidative stress and induces cerebral mitochondrial dysfunction. This mechanism may be involved in young cannabis users who develop ischemic stroke since THC might increase patient's vulnerability to stroke.

Introduction: The effect of eccentric (ECC) versus concentric (CON) training on metabolic properties in skeletal muscle is understood poorly. We determined the responses in oxidative capacity and mitochondrial H2 O2 production after eccentric (ECC) versus concentric (CON) training performed at similar mechanical power., Methods: Forty-eight rats performed 5- or 20-day eccentric (ECC) or concentric (CON) training programs. Mitochondrial respiration, H2 O2 production, citrate synthase activity (CS), and skeletal muscle damage were assessed in gastrocnemius (GAS), soleus (SOL) and vastus intermedius (VI) muscles., Results: Maximal mitochondrial respiration improved only after 20 days of concentric (CON) training in GAS and SOL. H2 O2 production increased specifically after 20 days of eccentric ECC training in VI. Skeletal muscle damage occurred transiently in VI after 5 days of ECC training., Conclusions: Twenty days of ECC versus CON training performed at similar mechanical power output do not increase skeletal muscle oxidative capacities, but it elevates mitochondrial H2 O2 production in VI, presumably linked to transient muscle damage., (© 2014 Wiley Periodicals, Inc.)

Objective: Lower limb ischemia-reperfusion results in skeletal muscle mitochondrial alterations, production of reactive oxygen species (ROS), and remote organ impairments that are largely involved in patient prognosis. However, whether ischemia without reperfusion increases ROS production and precedes mitochondrial alteration and whether mitochondrial dysfunction occurs early in remote organs is unknown. This study determined muscle mitochondrial function and ROS production after ischemia alone, or followed by two periods of reperfusion, and investigated heart, lung, liver, kidney, and brain mitochondrial functions after lower limb ischemia-reperfusion., Methods: Wistar rats were randomized into four groups: sham (aortic exposure but no ischemia, n = 9), I3 (ischemia alone induced by aortic cross-clamping for 3 hours, n = 9), I3R10' and I3R2 (aortic cross-clamping, followed by reperfusion for 10 minutes [n = 8] or 2 hours [n = 9]). Blood lactate, alanine aminotransferase, aspartate aminotransferase, and creatinine were measured. Mitochondrial respiratory chain complexes I, II, III, and IV activities and mitochondrial coupling (acceptor control ratio) were analyzed using a Clark oxygen electrode in skeletal muscle, lung, heart, brain, liver, and kidney. ROS production was determined using dihydroethidium staining in muscle, heart, liver, and kidney. Inflammation was also investigated in remote organs (heart, liver, and kidney) using monocyte-macrophage-2 antibody staining., Results: Lactate level increased after ischemia in all groups. In muscle, ROS increased significantly after ischemia alone (+324% ± 66%; P = .038), normalized after 10 minutes of reperfusion, and increased again at 2 hours of reperfusion (+349.2 ± 67%; P = .024). Interestingly, mitochondrial function was unaffected by ischemia alone or followed by 10 minutes of reperfusion, but maximal mitochondrial oxidative capacity (6.10 ± 0.51 vs. 4.24 ± 0.36 μmol/min/g, -30%; P < .05) and mitochondrial coupling decreased after 2 hours of reperfusion (1.93 ± 0.17 vs. 1.33 ± 0.07, -45%; P < .01), in sham and I3R2 rats, respectively. Despite increased serum aspartate aminotransferase (×13; P < .0001), alanine aminotransferase (×6; P = .0019), and creatinine (×3; P = .0004), remote organs did not show mitochondrial alteration, inflammation, or ROS production enhancement after 2 hours of reperfusion., Conclusions: Oxidative stress precedes skeletal muscle mitochondrial dysfunction during lower limb ischemia. Such a kinetic explains the efficacy of ischemic preconditioning and supports that therapy should be conducted even during ongoing ischemia, suggesting that ischemic preconditioning might be a successful approach., (Copyright © 2014 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Irrespective of the organ involved, restoration of blood flow to ischemic tissue is vital, although reperfusion per se is deleterious. In the setting of vascular surgery, even subtle skeletal muscle ischemia contributes to remote organ injuries and perioperative and long-term morbidities. Reperfusion-induced injury is thought to participate in up to 40% of muscle damage. Recently, the pathophysiology of lower limb ischemia-reperfusion (IR) has been largely improved, acknowledging a key role for mitochondrial dysfunction mainly characterized by impaired mitochondrial oxidative capacity and premature mitochondrial permeability transition pore opening. Increased oxidative stress triggered by an imbalance between reactive oxygen species (ROS) production and clearance, and facilitated by enhanced inflammation, appears to be both followed and instigated by mitochondrial dysfunction. Mitochondria are both actors and target of IR and therapeutic strategies modulating degree of ROS production could enhance protective signals and allow for mitochondrial protection through a mitohormesis mechanism., (Copyright © 2014. Published by Elsevier Ltd.)

