miR-1, miR-133a, miR-29b and skeletal muscle fibrosis in chronic limb-threatening ischaemia
Abstract Chronic limb-threatening ischaemia (CLTI), the most severe manifestation of peripheral arterial disease (PAD), is associated with a poor prognosis and high amputation rates. Despite novel therapeutic approaches being investigated, no significant clinical benefits have been observed yet. Und...
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Nature Portfolio
2024-11-01
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| Online Access: | https://doi.org/10.1038/s41598-024-76415-9 |
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| author | Alan J. Keane Clara Sanz-Nogués Dulan Jayasooriya Michael Creane Xizhe Chen Caomhán J. Lyons Isha Sikri Katarzyna Goljanek-Whysall Timothy O’Brien |
| author_facet | Alan J. Keane Clara Sanz-Nogués Dulan Jayasooriya Michael Creane Xizhe Chen Caomhán J. Lyons Isha Sikri Katarzyna Goljanek-Whysall Timothy O’Brien |
| author_sort | Alan J. Keane |
| collection | DOAJ |
| description | Abstract Chronic limb-threatening ischaemia (CLTI), the most severe manifestation of peripheral arterial disease (PAD), is associated with a poor prognosis and high amputation rates. Despite novel therapeutic approaches being investigated, no significant clinical benefits have been observed yet. Understanding the molecular pathways of skeletal muscle dysfunction in CLTI is crucial for designing successful treatments. This study aimed to identify miRNAs dysregulated in muscle biopsies from PAD cohorts. Using MIcroRNA ENrichment TURned NETwork (MIENTURNET) on a publicly accessible RNA-sequencing dataset of PAD cohorts, we identified a list of miRNAs that were over-represented among the upregulated differentially expressed genes (DEGs) in CLTI. Next, we validated the altered expression of these miRNAs and their targets in mice with hindlimb ischaemia (HLI). Our results showed a significant downregulation of miR-1, miR-133a, and miR-29b levels in the ischaemic limbs versus the contralateral non-ischaemic limb. A miRNA target protein-protein interaction network identified extracellular matrix components, including collagen-1a1, -3a1, and -4a1, fibronectin-1, fibrin-1, matrix metalloproteinase-2 and -14, and Sparc, which were upregulated in the ischaemic muscle of mice. This is the first study to identify miR-1, miR-133a, and miR-29b as potential contributors to fibrosis and vascular pathology in CLTI muscle, which supports their potential as novel therapeutic agents for this condition. |
| format | Article |
| id | doaj-art-166524dc20094da3b7a8d6a8fafaef6e |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-166524dc20094da3b7a8d6a8fafaef6e2025-08-20T02:49:17ZengNature PortfolioScientific Reports2045-23222024-11-0114111710.1038/s41598-024-76415-9miR-1, miR-133a, miR-29b and skeletal muscle fibrosis in chronic limb-threatening ischaemiaAlan J. Keane0Clara Sanz-Nogués1Dulan Jayasooriya2Michael Creane3Xizhe Chen4Caomhán J. Lyons5Isha Sikri6Katarzyna Goljanek-Whysall7Timothy O’Brien8Regenerative Medicine Institute (REMEDI), University of GalwayRegenerative Medicine Institute (REMEDI), University of GalwayRegenerative Medicine Institute (REMEDI), University of GalwayRegenerative Medicine Institute (REMEDI), University of GalwayRegenerative Medicine Institute (REMEDI), University of GalwayRegenerative Medicine Institute (REMEDI), University of GalwayRegenerative Medicine Institute (REMEDI), University of GalwayRegenerative Medicine Institute (REMEDI), University of GalwayRegenerative Medicine Institute (REMEDI), University of GalwayAbstract Chronic limb-threatening ischaemia (CLTI), the most severe manifestation of peripheral arterial disease (PAD), is associated with a poor prognosis and high amputation rates. Despite novel therapeutic approaches being investigated, no significant clinical benefits have been observed yet. Understanding the molecular pathways of skeletal muscle dysfunction in CLTI is crucial for designing successful treatments. This study aimed to identify miRNAs dysregulated in muscle biopsies from PAD cohorts. Using MIcroRNA ENrichment TURned NETwork (MIENTURNET) on a publicly accessible RNA-sequencing dataset of PAD cohorts, we identified a list of miRNAs that were over-represented among the upregulated differentially expressed genes (DEGs) in CLTI. Next, we validated the altered expression of these miRNAs and their targets in mice with hindlimb ischaemia (HLI). Our results showed a significant downregulation of miR-1, miR-133a, and miR-29b levels in the ischaemic limbs versus the contralateral non-ischaemic limb. A miRNA target protein-protein interaction network identified extracellular matrix components, including collagen-1a1, -3a1, and -4a1, fibronectin-1, fibrin-1, matrix metalloproteinase-2 and -14, and Sparc, which were upregulated in the ischaemic muscle of mice. This is the first study to identify miR-1, miR-133a, and miR-29b as potential contributors to fibrosis and vascular pathology in CLTI muscle, which supports their potential as novel therapeutic agents for this condition.https://doi.org/10.1038/s41598-024-76415-9Chronic limb-threatening ischaemiaFibrosisMuscle regenerationMicroRNAs |
| spellingShingle | Alan J. Keane Clara Sanz-Nogués Dulan Jayasooriya Michael Creane Xizhe Chen Caomhán J. Lyons Isha Sikri Katarzyna Goljanek-Whysall Timothy O’Brien miR-1, miR-133a, miR-29b and skeletal muscle fibrosis in chronic limb-threatening ischaemia Scientific Reports Chronic limb-threatening ischaemia Fibrosis Muscle regeneration MicroRNAs |
| title | miR-1, miR-133a, miR-29b and skeletal muscle fibrosis in chronic limb-threatening ischaemia |
| title_full | miR-1, miR-133a, miR-29b and skeletal muscle fibrosis in chronic limb-threatening ischaemia |
| title_fullStr | miR-1, miR-133a, miR-29b and skeletal muscle fibrosis in chronic limb-threatening ischaemia |
| title_full_unstemmed | miR-1, miR-133a, miR-29b and skeletal muscle fibrosis in chronic limb-threatening ischaemia |
| title_short | miR-1, miR-133a, miR-29b and skeletal muscle fibrosis in chronic limb-threatening ischaemia |
| title_sort | mir 1 mir 133a mir 29b and skeletal muscle fibrosis in chronic limb threatening ischaemia |
| topic | Chronic limb-threatening ischaemia Fibrosis Muscle regeneration MicroRNAs |
| url | https://doi.org/10.1038/s41598-024-76415-9 |
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