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miR-1, miR-133a, miR-29b and skeletal muscle fibrosis in chronic limb-threatening ischaemia
Alan J Keane1, Clara Sanz-Nogués2,3, Dulan Jayasooriya1
1Regenerative Medicine Institute (REMEDI), University of Galway, Biomedical Sciences 1st Floor South, Corrib Village, Dangan, Galway, Ireland.
Insights
MicroRNAs miR-1, miR-133a, and miR-29b are downregulated in chronic limb-threatening ischaemia (CLTI) muscle. These findings suggest their potential as therapeutic targets for CLTI, a severe form of peripheral arterial disease.
Area of Science:
- Molecular biology
- Vascular medicine
- Biochemistry
Background:
- Chronic limb-threatening ischaemia (CLTI) is the most severe form of peripheral arterial disease (PAD), characterized by poor prognosis and high amputation rates.
- Current therapeutic strategies for CLTI lack significant clinical benefits, highlighting the need for understanding underlying molecular mechanisms.
- Skeletal muscle dysfunction is a key feature of CLTI, and identifying its molecular drivers is essential for developing effective treatments.
Purpose of the Study:
- To identify microRNAs (miRNAs) that are dysregulated in skeletal muscle of patients with PAD.
- To investigate the role of these dysregulated miRNAs in the pathophysiology of CLTI.
- To explore the potential of identified miRNAs as therapeutic targets for CLTI.
Main Methods:
- Utilized MIcroRNA ENrichment TURned NETwork (MIENTURNET) on a public RNA-sequencing dataset of PAD cohorts to identify dysregulated miRNAs.
- Validated the expression levels of candidate miRNAs and their predicted targets in a mouse model of hindlimb ischaemia (HLI).
- Constructed a miRNA target protein-protein interaction network to elucidate molecular pathways involved in CLTI-associated muscle pathology.
Main Results:
- Significant downregulation of miR-1, miR-133a, and miR-29b was observed in the ischaemic limbs compared to non-ischaemic limbs in the HLI mouse model.
- The study identified extracellular matrix components (e.g., collagens, fibronectin, MMPs) as upregulated targets of these downregulated miRNAs in ischaemic muscle.
- A miRNA-target network revealed potential links between miR-1, miR-133a, miR-29b, and pathways contributing to fibrosis and vascular pathology in CLTI.
Conclusions:
- This study is the first to identify miR-1, miR-133a, and miR-29b as potentially contributing to fibrosis and vascular pathology in CLTI skeletal muscle.
- The downregulation of these miRNAs in ischaemic muscle suggests their protective role against CLTI progression.
- These miRNAs represent promising novel therapeutic targets for managing CLTI and preventing amputation.
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.
