Desmin Degradation in the Skeletal Muscle of Patients with Chronic Critical Illness

Abstract

Chronically critically ill patients lose a significant amount of muscle mass during their stay in the intensive care unit, which can have long-term detrimental consequences. This, among other factors, leads to the degradation of the muscle cytoskeleton’s integrity, and at present there are no comprehensive studies that describe the mechanisms b-ehind the development of this process. The purpose of this study was to investigate the signaling processes that contribute to the degradation of desmin in patients with critical illness myopathy (CIM). Incisional muscle biopsies were taken from the soleus muscle from 6 patients undergoing treatment at the A.L. Polenov Russian Research Institute - branch of the Almazov National Medical Research Center, with chronic impairment of consciousness (lasting at least 2 months). Muscle biopsies taken from healthy men using a needle biopsy technique were used as controls. Biopsies were frozen in liquid nitrogen for subsequent Western blot and PCR analysis, as well as immunohistochemical studies. The analysis showed that fibers with an altered histological pattern of desmin were visually identified in 4 out of 6 patients studied. We also observed a significant decrease in desmin content by 69% and a 24% decrease in its mRNA content in patients with CIM. Desmin breakdown may be associated with increased calpain activity and activation of the ubiquitin-proteasome system. In this study, the content of calpain-1 increased under conditions of CIM at the protein level, but remained unchanged at the mRNA level. We observed changes in GSK3-β (Ser9) phosphorylation, which is a crucial step in the d-epolymerization of desmin filaments by calpain-1. A study on ubiquitin ligases revealed a significant 155% increase in the expression of Trim32, along with a decrease in the e-xpression of Atrogin1 and MuRF1. Thus, in this study, we observed a decrease in desmin content under conditions of CIM. The breakdown of desmin may be due to increased phosphorylation by GSK3β and subsequent cleavage by calpain-1. In addition, we observed an increase in the expression of the E3 ubiquitin ligase Trim32, the activity of which, according to literature, also increases after phosphorylation of desmin.