Muscle Proteolysis Induced by a Circulating Peptide in Patients with Sepsis or Trauma

Abstract

Accelerated proteolysis of muscle is characteristic in patients with trauma or sepsis, but its cause is not well understood. Using rat muscle in vitro, we developed a bioassay to compare the proteolytic activity of plasma from 50 patients with trauma or sepsis with that of plasma from 14 normal volunteers and from 15 patients who had undergone "clean" elective surgical procedures. The mean proteolytic activity in the plasma of patients with trauma or sepsis was found to be 190 +/- 8.0 per cent of the control value (rat muscle incubated in medium alone), whereas the activity in normal plasma was 124 +/- 4.5 per cent (P less than 0.001). The activity in the plasma of patients who had undergone elective surgery was slightly elevated at 142 +/- 2.5 per cent (P less than 0.005). In 25 of the patients with trauma or sepsis the rate of amino acid release from one leg was measured by subtracting the concentration of tyrosine plus phenylalanine in the femoral artery plasma from that in the femoral vein; this rate correlated well with the bioactivity of the plasma in the bioassay system (r = 0.67, P less than 0.001). By means of ultrafiltration and chromatography, the plasma factor inducing proteolysis was isolated and found to be a peptide, probably containing sialic acid, with a chain of 33 amino acids and a molecular weight of approximately 4274 daltons.

Bioactivity of skeletal muscle proteolysis-inducing factors in the plasma proteins from cancer patients with weight loss

“…TNF-a has been suggested to contribute to the development of the complex metabolic changes leading to cachexia because it suppresses lipoprotein lipase activity (Kawakami & Cerami, 1981;Semb et al, 1987); and rodents given daily injections of this cytokine (Stovroff et al, 1988;Tracey et al, 1988), or inoculated with a TNF/cachectinsecreting tumour (Oliff et al, 1987) progressively decline food intake and develop severe body wasting. Recent studies have revealed that mobilisation of amino acids from skeletal muscle tissue of patients undergoing infectious illness, trauma or sepsis is mediated by a hormone-like protein called proteolysis-inducing factor (PIF) (Clowes et al, 1983). This protein secreted by activated monocytes may be IL-1 or a IL-i-like peptide (Baracos et al, 1983;Dinarello et al, 1984).…”

“…In fact, we detected moderate levels of IL-1-P in six of the 20 plasma samples from cancer patients. IL-1 and an IL-1-derived fragment may be the causative agents of accelerated skeletal muscle protein catabolism in febrile patients (Clowes et al, 1983;Baracos et al, 1983;Dinarello et al, 1984). In agreement with these reports, it was shown here that recombinant human IL-1-o and IL-1-P can stimulate protein catabolism in a rat-diaphragm muscle bioassay.…”

Sarcopenia and its implications for the elderly

“…Activation of the immune system leads to production of in¯ammatory cytokines such as interleukin-1b (IL-1), tumor necrosis factor (TNF), and interleukin-6 (IL-6), which can cause amino acid export from muscle (Baracos et al, 1983;Clowes et al, 1983;Tsujinaka et al, 1996). Such a situation has been clearly demonstrated for acute illness and for chronic in¯ammatory conditions such as rheumatoid arthritis and HIV infection (Roubenoff et al, 1994).…”

Dantrolene ameliorates the metabolic hallmarks of sepsis in rats and improves survival in a mouse model of endotoxemia.

“…Accelerated breakdown of muscle protein with marked muscle wasting and increased glucose uptake and glycolysis are hallmarks of sepsis (13,15 Dantrolene is known to act byinhibiting release but not uptake of calcium from thesarcoplasmic reticulum (16). In addition to malignant hyperthermia (16), dantrolene has been reported to be effective in treating patients with chronic myopathies characterized by muscle wasting (19).…”

“…It is important to relate the increase in [Ca2+]i in sepsis to the metabolic abnormalities that characterize the septic response to establish that increased [Ca2eli is a critical element in the pathogenesis ofthe disorder. Hallmarks of sepsis include an increase in protein degradation (13), increase in lactate (14), and increase in glucose uptake and utilization in skeletal muscle (15).…”