Irisin Protects Against Motor Dysfunction of Rats with Spinal Cord Injury via Adenosine 5'-Monophosphate (AMP)-Activated Protein Kinase-Nuclear Factor Kappa-B Pathway

Abstract

The aim of the present research was to investigate the effects of irisin, a skeletal muscle-derived myokine, on spinal cord injury (SCI) in rats and explore the possible mechanisms. SCI model was constructed in male SD rats. The effects of irisin on SCI rats were assessed via behavior tests including Basso, Beattie, and Bresnahan (BBB) scoring method and inclined plane test, followed by histomorphology tests including HE staining, Nissl staining, and transmission electron microscope examination. Biochemical analyses including PCR, Western blots and ELISA were employed to further evaluate the changes at molecular level of SCI rats. In addition, lipopolysaccharide (LPS)-induced cell damage model was established in PC12 cells to verify the mechanism of irisin’s effect on nerve cells in vitro . Results showed that the BBB score and the angle of incline significantly decreased after SCI surgery, however, chronic irisin treatment improved SCI-induced motor dysfunction. HE and Nissl staining assays showed that SCI surgery induced histological injury of spinal cord, which could be reversed by irisin treatment. Morphological abnormality of nerve cells caused by SCI also could be alleviated by irisin. Further biochemical analyses showed that irisin inhibited SCI-induced overexpression of Interleukin-1β (IL-1β), Interleukin- 6 (IL-6), tumor necrosis factor alpha (TNF-α), inducible nitricoxidesynthase (iNOS) and Cyclooxygenase-2 (COX-2)], as well as nuclear factor kappa-B (NF-κB)p65 in rats, and the positive function of irisin could be reversed by Compound C treatment. In our in vitro study, LPS-induced declines of cell viability and neurite length of PC12 cell were inhibited by irisin treatment, and irisin inhibited LPS-induced overexpression of NF-κBp65, IL-1β, IL-6, TNF-α, iNOS and COX-2. These changes could be reversed by activated protein kinase (AMPK) siRNA pre-treatment. Taken together, irisin could protect the rats from SCI, and its protection is associated with the regulation of adenosine 5'-monophosphate-activated protein kinase (AMPK) - NF-κB signaling pathway.

Irisin Stimulates the Release of CXCL1 From Differentiating Human Subcutaneous and Deep-Neck Derived Adipocytes via Upregulation of NFκB Pathway

“…The absence of TNFα or IL-1β-upregulation and release during the differentiation in the presence of irisin excluded the possibility of endotoxin contamination of the recombinant hormone. Although irisin was reported previously to inhibit LPS-induced NFκB activation ( Mazur-Bialy et al, 2017 ; Jiang et al, 2020 ), adipocytes differentiated in the presence of both SN50 and irisin released less CXCL1 than those of treated with irisin alone ( Figure 5E ). Further research is needed to explore the irisin-induced molecular events in the distinct human adipocyte subsets.…”

Umbilical mesenchymal stem cell-derived exosomes facilitate spinal cord functional recovery through the miR-199a-3p/145-5p-mediated NGF/TrkA signaling pathway in rats

“…However, there is less evidence that exosomal miRNAs are involved in the protection of neurons at the early stage of SCI, and the underlying mechanism remains unclear. The injury model of PC12 cells was established by using LPS instead of other inflammatory cytokines as previously reported [ 19 ] because both LPS model and other inflammatory models truly reflect the damaged status of neurons under inflammation [ 20 , 21 ]. Through knockdown of mir-199a-3p/145-5p in exoxomes, we demonstrated the crucial role of mir-199a-3p/145-5p in the neuronal differentiation promoted by exosomes.…”

Photobiomodulation promotes repair following spinal cord injury by restoring neuronal mitochondrial bioenergetics via AMPK/PGC-1α/TFAM pathway

“…Routine animal care was performed after operation. Drug administration were conducted as previously described ( Jiang et al, 2020 ). Compound C (CC) (HY-13418a, MCE, United States) was dissolved in DMSO and normal saline successively.…”