Skeletal Muscle MiR-210 Expression is Associated with Mitochondrial Function in Peripheral Artery Disease Patients

Overview

Journal Transl Res

Publisher Elsevier

Specialty Pathology

Date 2022 Mar 15

PMID 35288364

Authors

Ahmed Ismaeel

Emma Fletcher

Dimitrios Miserlis

Marissa Wechsler

Evlampia Papoutsi

Gleb Haynatzki

Robert S Smith

William T Bohannon

Panagiotis Koutakis

Affiliations

Soon will be listed here.

Abstract

Previous studies have demonstrated that circulating microRNA (miR)-210 levels are elevated in peripheral artery disease (PAD) patients. MiR-210 is known to be a negative regulator of mitochondrial respiration; however, the relationship between miR-210 and mitochondrial function has yet to be studied in PAD. We aimed to compare skeletal muscle miR-210 expression of PAD patients to non-PAD controls (CON) and to examine the relationship between miR-210 expression and mitochondrial function. Skeletal muscle biopsies from CON (n = 20), intermittent claudication (IC) patients (n = 20), and critical limb ischemia (CLI) patients (n = 20) were analyzed by high-resolution respirometry to measure mitochondrial respiration of permeabilized fibers. Samples were also analyzed for miR-210 expression by real-time PCR. MiR-210 expression was significantly elevated in IC and CLI muscle compared to CON (P = 0.008 and P < 0.001, respectively). Mitochondrial respiration of electron transport chain (ETC) Complexes II (P = 0.001) and IV (P < 0.001) were significantly reduced in IC patients. Further, CLI patients demonstrated significant reductions in respiration during Complexes I (state 2: P = 0.04, state 3: P = 0.003), combined I and II (P < 0.001), II (P < 0.001), and IV (P < 0.001). The expression of the miR-210 targets, cytochrome c oxidase assembly factor heme A: farnesyltransferase (COX10), and iron-sulfur cluster assembly enzyme (ISCU) were down-regulated in PAD muscle. MiR-210 may play a role in the cellular adaptation to hypoxia and may be involved in the metabolic myopathy associated with PAD.

Citing Articles

miR-1, miR-133a, miR-29b and skeletal muscle fibrosis in chronic limb-threatening ischaemia.

Keane A, Sanz-Nogues C, Jayasooriya D, Creane M, Chen X, Lyons C Sci Rep. 2024; 14(1):29393.

PMID: 39592654 PMC: 11599917. DOI: 10.1038/s41598-024-76415-9.

Ultrastructural alterations and mitochondrial dysfunction in skeletal muscle of peripheral artery disease patients: implications for early therapeutic interventions.

Wilburn D, Fletcher E, Papoutsi E, Bohannon W, Haynatzki G, Zechmann B EXCLI J. 2024; 23:1208-1225.

PMID: 39574966 PMC: 11579521. DOI: 10.17179/excli2024-7592.

Mesenchymal stromal cell transplantation ameliorates fibrosis and microRNA dysregulation in skeletal muscle ischemia.

Sanz-Nogues C, Keane A, Creane M, Hynes S, Chen X, Lyons C Stem Cells. 2024; 42(11):976-991.

PMID: 39283740 PMC: 11541228. DOI: 10.1093/stmcls/sxae058.

Skeletal muscle desmin alterations following revascularization in peripheral artery disease claudicants.

Wilburn D, Miserlis D, Fletcher E, Papoutsi E, Ismaeel A, Bradley C Sci Rep. 2024; 14(1):12609.

PMID: 38824194 PMC: 11144188. DOI: 10.1038/s41598-024-63626-3.

Oxidative damage in the gastrocnemius predicts long-term survival in patients with peripheral artery disease.

Koutakis P, Hernandez H, Miserlis D, Thompson J, Papoutsi E, Mietus C NPJ Aging. 2024; 10(1):21.

PMID: 38580664 PMC: 10997596. DOI: 10.1038/s41514-024-00147-3.

References

Kozomara A, Birgaoanu M, Griffiths-Jones S . miRBase: from microRNA sequences to function. Nucleic Acids Res. 2018; 47(D1):D155-D162. PMC: 6323917. DOI: 10.1093/nar/gky1141. View

Voloboueva L, Sun X, Xu L, Ouyang Y, Giffard R . Distinct Effects of miR-210 Reduction on Neurogenesis: Increased Neuronal Survival of Inflammation But Reduced Proliferation Associated with Mitochondrial Enhancement. J Neurosci. 2017; 37(11):3072-3084. PMC: 5354339. DOI: 10.1523/JNEUROSCI.1777-16.2017. View

Muralimanoharan S, Maloyan A, Mele J, Guo C, Myatt L, Myatt L . MIR-210 modulates mitochondrial respiration in placenta with preeclampsia. Placenta. 2012; 33(10):816-23. PMC: 3439551. DOI: 10.1016/j.placenta.2012.07.002. View

