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Fundamental events driving the pathological processes of septic shock-induced multiorgan failure (MOF) at the cellular and subcellular levels remain debated. Emerging data implicate mitochondrial dysfunction as a critical factor in the pathogenesis of sepsis-associated MOF. If macrocirculatory and microcirculatory dysfunctions undoubtedly participate in organ dysfunction at the early stage of septic shock, an intrinsic bioenergetic failure, sometimes called "cytopathic hypoxia," perpetuates cellular dysfunction. Short-term failure of vital organs immediately threatens patient survival but long-term recovery is also severely hindered by persistent dysfunction of organs traditionally described as nonvital, such as skeletal muscle and peripheral blood mononuclear cells (PBMCs). In this review, we will stress how and why a persistent mitochondrial dysfunction in skeletal muscles and PBMC could impair survival in patients who overcome the first acute phase of their septic episode. First, muscle wasting protracts weaning from mechanical ventilation, increases the risk of mechanical ventilator-associated pneumonia, and creates a state of ICU-acquired muscle weakness, compelling the patient to bed. Second, failure of the immune system ("immunoparalysis") translates into its inability to clear infectious foci and predisposes the patient to recurrent nosocomial infections. We will finally emphasize how mitochondrial-targeted therapies could represent a realistic strategy to promote long-term recovery after sepsis.

Background: Lung and liver dysfunction is involved in gut ischemia-reperfusion (IR)-induced multiple organ failure. We compared the effects of ketamine and isoflurane on liver and lung mitochondrial oxidative capacity after gut IR., Methods: Adult male Wistar rats were randomized into 4 groups (controls and gut IR receiving either intraperitoneal ketamine or inhaled isoflurane). Maximal oxygen consumption and the activity of respiratory chain complexes were measured on isolated liver and lung mitochondria., Results: Gut IR significantly impaired liver and lung mitochondrial oxidative capacity when using ketamine but not isoflurane., Conclusions: Isoflurane preserved liver and lung mitochondrial oxidative capacity after gut IR.

The aim of this study was to investigate whether remote ischaemic per-conditioning might protect skeletal muscle during lower limb ischaemia–reperfusion (IR). Twenty-three male C57BL/6 mice were randomised into three groups: sham group (n = 7), IR group (unilateral tourniquet induced three hours of ischaemia followed by 24 hours of reperfusion, n = 8), and remote ischaemic per-conditioning group (RIPerC) (three cycles of 10 minute IR episodes on the non-ischaemic contralateral hindlimb, n = 8). Oxygraphy, spectrofluorometry, and electron paramagnetic resonance spectroscopy were performed in order to determine mitochondrial respiratory chain complexes activities, mitochondrial calcium retention capacity (CRC) and reactive oxygen species (ROS) production in skeletal muscle. IR impaired mitochondrial respiration (3.66 ± 0.98 vs. 7.31 ± 0. 54 μmol/min/g in ischaemic and sham muscles, p =.009 and p =.003 respectively) and tended to impair CRC (2.53 ± 0.32 vs. 3.64 ± 0.66 μmol/mg in ischaemic and sham muscles respectively, p =.066). IR did not modify ROS production (0.082 ± 0.004 vs. 0.070 ± 0.004 μmol/min/mg in ischaemic and sham muscles respectively, p =.74). RIPerC failed to restore mitochondrial respiration (3.82 ± 0.40 vs. 3.66 ± 0.98 μmol/min/g in ischaemic muscles from the RIPerC group and the IR group respectively, p =.45) and CRC (2.76 ± 0.3 vs. 2.53 ± 0.32 μmol/mg in ischaemic muscles from the RIPerC group and the IR group respectively, p =.25). RIPerC even impaired contralateral limb mitochondrial respiration (3.85 ± 0.34 vs. 7.31 ± 0. 54 μmol/min/g in contralateral muscles and sham muscles respectively, –47.3%, p =.009). RIPerC failed to protect ischaemic muscles and induced deleterious effects on the contralateral non-ischaemic muscles. These data do not support the concept of RIPerC. [ABSTRACT FROM AUTHOR]

