Cachectin/tumor necrosis factor mediates changes of skeletal muscle plasma membrane potential.

Abstract

Invasive bacterial infection in mammals often stimulates a fatal syndrome of hypotension, organ dysfunction and somatic tissue edema (1). This systemic response to critical illness in man is associated with somatic cell injury, as measured by a decrease in skeletal muscle transmembrane potential difference (Em), increased cellular sodium and water levels, and depletion of cellular potassium stores (2). These alterations in plasma membrane function are not temporally related to inadequate tissue perfusion or to depletion of high-energy phosphate stores (3). To date. no direct mediator for this deterioration of plasma membrane and electrolyte homeostasis has been identified .Recent work (4, 5) has shown that cachectin/tumor necrosis factor (TNF) is an important mediator of the lethal effects of endotoxin/LPS (6), and is produced in large quantities by macrophages exposed to endotoxin (7,8). High-affinity receptors for cachectin (7) stimulate altered cellular energy metabolism both in vivo and in vitro, but the evaluation of target tissues thus far has not demonstrated any adverse influence on normal cell viability. Several host tissues possess cachectin receptors (muscle, adipose, liver) (7) and exhibit extracellular responses at low receptor occupancy, a characteristic of many systemic mediators.Since passive immunization against cachectin confers a survival advantage in endotoxin/LPS-treated animals (6), we hypothesized that this monokine might affect skeletal muscle plasma membrane function during endotoxemia and shock. In this study, we observed that cachectin stimulated skeletal muscle fiber depolarization in an isolated muscle model. The plasma membrane response was prevented by pretreatment of cachectin with specific antibody to cachectin, and was not due to endotoxin/LPS. Measurement of muscle En, in vivo showed a similar decline after cachectin infusion .Recombinant human cachectin was prepared from a yeast expression system by previously described methods (4) and diluted in Krebs-Ringer-bicarbonate buffer (KRB) to the

Complete heart block in association with graft-versus-host disease

“…9 They suggested that tumor necrosis factor (TNF) may have caused the reversible heart block seen in their patient since TNF impairs muscle electrical activity. 10 TNF also decreases myocardial contractility. 11 Although tachyarrhythmias are more common, bradyarrhythmias and complete heart block have also been described in association with the therapeutic use of interleukin-2.…”

Participation of tumor necrosis factor in the mediation of gram negative bacterial lipopolysaccharide-induced injury in rabbits.

“…In an earlier study, 3/23 septic patients were found to have TNF levels of 3-20 pg/ml (71). Tracy et al employed a skeletal muscle depolarization assay to detect picomolar levels of TNF in plasma samples of critically ill patients (72,73). Using an ELISA with a sensitivity of 39 pg TNF/ml, Scuderi et al observed that TNF levels were frequently elevated in patients with kala-azar or malaria (67 and 70%, respectively; geometric mean 1 9 pg/ml) (74).…”

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

“…However, the above-mentioned CLP study did not claim to establish a cause-effect relationship for dantrolene to exclusively act on muscle [Ca 2ϩ ] i , since 1) only one time point was investigated (16 h post CLP or sham) and 2) dantrolene also significantly reduced plasma TNF-␣ and corticosteroids levels (202). Since TNF-␣ at 10 nM levels is known to depolarize resting membrane potentials in whole EDL and soleus muscles already after short incubation (712), it can be speculated that the associated increase seen in [Ca 2ϩ ] i in sepsis 16 h post-CLP may rather be an effect of increased plasma TNF-␣ because membrane depolarization has been shown to increase the membrane permeability towards Ca 2ϩ (120,188,771). Since the enhanced Ca 2ϩ uptake in K ϩ depolarized skeletal muscle from septic rats was blocked (57).]…”