Long-term administration of the mitochondria-targeted antioxidant mitoquinone mesylate fails to attenuate age-related oxidative damage or rescue the loss of muscle mass and function associated with aging of skeletal muscle.

Age-related skeletal muscle dysfunction is the underlying cause of morbidity that affects up to half the population aged 80 and over. Considerable evidence indicates that oxidative damage and mitochondrial dysfunction contribute to the sarcopenic phenotype that occurs with aging. To examine this, we administered the mitochondria-targeted antioxidant mitoquinone mesylate {[10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl] triphenylphosphonium; 100 µM} to wild-type C57BL/6 mice for 15 wk (from 24 to 28 mo of age) and investigated the effects on age-related loss of muscle mass and function, changes in redox homeostasis, and mitochondrial organelle integrity and function. We found that mitoquinone mesylate treatment failed to prevent age-dependent loss of skeletal muscle mass associated with myofiber atrophy or alter a variety of in situ and ex vivo muscle function analyses, including maximum isometric tetanic force, decline in force after a tetanic fatiguing protocol, and single-fiber-specific force. We also found evidence that long-term mitoquinone mesylate administration did not reduce mitochondrial reactive oxygen species or induce significant changes in muscle redox homeostasis, as assessed by changes in 4-hydroxynonenal protein adducts, protein carbonyl content, protein nitration, and DNA damage determined by the content of 8-hydroxydeoxyguanosine. Mitochondrial membrane potential, abundance, and respiration assessed in permeabilized myofibers were not significantly altered in response to mitoquinone mesylate treatment. Collectively, these findings demonstrate that long-term mitochondria-targeted mitoquinone mesylate administration failed to attenuate age-related oxidative damage in skeletal muscle of old mice or provide any protective effect in the context of muscle aging.-Sakellariou, G. K., Pearson, T., Lightfoot, A. P., Nye, G. A., Wells, N., Giakoumaki, I. I., Griffiths, R. D., McArdle, A., Jackson, M. J. Long-term administration of the mitochondria-targeted antioxidant mitoquinone mesylate fails to attenuate age-related oxidative damage or rescue the loss of muscle mass and function associated with aging of skeletal muscle.

Metabolic and nutritional support of critically ill patients: consensus and controversies.

The results of recent large-scale clinical trials have led us to review our understanding of the metabolic response to stress and the most appropriate means of managing nutrition in critically ill patients. This review presents an update in this field, identifying and discussing a number of areas for which consensus has been reached and others where controversy remains and presenting areas for future research. We discuss optimal calorie and protein intake, the incidence and management of re-feeding syndrome, the role of gastric residual volume monitoring, the place of supplemental parenteral nutrition when enteral feeding is deemed insufficient, the role of indirect calorimetry, and potential indications for several pharmaconutrients.

Sedation, delirium and psychological distress: let's not be deluded.

New ways of approaching sedation and analgesia are being considered in our endeavour to improve our management of the ventilated patient. Long-term psychological problems are not insignificant and before we can assume benefit or harm of any new approach we must not delude ourselves by using sampling methods that can miss those patients most at risk.

Intensive care unit-acquired weakness.

OBJECTIVE: Severe weakness is being recognized as a complication that impacts significantly on the pace and degree of recovery and return to former functional status of patients who survive the organ failures that mandate life-support therapies such as mechanical ventilation. Despite the apparent importance of this problem, much remains to be understood about its incidence, causes, prevention, and treatment. DESIGN: Review from literature and an expert round-table. SETTING: The Brussels Round Table Conference in 2009 convened more than 20 experts in the fields of intensive care, neurology, and muscle physiology to review current understandings of intensive care unit-acquired weakness and to improve clinical outcome. MAIN RESULTS: Formal electrophysiological evaluation of patients with intensive care unit-acquired weakness can identify peripheral neuropathies, myopathies, and combinations of these disorders, although the correlation of these findings to weakness measurable at the bedside is not always precise. For routine clinical purposes, bedside assessment of neuromuscular function can be performed but is often confounded by complicating factors such as sedative and analgesic administration. Risk factors for development of intensive care unit-acquired weakness include bed rest itself, sepsis, and corticosteroid exposure. A strong association exists between weakness and long-term ventilator dependence; weakness is a major determinant of patient outcomes after surviving acute respiratory failure and may be present for months, or indefinitely, in the convalescence phase of critical illness. CONCLUSION: Although much has been learned about the physiology and cell and molecular biology of skeletal and diaphragm dysfunction under conditions of aging, exercise, disuse, and sepsis, the application of these understandings to the bedside requires more study in both bench models and patients. Although a trend toward greater immobilization and sedation of patients has characterized the past several decades of intensive care unit care, recent studies have demonstrated that early physical and occupational therapy, including during the period of intubation and ventilator support, can be safely performed and will likely improve patient outcomes with regard to functional status.