Objectives: Diabetic patients respond poorly to revascularization for peripheral arterial disease (PAD) but the underlying mechanisms are not well understood. We aimed to determine whether diabetes worsens ischemia-reperfusion (IR)-induced muscle dysfunction and the involvement of endogenous protective kinases in this process. Materials and Methods: Streptozotocin-induced diabetic and non-diabetic rats were randomized to control or to IR injury (3 h of aortic cross-clamping and 2 h of reperfusion). Mitochondrial respiration, reactive oxygen species (ROS) production, protein levels of superoxide dismutase (SOD2) and endogenous protective kinases (RISK and SAFE pathways) were investigated in rat gastrocnemius, together with upstream (GSK-3b) and downstream (cleaved caspase-3) effectors of apoptosis. Results: Although already impaired when compared to non-diabetic controls at baseline, the decline in mitochondrial respiration after IR wasmore severe in diabetic rats. In diabetic animals, IR-triggered oxidative stress (increased ROS production and reduced SOD2 levels) and effectors of apoptosis (reduced GSK-3b inactivation and higher cleaved caspase-3 levels) were increased to a higher level than in the non-diabetics. IR had no effect on the RISK pathway in non-diabetics and diabetic rats, but increased STAT 3 only in the latter. Conclusion: Type 1 diabetes worsens IR-induced skeletal muscle injury, endogenous protective pathways not being efficiently stimulated. [ABSTRACT FROM AUTHOR]

Old patients exhibit muscle impairments and increased perioperative risk during vascular surgery procedures. Although aging generally impairs protective mechanisms, data are lacking concerning skeletal muscle in elderly. We tested whether cyclosporine A (CsA), which protects skeletal muscle from ischemia-reperfusion ( IR) in young rats, might reduce skeletal muscle mitochondrial dysfunction and oxidative stress in aging rats submitted to hindlimb IR. Wistar rats aged 71-73 weeks were randomized to IR (3 h unilateral tourniquet application and 2 h reperfusion) or IR + CsA (10 mg/kg cyclosporine IV before reperfusion). Maximal oxidative capacity ( VMax), acceptor control ratio ( ACR), and relative contribution of the mitochondrial respiratory chain complexes II, III, IV ( VSucc), and IV ( VTMPD/Asc), together with calcium retention capacity ( CRC) a marker of apoptosis, and tissue reactive oxygen species ( ROS) production were determined in gastrocnemius muscles from both hindlimbs. Compared to the nonischemic hindlimb, IR significantly reduced mitochondrial coupling, VMax (from 7.34 ± 1.50 to 2.87 ± 1.22 μ MO2/min/g; P < 0.05; −70%), and VSucc (from 6.14 ± 1.07 to 3.82 ± 0.83 μ MO2/min/g; P < 0.05; −42%) but not VTMPD/Asc. IR also decreased the CRC from 15.58 ± 3.85 to 6.19 ± 0.86 μ MCa2+/min/g; P < 0.05; −42%). These alterations were not corrected by CsA (−77%, −49%, and −32% after IR for VMax, VSucc, and CRC, respectively). Further, CsA significantly increased ROS production in both hindlimbs ( P < 0.05; +73%). In old rats, hindlimb IR impairs skeletal muscle mitochondrial function and increases oxidative stress. Cyclosporine A did not show protective effects. [ABSTRACT FROM AUTHOR]

New Findings What is the topic of this review? Muscle dysfunction is a common complication and an important independent prognostic factor in chronic obstructive pulmonary disease (COPD)., What advances does it highlight? In COPD patients, the vastus lateralis muscle presents with alterations that include a decrease in mitochondrial density and biogenesis, impaired mitochondrial respiration and coupling, as well as increased mitochondrial production of reactive oxygen species, possibly associated with increased mitochondrial apoptosis. These mitochondrial changes are accessible to conventional therapies, such as exercise and tobacco cessation, but potentially also to innovative management strategies, such as antioxidant treatment and supplementation with polyunsaturated fatty acids. Mitochondrial pathophysiology represents an emerging area of research in muscle dysfunction associated with COPD and has promising therapeutic implications., Muscle dysfunction is a common complication and an important prognostic factor in chronic obstructive pulmonary disease (COPD). As therapeutic strategies are still needed to treat this complication, gaining more insight into the process that leads to skeletal muscle decline in COPD appears to be an important issue. This review focuses on mitochondrial involvement in limb skeletal muscle alterations (decreased muscle mass, strength, endurance and power and increased fatigue) in COPD. Mitochondria are the main source of energy for the cells; they are involved in production of reactive oxygen species and activate an important pathway that leads to apoptosis. In COPD patients, skeletal muscles are characterized by decreased mitochondrial density and biogenesis, impaired activity and coupling of mitochondrial respiratory chain complexes, increased mitochondrial production of reactive oxygen species and, possibly, increased apoptosis. Of particular interest, a sedentary lifestyle, hypoxia, hypercapnia, tobacco smoking, corticosteroid therapy and, possibly, inflammation participate in this mitochondrial dysfunction, which is accessible to conventional therapies, such as exercise and tobacco cessation, as well as, potentially, to more innovative approaches, such as antioxidant treatment and supplementation with polyunsaturated fatty acids. [ABSTRACT FROM AUTHOR]