INCREASED MESSENGER-RNA LEVELS FOR COMPONENTS OF THE LYSOSOMAL, CA2-ACTIVATED, AND ATP-UBIQUITIN-DEPENDENT PROTEOLYTIC PATHWAYS IN SKELETAL-MUSCLE FROM HEAD TRAUMA PATIENTS()

The cellular mechanisms responsible for enhanced muscle protein breakd own in hospitalized patients, which frequently results in lean body wa sting, are unknown, To determine whether the lysosomal, Ca2+-activated , and ubiquitin proteasome proteolytic pathways are activated, we meas ured mRNA levels for components of these processes in muscle biopsies from severe head trauma patients, These patients exhibited negative ni trogen balance and increased rates of whole-body protein breakdown (as sessed by [C-13]leucine infusion) and of myofibrillar protein breakdow n (assessed by 3-methylhistidine urinary excretion), Increased muscle mRNA levels for cathepsin D, m-calpain, and critical components of the ubiquitin proteolytic pathway (i.e., ubiquitin, the 14-kDa ubiquitin- conjugating enzyme E2, and proteasome subunits) paralleled these metab olic adaptations, The data clearly support a role for multiple proteol ytic processes in increased muscle proteolysis. The ubiquitin proteoly tic pathway could be activated by altered glucocorticoid production an d/or increased circulating levels of interleukin 1 beta and interleuki n 6 observed in head trauma patients and account for the breakdown of myofibrillar proteins, as was recently reported in animal studies.