RESUMEN
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.
RESUMEN
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.
Asunto(s)
Envejecimiento/fisiología , Antioxidantes/farmacología , Mesilatos/farmacología , Mitocondrias/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Compuestos Organofosforados/farmacología , Carbonilación Proteica/efectos de los fármacos , Ubiquinona/análogos & derivados , Animales , Antioxidantes/administración & dosificación , Femenino , Masculino , Mesilatos/administración & dosificación , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Enfermedades Musculares/tratamiento farmacológico , Enfermedades Musculares/metabolismo , Compuestos Organofosforados/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Ubiquinona/administración & dosificación , Ubiquinona/farmacologíaRESUMEN
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.
Asunto(s)
Depuradores de Radicales Libres/farmacología , Mitocondrias/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , Oligopéptidos/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Brefeldino A/farmacología , Línea Celular , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Regulación de la Expresión Génica , Aparato de Golgi/efectos de los fármacos , Aparato de Golgi/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Ratones , Mitocondrias/metabolismo , Fibras Musculares Esqueléticas/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Transducción de Señal , Superóxidos/antagonistas & inhibidores , Superóxidos/metabolismo , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
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.
Asunto(s)
Enfermedad Crítica/terapia , Ingestión de Energía , Nutrición Enteral/métodos , Nutrición Parenteral/métodos , Consenso , Proteínas en la Dieta/administración & dosificación , HumanosAsunto(s)
Lesión Pulmonar Aguda , Ingestión de Energía , Nutrición Enteral/métodos , Respiración Artificial , Femenino , Humanos , MasculinoRESUMEN
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.
Asunto(s)
Sedación Consciente/métodos , Cuidados Críticos/psicología , Femenino , Humanos , MasculinoRESUMEN
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.
Asunto(s)
Cuidados Críticos/métodos , Enfermedad Crítica/terapia , Registros Médicos , Trastornos por Estrés Postraumático/prevención & control , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Crítica/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/etiología , Adulto JovenRESUMEN
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.
Asunto(s)
Cuidados Críticos , Cuidados para Prolongación de la Vida , Insuficiencia Multiorgánica/terapia , Debilidad Muscular/etiología , Polineuropatías/etiología , Animales , Reposo en Cama , Convalecencia , Estudios Transversales , Modelos Animales de Enfermedad , Ambulación Precoz , Humanos , Tiempo de Internación/estadística & datos numéricos , Debilidad Muscular/epidemiología , Debilidad Muscular/prevención & control , Examen Neurológico , Terapia Ocupacional , Modalidades de Fisioterapia , Polineuropatías/epidemiología , Polineuropatías/prevención & control , Respiración Artificial , Insuficiencia Respiratoria/terapia , Factores de Riesgo , Sepsis/terapiaAsunto(s)
Enfermedad Crítica/rehabilitación , Unidades de Cuidados Intensivos , Tiempo de Internación/estadística & datos numéricos , Debilidad Muscular/rehabilitación , Reposo en Cama , Enfermedad Crítica/epidemiología , Humanos , Movimiento , Debilidad Muscular/epidemiología , Atención Dirigida al PacienteRESUMEN
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.
Asunto(s)
Proteínas de Choque Térmico/metabolismo , Inflamación/metabolismo , Músculo Esquelético/metabolismo , Sepsis/metabolismo , Animales , Enfermedad Crítica/rehabilitación , Glutamina/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , HumanosAsunto(s)
Amnesia/diagnóstico , Cuidados Críticos/psicología , Unidades de Cuidados Intensivos , Trastornos por Estrés Postraumático/diagnóstico , Amnesia/epidemiología , Enfermedad Crítica/psicología , Enfermedad Crítica/terapia , Deluciones/diagnóstico , Deluciones/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Tiempo de Internación , Masculino , Medición de Riesgo , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/psicología , Encuestas y Cuestionarios , SobrevivientesAsunto(s)
Neoplasias Abdominales/cirugía , Glucemia/metabolismo , Cuidados Críticos/métodos , Glutamina/sangre , Hiperglucemia/tratamiento farmacológico , Insulina/uso terapéutico , Proteínas Musculares/metabolismo , Complicaciones Posoperatorias/tratamiento farmacológico , Estudios Cruzados , Humanos , Hiperglucemia/sangre , Resistencia a la Insulina/fisiología , Nutrición Parenteral Total , Complicaciones Posoperatorias/sangre , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
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.
Asunto(s)
Métodos de Alimentación/efectos adversos , Cuidados Críticos/métodos , Enfermedad Crítica/terapia , Nutrición Enteral/efectos adversos , Nutrición Enteral/métodos , Humanos , Nutrición Parenteral/efectos adversos , Nutrición Parenteral/métodosRESUMEN
PURPOSE OF REVIEW: To examine current research on the psychological needs of both patients and their families following critical illness, and discuss how these may be met in a cost-effective manner. RECENT FINDINGS: Patients and their families have significant psychological problems following critical illness. To date, very few intensive care units have specialist psychological services to help with the aftermath of the illness experience. There are promising simple therapeutic interventions, such as intensive care unit diaries, that may be beneficial, but which require further research at present. SUMMARY: Currently, there is an awareness of the psychological sequelae of critical illness for patients and their family caregivers, and with this a responsibility to assess and appropriately help those who are unable to manage their distress. The development and application of specialist psychological services after an episode of critical illness, possibly using a stepped care model, is in its infancy. There are a few centres of excellence that are currently employing these resources, but the vast majority of patients and their families are left to cope on their own. This lack of psychological support has important implications for long-term recovery and quality of life following the episode of critical illness.