Sepsis is associated with increased mRNAs of the ubiquitin-proteasome proteolytic pathway in human skeletal muscle.

Abstract

Previous studies provided evidence that sepsis-induced muscle proteolysis in experimental animals is caused by increased ubiquitin-proteasome-dependent protein breakdown.It is not known if a similar mechanism accounts for muscle proteolysis in patients with sepsis.We determined mRNA levels for ubiquitin and the 20 S proteasome subunit HC3 by Northern blot analysis in muscle tissue from septic ( n ϭ 7) and non-septic ( n ϭ 11) patients.Plasma and muscle amino acid concentrations and concentrations in urine of 3-methylhistidine (3-MH), creatinine, and cortisol were measured at the time of surgery to assess the catabolic state of the patients.A three-to fourfold increase in mRNA levels for ubiquitin and HC3 was noted in muscle tissue from the septic patients concomitant with increased muscle levels of phenylalanine and 3-MH and reduced levels of glutamine.Total plasma amino acids were decreased by ‫ف‬ 30% in the septic patients.The 3-MH/creatinine ratio in urine was almost doubled in septic patients.The cortisol levels in urine were higher in septic than in control patients but this difference did not reach statistical significance.The results suggest that sepsis is associated with increased mRNAs of the ubiquitin-proteasome pathway in human skeletal muscle.( J. Clin.Invest.1997.99:163-168.)Key words: sepsis • ubiquitin • proteasome • muscle • proteolysis • human Methods Two groups of consecutive patients undergoing abdominal surgery were included in the study.One group ( n ϭ 7) consisted of patients with sepsis based on the following criteria: ( a ) clinical evidence of infection; ( b ) fever (body temperature Ͼ 38 Њ C) or hypothermia (body temperature Յ 36 Њ C); ( c ) tachycardia (heart rate Ͼ 90/min); ( d ) tachypnea (respiration rate Ͼ 20/min) or patient on ventilator; ( e ) positive blood culture was not required.These criteria were based on a report by Bone (9).The other group ( n ϭ 11) consisted of patients undergoing elective laparotomy for various non-septic conditions, such as peptic ulcer disease, ventral hernia, diverticulosis, and vascu-