{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T17:03:19Z","timestamp":1769878999244,"version":"3.49.0"},"reference-count":46,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,2,28]],"date-time":"2020-02-28T00:00:00Z","timestamp":1582848000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002739","name":"Aarhus Universitets Forskningsfond","doi-asserted-by":"publisher","award":["AUFF-E-2O15-FLS-7-32"],"award-info":[{"award-number":["AUFF-E-2O15-FLS-7-32"]}],"id":[{"id":"10.13039\/501100002739","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Mitochondrial dysfunction has been implicated as a central mechanism in the metabolic myopathy accompanying critical limb ischemia (CLI). However, whether mitochondrial dysfunction is directly related to lower extremity ischemia and the structural and molecular mechanisms underpinning mitochondrial dysfunction in CLI patients is not understood. Here, we aimed to study whether mitochondrial dysfunction is a distinctive characteristic of CLI myopathy by assessing mitochondrial respiration in gastrocnemius muscle from 14 CLI patients (65.3 \u00b1 7.8 y) and 15 matched control patients (CON) with a similar comorbidity risk profile and medication regimen but without peripheral ischemia (67.4 \u00b1 7.4 y). Furthermore, we studied potential structural and molecular mechanisms of mitochondrial dysfunction by measuring total, sub-population, and fiber-type-specific mitochondrial volumetric content and cristae density with transmission electron microscopy and by assessing mitophagy and fission\/fusion-related protein expression. Finally, we asked whether commonly used biomarkers of mitochondrial content are valid in patients with cardiovascular disease. CLI patients exhibited inferior mitochondrial respiration compared to CON. This respiratory deficit was not related to lower whole-muscle mitochondrial content or cristae density. However, stratification for fiber types revealed ultrastructural mitochondrial alterations in CLI patients compared to CON. CLI patients exhibited an altered expression of mitophagy-related proteins but not fission\/fusion-related proteins compared to CON. Citrate synthase, cytochrome c oxidase subunit IV (COXIV), and 3-hydroxyacyl-CoA dehydrogenase (\u03b2-HAD) could not predict mitochondrial content. Mitochondrial dysfunction is a distinctive characteristic of CLI myopathy and is not related to altered organelle content or cristae density. Our results link this intrinsic mitochondrial deficit to dysregulation of the mitochondrial quality control system, which has implications for the development of therapeutic strategies.<\/jats:p>","DOI":"10.3390\/cells9030570","type":"journal-article","created":{"date-parts":[[2020,3,2]],"date-time":"2020-03-02T07:35:30Z","timestamp":1583134530000},"page":"570","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Mitochondrial Structure and Function in the Metabolic Myopathy Accompanying Patients with Critical Limb Ischemia"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7125-1753","authenticated-orcid":false,"given":"Thomas","family":"Groennebaek","sequence":"first","affiliation":[{"name":"Department of Public Health, Aarhus University, 8000 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7885-7288","authenticated-orcid":false,"given":"Tine Borum","family":"Billeskov","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark"},{"name":"Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camilla Tvede","family":"Schytz","sequence":"additional","affiliation":[{"name":"Department of Public Health, Aarhus University, 8000 Aarhus, Denmark"},{"name":"Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, 5230 Odense, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2502-2102","authenticated-orcid":false,"given":"Nichlas Riise","family":"Jespersen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6358-8962","authenticated-orcid":false,"given":"Hans Erik","family":"B\u00f8tker","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rikke Kathrine Jentoft","family":"Olsen","sequence":"additional","affiliation":[{"name":"Research Unit for Molecular Medicine, Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7980-5295","authenticated-orcid":false,"given":"Nikolaj","family":"Eldrup","sequence":"additional","affiliation":[{"name":"Department Vascular Surgery, Rigshospitalet, Copenhagen University, 2100 Copenhagen, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1730-3094","authenticated-orcid":false,"given":"Joachim","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, 5230 Odense, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean","family":"Farup","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank Vincenzo","family":"de Paoli","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark"},{"name":"Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, 8200 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5810-5241","authenticated-orcid":false,"given":"Kristian","family":"Vissing","sequence":"additional","affiliation":[{"name":"Department of Public Health, Aarhus University, 8000 Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e463","DOI":"10.1161\/CIRCULATIONAHA.106.174526","article-title":"ACC\/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): A collaborative report from the American Association for Vascular Surgery\/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC\/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; 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