Objective: By binding to cyclophilin D, cyclosporine A (CsA) inhibits mitochondrial permeability transition pore (mPTP) opening and prevents mitochondrial dysfunction and ultimately cell death after ischemia-reperfusion (IR) injury in cardiac muscle. This study tested whether CsA would decrease skeletal muscle oxidative stress and mitochondrial dysfunctions after aortic cross-clamping related IR., Methods: Forty-five Wistar rats were investigated. The sham group (n = 8) had aortic exposure but no ischemia, the IR group (n = 10) had aortic cross-clamping for 3 hours followed by 2 hours of reperfusion, and the IR+CsA group (n = 9) had two intraperitoneal injections of 10 mg of CsA at 90 and 150 minutes of ischemia before reperfusion. Mitochondrial coupling (acceptor control ratio) and mitochondrial respiratory chain complexes' activities were measured. Reactive oxygen species (ROS) production, cyclophilin D expression, and muscle inflammation were determined using dihydroethidium staining, Western blot, and immunohistochemistry, respectively. An additional 18 sham rats were investigated to determine CsA blood levels and the effects of CsA on mitochondrial respiration and calcium retention capacity, a marker of mPTP opening, both in myocardium and gastrocnemius with and without CsA., Results: Compared with sham, IR decreased mitochondrial coupling (1.38 ± 0.06 vs 1.98 ± 0.20; P = .0092), increased ROS production (3992 ± 706 arbitrary units [AU] vs 1812 ± 322 AU; P = .033), was associated with macrophage infiltration, and decreased maximal oxidative capacity (V(max): 4.08 ± 0.38 μmol O(2)/min/g vs 5.98 ± 0.56 μmol O(2)/min/g; P = .015). Despite IR, CsA treatment totally restored mitochondrial coupling (1.93 ± 0.12; P = .023 vs IR), normalized ROS (1569 ± 348 AU; P = .0098 vs IR), and decreased inflammation. The V(max) was slightly enhanced (5.02 ± 0.39 μmol O(2)/min/g; P = .33 vs IR; P = .35 vs sham). Compared with myocardium, gastrocnemius muscle was characterized by a decreased cyclophilin D content (-50%) associated with an earlier opening of mPTP (calcium retention capacity increased from 10.85 ± 1.35 μM/mg dry weight [DW] to 12.11 ± 2.77 μM/mg DW; P = .65; and from 11.07 ± 1.67 to 37.65 ± 11.41 μM/mg DW; P = .0098 in gastrocnemius and heart, respectively)., Conclusions: Cyclosporine A normalized ROS production, decreased inflammation, and restored mitochondrial coupling during aortic cross-clamping. Incomplete Vmax protection might be due to low cyclophilin D expression in gastrocnemius, preventing CsA from blocking mPTP opening., (Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Ageing is associated with skeletal muscle impairment. Changes in mitochondrial homeostasis are thought to play a key role in this process. This study examined whether chronic intake of polyphenols (PPs), which are known to be modulators of oxidative stress, might prevent the age-related decline of mitochondrial functions in skeletal muscle. Three groups of 10 Wistar rats were investigated. Rats aged 16 weeks were compared with rats aged 40 weeks that were given 75 mg kg(-1) day(-1) PPs or solvent in the drinking water starting at week 16. Mitochondrial respiratory chain complex activities were measured in saponin-skinned fibres of soleus muscles using glutamate-malate (V(max)), succinate (V(succ)) and N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride-ascorbate (V(TMPD)). Production of reactive oxygen species was assessed using dihydroethidium staining. Transcript levels of genes involved in antioxidant defence were determined using RT-PCR. Ageing reduced muscle V(max) (from 8.8 ± 0.45 to 6.17 ± 0.51 μmol O(2) min(-1) g(-1), -30.5%, P < 0.01), V(TMPD) (from 20.67 ± 1.24 to 16.55 ± 1.16 μmol O(2) min(-1) g(-1), -19.9%, P < 0.05), increased production of reactive oxygen species (from 100 ± 9.9 to 351.1 ± 31.7%) and decreased transcripts of mitochondrial superoxide dismutase 2 (-59.3%, P < 0.01), peroxisome proliferator-activated receptor γ coactivator-1β (PGC-1β; -61.5%, P < 0.05) and sirtuin 1 (-54.2%, P < 0.05). Chronic PP intake normalized V(max) (8.63 ± 0.63 μmol O(2) min(-1) g(-1)), decreased production of reactive oxygen species (141.7 ± 16.7%, P < 0.001) and enhanced antioxidant defence (superoxide dismutase 2 expression, +151.3%, P < 0.05) and PGC-1β expression (+185.7%, P < 0.05) in comparison to age-matched untreated rats. The present data indicate that regular intake of PPs starting at a young age prevents age-related mitochondrial respiratory impairment in skeletal muscle, probably through decreased oxidative stress and enhancement of PGC-1β expression.

