Pathophysiology of peripheral muscle wasting in cardiac cachexia
Many different mechanisms have been proposed to explain muscle wasting in patients with heart failure; however, the pathogenesis remains largely obscure. This manuscript looks at current developments concerning the pathophysiology of skeletal muscle wasting in cardiac cachexia.
Many studies have shown that malnutrition, malabsorption, metabolic dysfunction, anabolic/catabolic imbalance, inflammatory and neurohormonal activation, and cell death play an important role in the pathogenesis of wasting in cardiac cachexia. However, the aetiology of the muscle changes is not entirely clear. In biopsies of skeletal muscles from animals with cardiac cachexia increased rates of protein degradation have been observed, with increased activity of the ubiquitin-proteasome proteolytic pathway. Skeletal muscle apoptosis may also play a role in muscle atrophy and wasting and can be partly prevented by neurohormonal inhibition, but it has recently been reported that in cachectic patients with chronic heart failure apoptosis is not the main pathway of cell death and muscle loss.
Many hypotheses have been used to explain the pathogenesis of muscle wasting in cardiac cachexia. Cardiac cachexia is a multifactorial disorder, and the targeting of different pathways will be necessary for effective treatment. The immune and neurohormonal abnormalities present in chronic heart failure may play a significant role in the pathogenesis of the wasting process. It has been suggested that common pathogenetic mechanisms underlie the loss of muscle mass in different cachectic states. More studies are needed to show whether there is a common pathway in cardiac cachexia and the other cachectic states.
Available from: Norman Mangner
- "Impaired skeletal muscle function is frequently seen in a large variety of systemic disorders including congestive heart failure (CHF) and sepsis , . While the above disorders develop in quite distinct clinical conditions, they all inflict similar skeletal muscles dysfunctions, including impaired contractility, reduced muscle protein synthesis, and enhanced muscle protein degradation and ubiquitination , , . However, not only are the peripheral muscles affected by these mechanisms but also the respiratory muscles, in particular the diaphragm, which may also develop a secondary myopathy . "
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ABSTRACT: Inflammatory cytokines like tumor necrosis factor alpha (TNF-α) are elevated in congestive heart failure and are known to induce the production of reactive oxygen species as well as to deteriorate respiratory muscle function.
Given the antioxidative effects of exercise training, the aim of the present study was to investigate if exercise training is capable of preventing a TNF-α induced loss of diaphragmatic force in mice and, if so, to elucidate the potential underlying mechanisms.
Prior to intraperitoneal injection of TNF-α or saline, C57Bl6 mice were assigned to four weeks of exercise training or sedentary behavior. Diaphragmatic force and power generation were determined in vitro. Expression/activity of radical scavenger enzymes, enzymes producing reactive oxygen species and marker of oxidative stress were measured in the diaphragm.
In sedentary animals, TNF-α reduced specific force development by 42% concomitant with a 2.6-fold increase in the amount of carbonylated α-actin and creatine kinase. Furthermore, TNF-α led to an increased NAD(P)H oxidase activity in both sedentary and exercised mice whereas xanthine oxidase activity and intramitochondrial ROS production was only enhanced in sedentary animals by TNF-α. Exercise training prevented the TNF-α induced force reduction and led to an enhanced mRNA expression and activity of glutathione peroxidase. Carbonylation of proteins, in particular of α-actin and creatine kinase, was diminished by exercise training.
TNF-α reduces the force development in the diaphragm of mice. This effect is almost abolished by exercise training. This may be a result of reduced carbonylation of proteins due to the antioxidative properties of exercise training.
PLoS ONE 01/2013; 8(1):e52274. DOI:10.1371/journal.pone.0052274 · 3.23 Impact Factor
Available from: Andreo Fernando Aguiar
- "With skeletal muscle atrophy , myonuclei numbers decrease, decreasing DNA units in overtrained muscle, thereby decreasing synthesis and increasing degradation rate of muscle proteins; this promotes the development of overtraining myopathy (Seene et al., 1999). Although the mechanisms responsible for muscle atrophy are not completely defined, several factors seem to be involved; these include reduced neuromuscular activity, systemic activation of neurohormones and inflammatory cytokines (Dalla Libera et al., 2001; Filippatos et al., 2005), myostatin/follistatin imbalance (Lima et al., 2010), and ubiquitin-proteasome pathway activation (Schulze and Upä te, 2005). The ubiquitin-proteasomal pathway, which includes the muscle-specific E3 ligases, atrogin-1/muscle atrophy F-box (MAFbx), and muscle RING Finger 1 (MuRF1), is known to be a powerful contributor to muscle proteolysis (Bodine et al., 2001; Gomes et al., 2001). "
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ABSTRACT: The aim of this study was to test whether high-intensity resistance training with insufficient recovery time between bouts, could result in a decrease of muscle fiber cross-sectional area (CSA), alter fiber-type frequencies and myosin heavy chain (MHC) isoform content in rat skeletal muscle. Wistar rats were divided into two groups: trained (Tr) and control (Co). Tr group were subjected to a high-intensity resistance training program (5 days/week) for 12 weeks, involving jump bouts into water, carrying progressive overloads based on percentage body weight. At the end of experiment, animals were sacrificed, superficial white (SW) and deep red (DR) portions of the plantaris muscle were removed and submitted to mATPase histochemical reaction and SDS-PAGE analysis. Throughout the experiment, both groups increased body weight, but Tr was lower than Co. There was a significant reduction in IIA and IID muscle fiber CSA in the DR portion of Tr compared to Co. Muscle fiber-type frequencies showed a reduction in Types I and IIA in the DR portion and IID in the SW portion of Tr compared to Co; there was an increase in Types IIBD frequency in the DR portion. Change in muscle fiber-type frequency was supported by a significant decrease in MHCI and MHCIIa isoforms accompanied by a significant increase in MHCIIb isoform content. MHCIId showed no significant differences between groups. These data show that high-intensity resistance training with insufficient recovery time between bouts promoted muscle atrophy and a transition from slow-to-fast contractile activity in rat plantaris muscle.