Intensive care diaries reduce new onset post traumatic stress disorder following critical illness: a randomised, controlled trial.

INTRODUCTION: Patients recovering from critical illness have been shown to be at risk of developing Post Traumatic Stress disorder (PTSD). This study was to evaluate whether a prospectively collected diary of a patient's intensive care unit (ICU) stay when used during convalescence following critical illness will reduce the development of new onset PTSD. METHODS: Intensive care patients with an ICU stay of more than 72 hours were recruited to a randomised controlled trial examining the effect of a diary outlining the details of the patients ICU stay on the development of acute PTSD. The intervention patients received their ICU diary at 1 month following critical care discharge and the final assessment of the development of acute PTSD was made at 3 months. RESULTS: 352 patients were randomised to the study at 1 month. The incidence of new cases of PTSD was reduced in the intervention group compared to the control patients (5% versus 13%, P = 0.02). CONCLUSIONS: The provision of an ICU diary is effective in aiding psychological recovery and reducing the incidence of new PTSD. TRIAL REGISTRATION: NCT00912613.

Muscle in defense.

The physical inactivity of the critically ill patient is an abnormal state that compromises muscle function to an extent that the immobile skeletal muscle may not simply be a bystander in the disease process.Skeletal muscle seems to maintain a system of defense against inflammation through heat shock proteins and the production of myokines. It contributes in a bidirectional role in systemic inflammatory signaling and the modulation of the inflammatory response. Skeletal muscle is a major contributor to whole-body glucose and protein metabolism, exemplified by its role in nutrient provision for the immune system and other rapidly dividing tissues through glutamine production.

The role of hormones, cytokines and heat shock proteins during age-related muscle loss.

Ageing is associated with a progressive decline of muscle mass, strength, and quality, a condition known as sarcopenia. Due to the progressive ageing of western populations, age-related sarcopenia is a major public health problem. Several possible mechanisms for age-related muscle atrophy have been described; however the precise contribution of each is unknown. Age-related muscle loss is thought to be a multi-factoral process composed of events such as physical activity, nutritional intake, oxidative stress, inflammatory insults and hormonal changes. There is a need for a greater understanding of the loss of muscle mass with age as this could have a dramatic impact on the elderly and critically ill if this research leads to maintenance or improvement in functional ability. This review aims to outline the process of skeletal muscle degeneration with ageing, normal and aberrant skeletal muscle regeneration, and to address recent research on the effects of gender and sex steroid hormones during the process of age-related muscle loss.

Too much of a good thing: the curse of overfeeding.

Enteral nutrition (EN) gives a legacy of under nutrition in intensive care patients but few appreciate that parenteral nutrition (PN) carries the other risk of overfeeding if used injudiciously. Over-feeding presents a significant metabolic stress but tight glycaemic control is now masking the traditional warning signs and does not on its own negate the need to give patients the right amount at the right time.

Significant cognitive dysfunction in non-delirious patients identified during and persisting following critical illness.

OBJECTIVE: Recent studies have shown significant cognitive problems some months after critical illness. However there has been no research examining cognitive function within the intensive care unit (ICU) in non-delirious patients. DESIGN AND SETTING: A prospective study in an ICU. PATIENTS AND PARTICIPANTS: Using the Cambridge Neuropsychological Test Automated Battery (CANTAB), 30 long-stay, tracheal-intubated ICU patients were tested. Prior to testing on ICU the Confusion Assessment Measure (CAM-ICU) was administered and only those patients clearly not delirious and off sedation for several days were tested. The CANTAB tests were repeated a week after ICU discharge on the general ward and then again at 2 months. Sixteen patients completed the follow-up. RESULTS: While on ICU all 30 patients showed significant problems with strategic thinking and problem solving; 20 patients had some problems with memory. The degree of difficulty with problem solving on ICU was correlated with length of ICU stay (p=0.011), age (p=0.036) and length of hospital stay post ICU (p=0.044). Problems with memory in ICU and on the general ward were correlated with admission APACHE II score (p=0.004 and p=0.005 respectively). At the 2-month follow-up 5 of 16 patients (31%) scored below the 25 percentile for memory and 8 of 16 (50%) below the 25 percentile for problem solving (Slater TA, Jones C, Griffiths RD, Wilson S, Benjamin K (2004) Cognitive impairment during and after intensive care: a pilot study. Intensive Care Med 30 [Suppl 1]:S199). CONCLUSIONS: Difficulties with problem solving and poor memory remained a significant issue for 2 months after ICU discharge.

Time course and differential responses of the major heat shock protein families in human skeletal muscle following acute nondamaging treadmill exercise.