Objectives: Mesenteric ischaemia/reperfusion (IR) may lead to liver mitochondrial dysfunction and multiple organ failure. We determined whether gut IR induces early impairment of liver mitochondrial oxidative activity and whether methylene blue (MB) might afford protection., Design: Controlled animal study., Materials and Methods: Rats were randomised into three groups: controls (n = 18), gut IR group (mesenteric ischaemia (60 min)/reperfusion (60 min)) (n = 18) and gut IR + MB group (15 mg kg(-1) MB intra-peritoneally) (n = 16). Study parameters were: serum liver function markers, blood lactate, standard histology and DNA fragmentation (apoptosis) on intestinal and liver tissue, maximal oxidative capacity of liver mitochondria (state 3) and activity of complexes II, III and IV of the respiratory chain measured using a Clark oxygen electrode., Results: Gut IR increased lactate deshydrogenase (+982%), aspartate and alanine aminotransferases (+43% and +74%, respectively) and lactate levels (+271%). It induced segmental loss of intestinal villi and cryptic apoptosis. It reduced liver state 3 respiration by 30% from 50.1 ± 3 to 35.2 ± 3.5 μM O(2) min(-1) g(-1) (P < 0.01) and the activity of complexes II, III and IV of the mitochondrial respiratory chain. Early impairment of liver mitochondrial respiration was related to blood lactate levels (r(2) = 0.45). MB restored liver mitochondrial function., Conclusions: MB protected against gut IR-induced liver mitochondria dysfunction., (Copyright © 2012 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Brain natriuretic peptide (BNP) reduces the extent of myocardial infarction. We aimed to determine whether BNP may reduce skeletal muscle mitochondrial dysfunctions and oxidative stress through mitochondrial K(ATP) (mK(ATP)) channel opening after ischemia-reperfusion (IR). Wistar rats were assigned to four groups: sham, 3-h leg ischemia followed by 2-h reperfusion (IR), pretreatment with BNP, and pretreatment with 5-hydroxydecanoic acid, an mK(ATP) channel blocker, before BNP. Mitochondrial respiratory chain complex activities of gastrocnemius muscles were determined using glutamate-malate (V(max)), succinate (V(succ)), and N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride ascorbate (V(TMPD/asc)). Apoptosis (Bax-to-Bcl2 mRNA ratio and caspase-3 activity) and oxidative stress (dihydroethidium staining) were also assessed. Compared with the sham group, IR significantly decreased V(max), reflecting complex I, II, and IV activities (-36%, 3.7 ± 0.3 vs. 5.8 ± 0.2 μmol O(2)·min(-1)·g dry wt(-1), P < 0.01), and V(TMPD/asc), reflecting complex IV activity (-37%, 8.6 ± 0.8 vs. 13.7 ± 0.9 μmol O(2)·min(-1)·g dry wt(-1), P < 0.01). IR increased Bax-to-Bcl2 ratio (+57%, 1.1 ± 0.1 vs. 0.7 ± 0.1, P < 0.05) and oxidative stress (+45%, 9,067 ± 935 vs. 6,249 ± 723 pixels, P > 0.05). BNP pretreatment reduced the above alterations, increasing V(max) (+38%, P < 0.05) and reducing Bax-to-Bcl2 ratio (-55%, P < 0.01) and oxidative stress (-58%, P < 0.01). BNP protection against deleterious IR effects on skeletal muscles was abolished by 5-hydroxydecanoic acid. Caspase-3 activities did not change significantly. Conversely, BNP injected during ischemia failed to protect against muscle injury. In addition to maintaining the activity of mitochondrial respiratory chain complexes and possibly decreasing apoptosis, pretreatment with BNP protects skeletal muscle against IR-induced lesions, most likely by decreasing excessive production of radical oxygen species and opening mK(ATP) channels.

