Abstract
Exposure to microgravity induces skeletal muscle disorders including atrophy, muscle force decrease, fiber-type shift. Microgravity also contributes to immune-function alterations and modifies microRNAs (miRs) expression. To understand the link between microgravity-induced skeletal muscle atrophy and immune function deregulation, a bioinformatics study was performed. The web platform MiRNet was used for miRs-targets interaction analysis from previous proteomic studies on human soleus (SOL) and vastus lateralis (VL) muscles. We predicted miRs targeting deregulated gene expression following bed rest as a model of microgravity exposure; namely, let-7a-5p, miR-125b-5p for over-expressed genes in SOL and VL; miR-1-3p, miR-125b-5p and miR-1-3p, miR-95-5p for down-expressed genes in VL and SOL. The predicted miRs have important immune functions, exhibiting a significant role on both inflammation and atrophy. Let-7a down-expression leads to proliferation pathways promotion and differentiation pathway inhibition, whereas miR-1-3p over-expression yields anti-proliferative effect, promoting early differentiation. Such conflicting signals could lead to impairment between proliferation and differentiation in skeletal muscles. Moreover, promotion of an M2-like macrophage phenotype (IL-13, IL-10) by let-7a down-regulation and simultaneous promotion of an M1-like macrophage (IL-6, TNF-α) phenotype through the over-expression of EEF2 lead to a deregulation between M1/M2 tuning, that is responsible for a first pro-inflammatory/proliferative phase followed by an anti-inflammatory pro-myogenic phase during skeletal muscle regeneration after injury. These observations are important to understand the mechanism by which inflammation may play a significant role in skeletal muscle dysfunction in spaceflights, providing new links between immune response and skeletal muscle deregulation, which may be useful to further investigate possible therapeutic intervention.
Highlights
Microgravity poses one of the greatest risks to astronauts during prolonged missions (Williams et al, 2009)
The aim of the present work is to explore the mechanism by which the immune response to simulated microgravity may play a role in skeletal muscle dysfunction in spaceflights, providing a new mechanism linking the action of inflammatory cytokines to skeletal muscle deregulation
A list of modulated SOL and vastus lateralis (VL) miRs was used for miRNet analysis to look for miRs-targets connections
Summary
Microgravity poses one of the greatest risks to astronauts during prolonged missions (Williams et al, 2009). Exposure to microgravity results in decreased muscle strength and endurance, raising concerns that muscle atrophy could increase long-term spaceflight risk unless adequate countermeasures were undertaken. Muscle specific miRs (myomiRs) regulate several processes in skeletal muscle, such as myogenesis, muscle homeostasis and response to external stimuli. Muscle-specific miRs (myomiRs) control various processes in skeletal muscles, from myogenesis and muscle homeostasis to responses to environmental stimuli, such as exercise. We hypothesized that links might exist between skeletal muscle atrophy and inflammation deregulation triggered by microgravity. The aim of the present work is to explore the mechanism by which the immune response to simulated microgravity may play a role in skeletal muscle dysfunction in spaceflights, providing a new mechanism linking the action of inflammatory cytokines to skeletal muscle deregulation. MiRNet, an easyto-use web-based tool, helped us to identify new regulatory mechanisms associated to immune microgravity muscle atrophy
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