The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 08/2011; 294(8):1393-400. DOI:10.1002/ar.21428 · 1.54 Impact Factor
Available from: unirioja.es
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ABSTRACT: Objective: To analyze the existing nutritional situation in the patients with heart failure and its repercussion on mortality and stay. Method: Observational prospective descriptive study on 60 patients entered in cardiological ICU by heart failure between 24/05/2005 and 18/01/2006. There were excluded patients submissive recent surgery excluded themselves cardiac and in which nutritionals parameters were not obtained. Data on age, sex, fraction ejection, added nutritionals factors of risk took shelter, albumen, prealbumin total proteins and haemoglobin, as much to the entrance as weekly until the discharge or operation, in addition to the survival and hospital stay. Statistical analysis: SPSS 11.0 and SBS. Results: 73% were men. Average age 65,7±12,8 (27-87) A 47% presents/displays nutrition difficulties. To entrance 67% they had total proteins (TP) low, 55% albumin, 81% prealbumin (47% the 3) and 26.6% haemoglobin. In the first week they show an increase of PT (p=0,004) that stays in 2ª (p=0,05) The haemoglobin significantly diminishes during the entrance (p=0,015) 91% of the patients were put under depletive treatment. ?2 shows greater hospitable mortality (p<0,05) in patients with low TP, greater low albumen incidence in greater of 70 years (p<0,05) and more inferior numbers of prealbumin to the normal rank to the entrance that to the discharge (p<0,01) significant nondifferences between sexes, stay and fraction of ejection. Conclusions: the malnutrition in the heart failure is very high and worsens the prognosis. Nursing is responsible of the precocious detection, the design of suitable diets, its administration in the hospital and the education patient - family who assures the later maintenance. Objetivo: Analizar la situación nutricional existente en los pacientes con Insuficiencia Cardiaca (IC) y su repercusión sobre mortalidad y estancia. Método: Estudio prospectivo observacional descriptivo sobre 60 pacientes ingresados en UCI cardiológica por IC entre 24/05/2005 y 18/01/2006. Se excluyeron los pacientes sometidos a cirugía cardiaca reciente y en los que no se consiguieron parámetros nutricionales. Se recogieron datos sobre edad, sexo, fracción eyección, factores de riesgo nutricionales añadidos, albúmina, prealbúmina proteínas totales y hemoglobina, tanto al ingreso como semanalmente hasta el alta o intervención quirúrgica, además de la supervivencia y estancia hospitalaria. Análisis estadístico: SPSS versión 11.0 y SBS. Resultados: el 73% fueron hombres. Edad media 65,7±12,8 (27-87) Un 47% presentan dificultades de nutrición. Al ingreso 67% tenían proteínas totales (PT) bajas, 55% albúmina, 81% prealbúmina (47% los 3) y 26,6% hemoglobina. A la semana muestran un aumento de PT (p=0,004) que se mantiene en la 2ª (p=0,05) La hemoglobina disminuye significativamente durante el ingreso (p=0,015) El 91% de los pacientes fueron sometidos a tratamiento depletivo. ?2 muestra mayor mortalidad hospitalaria (p<0,05) en pacientes con PT bajas, mayor incidencia de albúmina baja en mayores de 70 años (p<0,05) y más cifras de prealbúmina inferiores al rango normal al ingreso que al alta (p<0,01) No diferencias significativas entre sexos, estancia y fracción de eyección. Conclusiones: la desnutrición en la IC es muy alta y empeora el pronóstico. Es misión de enfermería la detección precoz, el diseño de dietas adecuadas, su administración en el hospital y la educación paciente-familia que asegure el mantenimiento posterior.
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