Objective: Muscular injuries contribute to perioperative and long-term morbidity after vascular surgery in humans. We determined whether local and remote ischemic postconditioning might similarly decrease muscle mitochondrial dysfunction through reduced oxidative stress., Methods: Eighteen male Black-6 mice were divided in three groups: (1) sham mice had no ischemia (sham), (2) ischemia-reperfusion (IR) mice underwent 2-hour tourniquet-induced ischemia on both hind limbs, followed by 2-hour reperfusion, and (3) postconditioning (PoC) mice underwent four bouts of 30-second reperfusion and 30-second ischemia at the onset of reperfusion on the right limb; thus, the right limb underwent local PoC and left limb underwent remote PoC (rPoC). Maximal oxidative capacity (V(max)) of the gastrocnemius muscle mitochondrial respiratory chain was measured. Oxidative stress was evaluated by dihydroethidium staining. Expressions of genes involved in antioxidant defense (superoxide dismutase [SOD1], SOD2, glutathione peroxidase [GPx]), apoptosis (Bax, BclII), and inflammation (interleukin-6) were determined by quantitative real-time polymerase chain reaction. Muscle inflammation was determined using immunohistochemistry., Results: IR reduced V(max) (8.5 ± 2.2 vs 10.2 ± 1.8 μmol O(2)/min/g dry weight; P = .034), and increased dihydroethidium staining (134.8%; P = .039). IR decreased GPx expression (-47.9%; P = .048) and increased the proapoptotic marker Bax (255.5%; P = .020). Local PoC and rPoC further increased these deleterious effects. PoC decreased V(max) to 4.4 ± 1.4 μmol O(2)/min/g dry weight (sham vs PoC, -56.9% [P < .001]; IR vs PoC, -48.2% [P < .001]). rPoC similarly reduced V(max) to 5.1 ± 1.9 μmol O(2)/min/g dry weight (sham vs PoC, -50.0% [P < .001]; IR vs PoC, -40.0% [P = .001]). Dihydroethidium staining was further increased by PoC (207.2%; P = .002) and rPoC (305.4%; P < .001) compared with sham and was associated with macrophage infiltration. Local PoC increased SOD1, SOD2, and the antiapoptotic Bcl-2, and rPoC increased Bax (391.6%; P < .001) and the Bax/BclII ratio (621.7%; P < .001)., Conclusions: Local and remote ischemic postconditioning further increased injury by enhancing mitochondrial dysfunction, oxidative stress production, and inflammation. Caution should be applied when considering ischemic postconditioning in vascular surgery., (Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Physical exercise exacerbates the cytotoxic effects of statins in skeletal muscle. Mitochondrial impairments may play an important role in the development of muscular symptoms following statin treatment. Our objective was to characterize mitochondrial function and reactive oxygen species (ROS) production in skeletal muscle after exhaustive exercise in atorvastatin-treated rats. The animals were divided into four groups: resting control (CONT; n = 8) and exercise rats (CONT+EXE; n = 8) as well as resting (ATO; n = 10) and exercise (ATO+EXE; n = 8) rats that were treated with atorvastatin (10 mg·kg(-1)·day(-1) for 2 wk). Exhaustive exercise showed that the distance that was covered by treated animals was reduced (P < 0.05). Using dihydroethidium staining, we showed that the ROS level was increased by 60% in the plantaris muscle of ATO compared with CONT rats and was highly increased in ATO+EXE (226%) compared with that in CONT+EXE rats. The maximal mitochondrial respiration (V(max)) was decreased in ATO rats compared with that in CONT rats (P < 0.01). In CONT+EXE rats, V(max) significantly increased compared with those in CONT rats (P < 0.05). V(max) was significantly lower in ATO+EXE rats (-39%) compared with that in CONT+EXE rats (P < 0.001). The distance that was covered by rats significantly correlated with V(max) (r = 0.62, P < 0.01). The glycogen content was decreased in ATO, CONT+EXE, and ATO+EXE rats compared with that in CONT rats (P < 0.05). GLUT-4 mRNA expression was higher after exhaustive exercise in CONT+EXE rats compared with the other groups (P < 0.05). Our results show that exhaustive exercise exacerbated metabolic perturbations and ROS production in skeletal muscle, which may reduce the exercise capacity and promote the muscular symptoms in sedentary atorvastatin-treated animals.

