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Desmin Degradation in Skeletal Muscles of Patients with Chronic Critical Illness

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Abstract

Patients with chronic critical illness lose a considerable portion of their muscle mass while hospitalized in an intensive care unit, which can have long-term detrimental effects. Among other factors, this leads to a disintegration of muscle cytoskeleton, and currently there are no comprehensive studies describing the mechanisms behind the development of this pathology. Here, we aimed to investigate the signaling processes that contribute to desmin degradation in patients with critical illness myopathy (CIM). Incisional needle biopsies of the soleus muscle were taken from 6 patients with a chronic (≥ 2 months) disorder of consciousness, undergoing treatment at the Polenov Neurosurgical Institute (Almazov National Medical Research Center, St. Petersburg) and healthy men (control). Muscle tissue samples were frozen in liquid nitrogen for subsequent Western blot and PCR analyses, as well as immunohistochemical examination. The analysis showed that fibers with an altered histological desmin pattern were visually identified in 4 out of 6 patients. A significant decrease in desmin (by 69%) and its mRNA (by 24%) levels was observed in patients with CIM. Desmin degradation is known to occur due to increased calpain activity and activation of the ubiquitin-proteasome system. In this study, calpain-1 content increased in CIM patients at the protein level, while remaining unchanged at the mRNA level. We detected changes in GSK3-β Ser9-phosphorylation, which is a critical step in calpain-1-mediated depolymerization of desmin filaments. A study of ubiquitin ligases revealed a significant 155% increase in Trim32 expression paralleled by a decrease in Atrogin1 and MuRF1 expression. Thus, we observed a decrease in desmin content under CIM conditions. Desmin degradation may result from its increased GSK3β-mediated phosphorylation and subsequent calpain-1-mediated cleavage. Moreover, we found an increase in the expression of the E3 ubiquitin ligase Trim32 whose activity, according to the literature, also rises after desmin phosphorylation.

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ACKNOWLEDGMENTS

The authors are grateful to E.M. Lednev and T.F. Vepkhvadze for doing a needle biopsy, K.K. Kukanov and N.E. Voinov for collecting a biopsy material from the study group of patients.

Funding

The work was supported by the Russian Science Foundation (project No. 22-25-00615).

Author information

Authors and Affiliations

  1. Institute of Biomedical Problems, Russian Academy of Sciences, Moscow, Russia

    S. A. Tyganov, K. A. Zaripova, O. S. Turtikova, E. N. Skiteva, S. P. Belova & B. S. Shenkman

  2. Polenov Neurosurgical Institute, Almazov National Medical Research Centre, St. Petersburg, Russia

    E. N. Skiteva, Yu. M. Zabrodskaya, E. A. Kondratieva & A. N. Kondratiev

  3. AIMIS Healthcare Group, Сlinic Athonitissa, Limassol, Cyprus

    S. A. Kondratiev

  4. Kirov Military Medical Academy, St. Petersburg, Russia

    E. A. Kondratieva

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  1. S. A. Tyganov
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Contributions

Conceptualization and experimental design (B.S.Sh., A.N.K., Yu.M.Z., S.A.K.), biopsy material collection (S.A.K., E.N.S.), data collection (S.A.T., E.N.S., S.P.B., K.A.Z., O.N.T.), data processing (S.A.T., S.P.B., K.A.Z., O.N.T.), writing and editing the manuscript (S.A.T., B.S.Sh., E.A.K., S.A.K., Yu.M.Z.).

Corresponding author

Correspondence to S. A. Tyganov.

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ETHICS APPROVAL

All experimental procedures with the participation of human subjects complied the ethical standards of the National Research Ethics Committee and the 1964 Declaration of Helsinki with its subsequent revisions, or comparable ethical standards. All participants or their legal representatives gave their informed consent to be involved in research. The study was approved by the local Ethics Committee No. 1411-20 at Almazov National Medical Research Center (excerpt from the minutes of the meeting No. 11–20 dated November 16, 2020).

CONFLICT OF INTEREST

The authors declare that they have no conflict of interest.

Additional information

Translated by A. Polyanovsky

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Russian Text © The Author(s), 2023, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2023, Vol. 109, No. 12, pp. 1952–1962https://doi.org/10.31857/S0869813923120129.

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Tyganov, S.A., Zaripova, K.A., Turtikova, O.S. et al. Desmin Degradation in Skeletal Muscles of Patients with Chronic Critical Illness. J Evol Biochem Phys 59, 2381–2389 (2023). https://doi.org/10.1134/S0022093023060388

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