The exercise-induced expression of heat shock proteins (HSPs) in rodent models is relatively well defined. In contrast, comparable data from human studies are limited and the exercise-induced stress response of human skeletal muscle is far from understood. This study has characterized the time course and magnitude of the HSP response in the skeletal muscles of a healthy active, but untrained, young male population following a running exercise protocol. Eight subjects performed 45 min of treadmill running at a speed corresponding to their lactate threshold (11.7 +/- 0.5 km/h; 69.8 +/- 4.8% maximum O2 uptake). Muscle biopsies were obtained from the vastus lateralis muscle immediately before and at 24 h, 48 h, 72 h, and 7 days postexercise. Exercise induced a significant (P < 0.05) but variable increase in HSP70, heat shock cognate (HSC) 70, and HSP60 expression with peak increases (typically occurring at 48 h postexercise) to 210, 170, and 139% of preexercise levels, respectively. In contrast, exercise did not induce a significant increase in either HSP27, alphaB-crystallin, SOD 2 (MnSOD) protein content, or the activity of SOD and catalase. When examining baseline protein levels, HSC70, HSP27, and alphaB-crystallin appeared consistently expressed between subjects, whereas HSP70 and MnSOD displayed marked individual variation of up to 3- and 1.5-fold, respectively. These data are the first to define the time course and extent of HSP production in human skeletal muscle following a moderately demanding and nondamaging running exercise protocol. Data demonstrate a differential effect of aerobic exercise on specific HSPs.

Mitochondrial ROS regulate oxidative damage and mitophagy but not age-related muscle fiber atrophy.

Age-related loss of skeletal muscle mass and function is a major contributor to morbidity and has a profound effect on the quality of life of older people. The potential role of age-dependent mitochondrial dysfunction and cumulative oxidative stress as the underlying cause of muscle aging remains a controversial topic. Here we show that the pharmacological attenuation of age-related mitochondrial redox changes in muscle with SS31 is associated with some improvements in oxidative damage and mitophagy in muscles of old mice. However, this treatment failed to rescue the age-related muscle fiber atrophy associated with muscle atrophy and weakness. Collectively, these data imply that the muscle mitochondrial redox environment is not a key regulator of muscle fiber atrophy during sarcopenia but may play a key role in the decline of mitochondrial organelle integrity that occurs with muscle aging.

SS-31 attenuates TNF-α induced cytokine release from C2C12 myotubes.

TNF-α is a key inflammatory mediator and is proposed to induce transcriptional responses via the mitochondrial generation of Reactive Oxygen Species (ROS). The aim of this study was to determine the effect of TNF-α on the production of myokines by skeletal muscle. Significant increases were seen in the release of IL-6, MCP-1/CCL2, RANTES/CCL5 and KC/CXCL1 and this release was inhibited by treatment with Brefeldin A, suggesting a golgi-mediated release of cytokines by muscle cells. An increase was also seen in superoxide in response to treatment with TNF-α, which was localised to the mitochondria and this was also associated with activation of NF-κB. The changes in superoxide, activation of NF-kB and release of myokines were attenuated following pre-treatment with SS-31 peptide indicating that the ability of TNF-α to induce myokine release may be mediated through mitochondrial superoxide, which is, at least in part, associated with activation of the redox sensitive transcription factor NF-kB.

Post-traumatic stress disorder-related symptoms in relatives of patients following intensive care.

OBJECTIVE: To evaluate the effectiveness of the provision of information in the form of a rehabilitation program following critical illness in reducing psychological distress in the patients' close family. DESIGN: Randomised controlled trial, blind at follow-up with final assessment at 6 months. SETTING: Two district general hospitals and one teaching hospital. PATIENTS AND PARTICIPANTS: The closest family member of 104 recovering intensive care unit (ICU) patients. INTERVENTIONS: Ward visits, ICU clinic appointments at 2 and 6 months. Relatives and patients received the rehabilitation program at 1 week after ICU discharge. The program comprised a 6-week self-help manual containing information about recovery from ICU, psychological information and practical advice. MEASUREMENTS AND RESULTS: Psychological recovery of relatives was assessed by examining the rate of depression, anxiety, and post-traumatic stress disorder (PTSD)-related symptoms by 6 months after ICU. The proportion of relatives scoring in the range >19 on the Impact of Events Scale (cause for concern) was high in both groups at 49% at 6 months. No difference was shown in the rate of depression, anxiety, or PTSD-related symptoms between the study groups. CONCLUSION: A high incidence of psychological distress was evident in relatives. Written information concerning recovery from ICU provided to the patient and their close family did not reduce this. High levels of psychological distress in patients were found to be correlated with high levels in relatives.