Background: Cross-clamping of the aorta during abdominal aortic aneurysm surgery induces muscle ischaemia with resultant morbidity. This study tested whether ischaemic postconditioning would decrease mitochondrial dysfunction in skeletal muscle by reducing oxidative stress., Methods: Three groups (9 rats each) underwent surgery, including a control group without ischaemia and an ischaemia-reperfusion group that had 3 h ischaemia induced by aortic clamping and collateral vessel ligation, followed by 2 h of reperfusion. The third group had ischaemia for 3 h then underwent postconditioning comprising three short intervals of ischaemia-reperfusion at the onset of reperfusion. Activity of complexes I, II, III and IV of the mitochondrial respiratory chain was monitored in gastrocnemius muscle, along with oxidative stress measured by dihydroethidium (DHE) staining and antioxidant defence determined by measurement of glutathione levels., Results: Ischaemia-reperfusion alone caused a significant reduction in maximal oxidative capacity (-31.8 per cent; P = 0.002), activity of complexes II, III and IV (-34.5 per cent; P = 0.007) and complex IV activity (-30.6 per cent; P = 0.039). It also increased reactive oxygen species (DHE staining increased to 223.1 per cent of control value; P = 0.027) and reduced antioxidant defence (glutathione level -28.6 per cent; P = 0.039). Postconditioning counteracted these deleterious effects by increasing mitochondrial complex I, II, III and IV activities, restoring muscle DHE staining and preserving glutathione content., Conclusion: Ischaemic postconditioning protects skeletal muscle mitochondria against ischaemia-reperfusion injury by reducing oxidative stress and preserving antioxidant defence in an experimental model. Mitochondrial protection to reduce reperfusion injury in clinical vascular surgery may be warranted., (Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Aging is associated with oxidative stress-mediated endothelial dysfunction and decline in physical performance, which promote cardiovascular diseases. This study examined whether chronic intake of red wine polyphenols (RWPs), a rich source of natural antioxidants, prevents aging-related impairment of vascular function and physical exercise capacity. Vascular reactivity from 12, 20 and 40 week-old rats was assessed in organ chambers. Rats received from week 16 to 40 either solvent, RWPs or the antioxidant and NADPH oxidase inhibitor, apocynin. Aging was associated with blunted endothelium-dependent relaxations, oxidative stress (dihydroethidine staining), and an upregulation of eNOS, arginase I, NADPH oxidase p22phox and nox1 subunits, and AT1 and AT2 receptors (assessed by immunohistochemistry) in the mesenteric artery. RWPs and apocynin improved the endothelial dysfunction, normalized oxidative stress and the expression of the different proteins. RWPs also improved aging-related decline in physical exercise. Thus, intake of RWPs protects against aging-induced endothelial dysfunction and decline in physical performance. These effects likely involve the ability of RWPs to normalize oxidative stress and the expression of proteins involved in the formation of NO and the angiotensin II pathway., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Le postconditionnement est défini par la succession de cycles d’occlusion et de reperfusion d’un vaisseau dans les premiers instants de la reperfusion, faisant suite à une ischémie prolongée. Il permet de diminuer la taille de l’infarctus et protège la fonction des complexes de la chaîne respiratoire mitochondriale. Les études ont été menées jusqu’à présent sur le myocarde et objectivent des résultats encourageant. Notre objectif est d’évaluer l’effet protecteur du postconditionnement sur les capacités oxydatives mitochondriales du muscle squelettique. 40 rats Wistar on été utilisés pour l’étude, répartis en 4 groupes : un groupe shams (C) (n = 14), un groupe subissant 2 heures d’ischémie et 2 heures de reperfusion (I2HR) (n = 6), un groupe subissant 3 heures d’ischémie et 2 heures de reperfusion (I3HR) (n = 11), et un groupe postconditionnement (PostC) (n = 9). Nous avons mis au point un modèle d’ischémie-reperfusion par clampage aortique sous-rénal chez le rat Wistar, plus proche de la réalité clinique chez l’homme. Nous avons établi qu’il était nécessaire de réaliser 3 heures d’ischémie et 2 heures de reperfusion pour obtenir des lésions mitochondriales significatives sur le muscle gastrocnémien (diminution de 27 % des capacités oxydatives maximales entre le groupe C et I3HR). Le muscle soléaire oxydatif n’est pas touché. Pour notre protocole de postconditionnement nous avons réalisé des cycles 1, 2 et 4 minutes de déclampage, suivis à chaque fois de 5 minutes de réocclusion aortique. On note une augmentation dans le muscle glycolytique des capacités maximales d’oxydation dans le groupe PostC par rapport au groupe I3HR (5,9 ± 0,3 versus 4,76 ± 0,5μmol/min/g de poids sec, p = 0,07), ce qui correspond à 25 % d’augmentation. Il n’y a pas de différence entre le groupe shams et postconditionnement. Des résultats similaires sont observés au niveau du complexe II. Ainsi nous avons démontré que le postconditionnement joue un effet protecteur sur la chaîne respiratoire mitochondriale, au niveau des complexes I et II, dans le muscle gastrocnémien glycolytique. [Copyright &y& Elsevier]