Modulation of miR-29a and ADAM12 Reduces Post-Ischemic Skeletal Muscle Injury and Improves Perfusion Recovery and Skeletal Muscle Function in a Mouse Model of Type 2 Diabetes and Peripheral Artery Disease

Victor Lamin; Joseph Verry; Isaac Eigner-Bybee; Jordan D. Fuqua; Thomas Wong; Vitor A. Lira; Ayotunde O. Dokun

doi:10.3390/ijms23010429

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Modulation of miR-29a and ADAM12 Reduces Post-Ischemic Skeletal Muscle Injury and Improves Perfusion Recovery and Skeletal Muscle Function in a Mouse Model of Type 2 Diabetes and Peripheral Artery Disease

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Modulation of miR-29a and ADAM12 Reduces Post-Ischemic Skeletal Muscle Injury and Improves Perfusion Recovery and Skeletal Muscle Function in a Mouse Model of Type 2 Diabetes and Peripheral Artery Disease

Victor Lamin, Joseph Verry, Isaac Eigner-Bybee, Jordan D. Fuqua, Thomas Wong, Vitor A. Lira and Ayotunde O. Dokun

International journal of molecular sciences, Vol.23(1), p.429

01/01/2022

DOI: 10.3390/ijms23010429

PMCID: PMC8745107

PMID: 35008854

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Abstract

Both Type 1 diabetes mellitus (DM1) and type 2 diabetes mellitus (DM2) are associated with an increased risk of limb amputation in peripheral arterial disease (PAD). How diabetes contributes to poor PAD outcomes is poorly understood but may occur through different mechanisms in DM1 and DM2. Previously, we identified a disintegrin and metalloproteinase gene 12 (ADAM12) as a key genetic modifier of post-ischemic perfusion recovery. In an experimental PAD, we showed that ADAM12 is regulated by miR-29a and this regulation is impaired in ischemic endothelial cells in DM1, contributing to poor perfusion recovery. Here we investigated whether miR-29a regulation of ADAM12 is altered in experimental PAD in the setting of DM2. We also explored whether modulation of miR-29a and ADAM12 expression can improve perfusion recovery and limb function in mice with DM2. Our result showed that in the ischemic limb of mice with DM2, miR-29a expression is poorly downregulated and ADAM12 upregulation is impaired. Inhibition of miR-29a and overexpression of ADAM12 improved perfusion recovery, reduced skeletal muscle injury, improved muscle function, and increased cleaved Tie 2 and AKT phosphorylation. Thus, inhibition of miR-29a and or augmentation of ADAM12 improves experimental PAD outcomes in DM2 likely through modulation of Tie 2 and AKT signalling.

Physical Sciences

Biochemistry & Molecular Biology

Chemistry

Chemistry, Multidisciplinary

Life Sciences & Biomedicine

Science & Technology

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Title: Subtitle: Modulation of miR-29a and ADAM12 Reduces Post-Ischemic Skeletal Muscle Injury and Improves Perfusion Recovery and Skeletal Muscle Function in a Mouse Model of Type 2 Diabetes and Peripheral Artery Disease
Creators: Victor Lamin - Univ Iowa, Carver Coll Med, Div Endocrinol & Metab, Iowa City, IA 52242 USA
Joseph Verry - Univ Iowa, Carver Coll Med, Div Endocrinol & Metab, Iowa City, IA 52242 USA
Isaac Eigner-Bybee - Univ Iowa, Carver Coll Med, Div Endocrinol & Metab, Iowa City, IA 52242 USA
Jordan D. Fuqua - University of Iowa
Thomas Wong - Univ Iowa, Carver Coll Med, Div Endocrinol & Metab, Iowa City, IA 52242 USA
Vitor A. Lira - University of Iowa
Ayotunde O. Dokun - Univ Iowa, Carver Coll Med, Div Endocrinol & Metab, Iowa City, IA 52242 USA
Resource Type: Journal article
Publication Details: International journal of molecular sciences, Vol.23(1), p.429
DOI: 10.3390/ijms23010429
PMID: 35008854
PMCID: PMC8745107
NLM abbreviation: Int J Mol Sci
ISSN: 1661-6596
eISSN: 1422-0067
Publisher: Mdpi
Number of pages: 18
Language: English
Date published: 01/01/2022
Academic Unit: Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Health, Sport, and Human Physiology ; Internal Medicine
Record Identifier: 9984259657302771

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