{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T04:14:19Z","timestamp":1775103259676,"version":"3.50.1"},"reference-count":93,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,4,4]],"date-time":"2024-04-04T00:00:00Z","timestamp":1712188800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Peripheral arterial disease (PAD) strikes more than 200 million people worldwide and has a severe prognosis by potentially leading to limb amputation and\/or death, particularly in older patients. Skeletal muscle mitochondrial dysfunctions and oxidative stress play major roles in this disease in relation with ischemia-reperfusion (IR) cycles. Mitochondrial dynamics through impairment of fission\u2013fusion balance may contribute to skeletal muscle pathophysiology, but no data were reported in the setting of lower-limb IR despite the need for new therapeutic options. We, therefore, investigated the potential protective effect of mitochondrial division inhibitor-1 (mDivi-1; 50 mg\/kg) in young (23 weeks) and old (83 weeks) mice submitted to two-hour ischemia followed by two-hour reperfusion on systemic lactate, muscle mitochondrial respiration and calcium retention capacity, and on transcripts specific for oxidative stress and mitochondrial dynamics. At the systemic levels, an IR-related increase in circulating lactate was still major despite mDivi-1 use (+305.9% p &lt; 0.0001, and +269.4% p &lt; 0.0001 in young and old mice, respectively). Further, IR-induced skeletal muscle mitochondrial dysfunctions (more severely impaired mitochondrial respiration in old mice (OXPHOS CI state, \u201368.2% p &lt; 0.0001 and \u221284.9% p &lt; 0.0001 in 23- and 83-week mice) and reduced calcium retention capacity (\u201346.1% p &lt; 0.001 and \u221248.2% p = 0.09, respectively) were not corrected by mDivi-1 preconditioning, whatever the age. Further, mDivi-1 treatment did not oppose superoxide anion production (+71.4% p &lt; 0.0001 and +37.5% p &lt; 0.05, respectively). At the transcript level, markers of antioxidant enzymes (SOD 1, SOD 2, catalase, and GPx) and fission markers (Drp1, Fis) remained unchanged or tended to be decreased in the ischemic leg. Fusion markers such as mitofusin 1 or 2 decreased significantly after IR in both groups. In conclusion, aging enhanced the deleterious effects or IR on muscle mitochondrial respiration, and in this setting of lower-limb IR, mDivi-1 failed to protect the skeletal muscle both in young and old mice.<\/jats:p>","DOI":"10.3390\/ijms25074025","type":"journal-article","created":{"date-parts":[[2024,4,4]],"date-time":"2024-04-04T10:42:03Z","timestamp":1712227323000},"page":"4025","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Targeting Mitochondrial Dynamics during Lower-Limb Ischemia Reperfusion in Young and Old Mice: Effect of Mitochondrial Fission Inhibitor-1 (mDivi-1)"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8749-6827","authenticated-orcid":false,"given":"St\u00e9phanie","family":"Paradis","sequence":"first","affiliation":[{"name":"Biomedicine Research Center of Strasbourg (CRBS), UR 3072, \u201cMitochondria, Oxidative Stress and Muscle Plasticity\u201d, Faculty of Medicine, University of Strasbourg, 67081 Strasbourg, France"},{"name":"Department of Physiology and Functional Explorations, University Hospital of Strasbourg, 67000 Strasbourg, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3557-2642","authenticated-orcid":false,"given":"Anne-Laure","family":"Charles","sequence":"additional","affiliation":[{"name":"Biomedicine Research Center of Strasbourg (CRBS), UR 3072, \u201cMitochondria, Oxidative Stress and Muscle Plasticity\u201d, Faculty of Medicine, University of Strasbourg, 67081 Strasbourg, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margherita","family":"Giannini","sequence":"additional","affiliation":[{"name":"Biomedicine Research Center of Strasbourg (CRBS), UR 3072, \u201cMitochondria, Oxidative Stress and Muscle Plasticity\u201d, Faculty of Medicine, University of Strasbourg, 67081 Strasbourg, France"},{"name":"Department of Physiology and Functional Explorations, University Hospital of Strasbourg, 67000 Strasbourg, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alain","family":"Meyer","sequence":"additional","affiliation":[{"name":"Biomedicine Research Center of Strasbourg (CRBS), UR 3072, \u201cMitochondria, Oxidative Stress and Muscle Plasticity\u201d, Faculty of Medicine, University of Strasbourg, 67081 Strasbourg, France"},{"name":"Department of Physiology and Functional Explorations, University Hospital of Strasbourg, 67000 Strasbourg, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Lejay","sequence":"additional","affiliation":[{"name":"Biomedicine Research Center of Strasbourg (CRBS), UR 3072, \u201cMitochondria, Oxidative Stress and Muscle Plasticity\u201d, Faculty of Medicine, University of Strasbourg, 67081 Strasbourg, France"},{"name":"Vascular Surgery Department, University Hospital of Strasbourg, 67000 Strasbourg, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2094-2842","authenticated-orcid":false,"given":"Samy","family":"Talha","sequence":"additional","affiliation":[{"name":"Biomedicine Research Center of Strasbourg (CRBS), UR 3072, \u201cMitochondria, Oxidative Stress and Muscle Plasticity\u201d, Faculty of Medicine, University of Strasbourg, 67081 Strasbourg, France"},{"name":"Department of Physiology and Functional Explorations, University Hospital of Strasbourg, 67000 Strasbourg, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2666-6877","authenticated-orcid":false,"given":"Gilles","family":"Laverny","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC), 67400 Illkirch, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Charloux","sequence":"additional","affiliation":[{"name":"Biomedicine Research Center of Strasbourg (CRBS), UR 3072, \u201cMitochondria, Oxidative Stress and Muscle Plasticity\u201d, Faculty of Medicine, University of Strasbourg, 67081 Strasbourg, France"},{"name":"Department of Physiology and Functional Explorations, University Hospital of Strasbourg, 67000 Strasbourg, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernard","family":"Geny","sequence":"additional","affiliation":[{"name":"Biomedicine Research Center of Strasbourg (CRBS), UR 3072, \u201cMitochondria, Oxidative Stress and Muscle Plasticity\u201d, Faculty of Medicine, University of Strasbourg, 67081 Strasbourg, France"},{"name":"Department of Physiology and Functional Explorations, University Hospital of Strasbourg, 67000 Strasbourg, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1016\/j.amjmed.2019.04.043","article-title":"Peripheral Artery Disease: Past, Present, and Future","volume":"132","author":"Campia","year":"2019","journal-title":"Am. 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