Schmidt C, Ryan T, Lin C, Inigo M, Green T, Brault J . Diminished force production and mitochondrial respiratory deficits are strain-dependent myopathies of subacute limb ischemia. J Vasc Surg. 2016; 65(5):1504-1514.e11. PMC: 5403600. DOI: 10.1016/j.jvs.2016.04.041. View

Raitoharju E, Lyytikainen L, Levula M, Oksala N, Mennander A, Tarkka M . miR-21, miR-210, miR-34a, and miR-146a/b are up-regulated in human atherosclerotic plaques in the Tampere Vascular Study. Atherosclerosis. 2011; 219(1):211-7. DOI: 10.1016/j.atherosclerosis.2011.07.020. View

Chen Z, Li Y, Zhang H, Huang P, Luthra R . Hypoxia-regulated microRNA-210 modulates mitochondrial function and decreases ISCU and COX10 expression. Oncogene. 2010; 29(30):4362-8. DOI: 10.1038/onc.2010.193. View

Li P, Jiao J, Gao G, Prabhakar B . Control of mitochondrial activity by miRNAs. J Cell Biochem. 2011; 113(4):1104-10. PMC: 3325319. DOI: 10.1002/jcb.24004. View

McDermott M, Liu K, Greenland P, Guralnik J, Criqui M, Chan C . Functional decline in peripheral arterial disease: associations with the ankle brachial index and leg symptoms. JAMA. 2004; 292(4):453-61. DOI: 10.1001/jama.292.4.453. View

Semenza G . Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1. Biochem J. 2007; 405(1):1-9. DOI: 10.1042/BJ20070389. View

10.

Tong W, Rouault T . Functions of mitochondrial ISCU and cytosolic ISCU in mammalian iron-sulfur cluster biogenesis and iron homeostasis. Cell Metab. 2006; 3(3):199-210. DOI: 10.1016/j.cmet.2006.02.003. View

11.

Chan Y, Banerjee J, Choi S, Sen C . miR-210: the master hypoxamir. Microcirculation. 2011; 19(3):215-23. PMC: 3399423. DOI: 10.1111/j.1549-8719.2011.00154.x. View

12.

Zhang J, Rao G, Qiu J, He R, Wang Q . MicroRNA-210 improves perfusion recovery following hindlimb ischemia via suppressing reactive oxygen species. Exp Ther Med. 2020; 20(6):236. PMC: 7604736. DOI: 10.3892/etm.2020.9366. View

13.

Huang X, Ding L, Bennewith K, Tong R, Welford S, Ang K . Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation. Mol Cell. 2009; 35(6):856-67. PMC: 2782615. DOI: 10.1016/j.molcel.2009.09.006. View

14.

Ma X, Wang J, Li J, Ma C, Chen S, Lei W . Loading MiR-210 in Endothelial Progenitor Cells Derived Exosomes Boosts Their Beneficial Effects on Hypoxia/Reoxygeneation-Injured Human Endothelial Cells via Protecting Mitochondrial Function. Cell Physiol Biochem. 2018; 46(2):664-675. DOI: 10.1159/000488635. View

15.

Sun W, Zhao L, Song X, Zhang J, Xing Y, Liu N . MicroRNA-210 Modulates the Cellular Energy Metabolism Shift During H2O2-Induced Oxidative Stress by Repressing ISCU in H9c2 Cardiomyocytes. Cell Physiol Biochem. 2017; 43(1):383-394. DOI: 10.1159/000480417. View

16.

Zaccagnini G, Maimone B, Fuschi P, Longo M, da Silva D, Carrara M . Hypoxia-Induced miR-210 Is Necessary for Vascular Regeneration upon Acute Limb Ischemia. Int J Mol Sci. 2019; 21(1). PMC: 6981725. DOI: 10.3390/ijms21010129. View

17.

Zhou X, Yuan P, He Y . Role of microRNAs in peripheral artery disease (review). Mol Med Rep. 2012; 6(4):695-700. DOI: 10.3892/mmr.2012.978. View

18.

Faul F, Erdfelder E, Buchner A, Lang A . Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods. 2009; 41(4):1149-60. DOI: 10.3758/BRM.41.4.1149. View

19.

Grosso S, Doyen J, Parks S, Bertero T, Paye A, Cardinaud B . MiR-210 promotes a hypoxic phenotype and increases radioresistance in human lung cancer cell lines. Cell Death Dis. 2013; 4:e544. PMC: 3615727. DOI: 10.1038/cddis.2013.71. View

20.

Das M, Andreassen R, Haugen T, Furu K . Identification of Endogenous Controls for Use in miRNA Quantification in Human Cancer Cell Lines. Cancer Genomics Proteomics. 2015; 13(1):63-8. View