Projects / Programmes
Molecular mechanisms of specificity in regulation of secretion and action of muscle-derived cytokines
| Code |
Science |
Field |
Subfield |
| 3.07.00 |
Medical sciences |
Metabolic and hormonal disorders |
|
| 3.01.00 |
Medical sciences |
Microbiology and immunology |
|
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
Myokines, skeletal muscle, IL-6, pro-inflammatory cytokines, tocilizumab, JAK inhibitors
Data for the last 5 years (citations for the last 10 years) on
December 5, 2023;
A3 for period
2017-2021
Data for ARIS tenders (
04.04.2019 – Programme tender,
archive
)
| Database |
Linked records |
Citations |
Pure citations |
Average pure citations |
| WoS |
919 |
33,896 |
30,454 |
33.14 |
| Scopus |
817 |
37,613 |
34,085 |
41.72 |
Researchers (25)
Organisations (4)
Abstract
Title: Molecular mechanisms of specificity in regulation of secretion and action of muscle-derived cytokines Acronym: MyoCRINE Background: Physical activity is one of the most effective measures against chronic non-communicable diseases (NCDs), including obesity, type 2 diabetes, cardiovascular diseases, some types of cancer, and neuropsychiatric disorders. Secretion of interleukin-6 (IL-6) and other myokines from contracting skeletal muscle is thought to represent a major mechanism by which exercise protects against these diseases. Myokine signalling could therefore be exploited for pharmacological treatment of these diseases. Unfortunately, clinically useful myokine-based therapies have not emerged. In contrast, therapies that block the action of IL-6, a prototypical myokine and the founding member of the myokine family, have had great clinical success in rheumatology. Thus, there seems to be a major gap in our understanding of beneficial effects of IL-6 as a myokine. Problem identification: Increase in IL-6 secretion from contracting skeletal muscles during exercise suppresses inflammation and improves metabolic homeostasis. In contrast, increased IL-6 secretion from immune cells and adipose tissue, which occurs in chronic inflammatory rheumatic diseases, obesity, physical inactivity, as well as ageing, promotes inflammation and leads to metabolic dysregulation. Mechanisms which determine whether IL-6 opposes or promotes inflammatory processes and impairment of metabolic regulation have not been explained. Hypotheses: To explain the opposing actions of IL-6 and overcome the gaps in current explanations, we formulated three hypotheses: 1) Contractions and other stimuli lead to secretion of distinct intracellular pools of IL-6; 2) Muscle- and stimulus-specific posttranslational modifications modulate actions of IL-6; 3) IL-6 has alternative (non-canonical) IL-6 receptor(s). Objectives of the project: The overarching objective of the MyoCRINE project is to reconcile the contradictory and opposing actions of muscle-derived IL-6 (a myokine) vs. IL-6 that is derived from other sources (not a myokine). Specific objectives of the project are: 1) To explore whether and how contractions regulate specific intracellular pools of IL-6; 2) To investigate regulation and biological roles of posttranslational modifications of IL-6, 3) To investigate the role of non-canonical IL-6 receptors. Implementation: The objectives of the MyoCRINE project will be met by an interdisciplinary team of basic biomedical researchers from Faculty of Medicine (University of Ljubljana) and Jozef Stefan Institute in collaboration with researchers and clinicians from Department of Rheumatology (University Medical Centre Ljubljana) and Intensive Care Unit (General and Teaching Hospital Celje). The interdisciplinary team will carry out state-of-the-art research using advanced techniques and models, such as in vitro innervated contracting human skeletal muscle cells, advanced quantitative fluorescence microscopy with confocal and super-resolution microscopy STED and SIM, proximity-dependent biotin identification (BioID), as well as standard techniques of molecular biology. Collaboration with clinical specialist in rheumatology and intensive care will enable analysis of clinical data and samples, thus increasing the likelihood of translation from bench to bedside. Significance: The MyoCRINE project is expected to make significant new contributions to the field of IL-6 and myokine biology as regards molecular mechanisms of varied and contradictory biological actions of IL-6. Investigation of posttranslational modifications of IL-6 may contribute to development of new diagnostic tests that detect IL-6 molecules with different tissue sources or biological actions. Further, if alternative IL-6 receptor exists, it could represent a novel pharmacological target.
