MicroRNA miR-675 promotes the inflammatory response in muscle cells to promote muscle loss in COPD and following surgery.

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  • MicroRNA miR-675 promotes the inflammatory response in muscle cells to promote muscle loss in COPD and following surgery.

New Perspectives on the Physiological Basis of Muscle Loss (University of Exeter, UK) (2024) Proc Physiol Soc 60, C01

Oral Communications: MicroRNA miR-675 promotes the inflammatory response in muscle cells to promote muscle loss in COPD and following surgery.

Narmin Akhundova1, Mark Griffiths1, Paul Kemp1,

1National Heart and Lung Institute, Imperial College London LONDON United Kingdom, 2National Heart and Lung Institute, Imperial College London LONDON United Kingdom,

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We and others have shown that the microRNA miR-675 and its host gene H19 associate with reduced muscle mass in patients with COPD and in older individuals.  To determine the mechanisms by which miR-675 may contribute to muscle loss we compared its expression with that of all genes quantified by microarray in the quadriceps biopsies from 41 COPD patients and 12 controls then defined gene sets associating with H19/miR-675 expression by gene set enrichment analysis (GSEA).  In patients, H19 and miR-675 were tightly correlated (r=0.0.67, p=4×10-8) and both associated with epithelial mesenchymal transition (EMT) and myc regulated gene sets (both at FDR<0.001).  miR-675 but not H19 expression was positively associated with TNFa signalling at an FDR<0.05.  We next analysed miR-675 expression in 18 patients undergoing aortic surgery.  Pre-surgical miR-675 expression was correlated with post-surgical gene expression quantified by RNAseq and the correlations analysed with GSEA.  This analysis showed that genes positively correlated with pre-surgical miR-675 associated were enriched for inflammatory gene sets including the TNFa signalling gene set (2.9 normalised enrichment score (NES), FDR<0.001) and those negatively correlated were enriched for genes associated with oxidative phosphorylation (NES=-5.0, FDR <0.001) and myogenesis (NES=-4.0, FDR<0.001). 

To understand this phenomenon, we determined the effect of miR-675 and its antagomiR on TNFa induced expression of MCP-1 in mouse C2C12 and human LHCN myoblasts.  miR-675-5p enhanced basal MCP-1 expression in the absence of TNFa and the miR-675 antagomiR suppressed TNF-a induced MCP-1 expression. 

To determine the mechanism by which this increase in inflammatory susceptibility occurred we determined the effect of miR-675-5p by RNAseq in LHCN cells in basal and TNFa treated conditions.  Determination of differential gene expression followed by GSEA showed that genes elevated by transfection with miR-675 were enriched for those associated with the TNFa signalling both with and without TNFa stimulation (NES =2.0, FDR<0.001in the absence or presence of TNFa).  Gene sets suppressed in the presence of miR-675 were enriched for those associated with cell proliferation in particular E2F and myc targets. 

The genes showing the increased expression in the presence of miR-675 included both SAA1 and SAA2 as well as a number of members of the TNF receptor superfamily (including TNFSFR1B, TNFRSF9, TNFSFR10B, TNFSFR10D, TNFSFR11B). Future work will be designed to determine the mechanism by which miR-675 promotes expression of these genes.

Together these data indicate that the inflammatory response of muscle cells is increased by miR-675 providing a mechanism by which this miRNA enhances muscle atrophy.

Where applicable, experiments conform with Society ethical requirements.

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