{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T14:38:38Z","timestamp":1780756718225,"version":"3.54.1"},"reference-count":43,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T00:00:00Z","timestamp":1616544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014262","name":"Soci\u00e9t\u00e9 Fran\u00e7aise d\u2019Anesth\u00e9sie et de R\u00e9animation","doi-asserted-by":"publisher","award":["Contrat de Recherche 2012"],"award-info":[{"award-number":["Contrat de Recherche 2012"]}],"id":[{"id":"10.13039\/501100014262","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Iron deficiency (ID), with or without anemia, is responsible for physical fatigue. This effect may be linked to an alteration of mitochondrial metabolism. Our aim was to assess the impact of ID on skeletal striated muscle mitochondrial metabolism. Iron-deficient non-anemic mice, obtained using a bloodletting followed by a low-iron diet for three weeks, were compared to control mice. Endurance was assessed using a one-hour submaximal exercise on a Rotarod device and activities of mitochondrial complexes I and IV were measured by spectrophotometry on two types of skeletal striated muscles, the soleus and the quadriceps. As expected, ID mice displayed hematologic markers of ID and reduced iron stores, although none of them were anemic. In ID mice, endurance was significantly reduced and activity of the respiratory chain complex I, normalized to citrate synthase activity, was significantly reduced in the soleus muscle but not in the quadriceps. Complex IV activities were not significantly different, neither in the soleus nor in the quadriceps. We conclude that ID without anemia is responsible for impaired mitochondrial complex I activity in skeletal muscles with predominant oxidative metabolism. These results bring pathophysiological support to explain the improved physical activity observed when correcting ID in human. Further studies are needed to explore the mechanisms underlying this decrease in complex I activity and to assess the role of iron therapy on muscle mitochondrial metabolism.<\/jats:p>","DOI":"10.3390\/nu13041056","type":"journal-article","created":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T21:36:51Z","timestamp":1616621811000},"page":"1056","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Iron Deficiency without Anemia Decreases Physical Endurance and Mitochondrial Complex I Activity of Oxidative Skeletal Muscle in the Mouse"],"prefix":"10.3390","volume":"13","author":[{"given":"Emmanuel","family":"Rineau","sequence":"first","affiliation":[{"name":"MitoVasc Institut, UMR CNRS 6015\u2014INSERM 1083, University of Angers, 49100 Angers, France"},{"name":"Department of Anesthesia and Critical Care, University Hospital of Angers, 49100 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3094-8121","authenticated-orcid":false,"given":"Na\u00efg","family":"Gueguen","sequence":"additional","affiliation":[{"name":"MitoVasc Institut, UMR CNRS 6015\u2014INSERM 1083, University of Angers, 49100 Angers, France"},{"name":"Department of Biochemistry and Genetics, University Hospital of Angers, 49100 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Procaccio","sequence":"additional","affiliation":[{"name":"MitoVasc Institut, UMR CNRS 6015\u2014INSERM 1083, University of Angers, 49100 Angers, France"},{"name":"Department of Biochemistry and Genetics, University Hospital of Angers, 49100 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck","family":"Genevi\u00e8ve","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Hospital of Angers, 49100 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Reynier","sequence":"additional","affiliation":[{"name":"MitoVasc Institut, UMR CNRS 6015\u2014INSERM 1083, University of Angers, 49100 Angers, France"},{"name":"Department of Biochemistry and Genetics, University Hospital of Angers, 49100 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1094-0285","authenticated-orcid":false,"given":"Daniel","family":"Henrion","sequence":"additional","affiliation":[{"name":"MitoVasc Institut, UMR CNRS 6015\u2014INSERM 1083, University of Angers, 49100 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigismond","family":"Lasocki","sequence":"additional","affiliation":[{"name":"MitoVasc Institut, UMR CNRS 6015\u2014INSERM 1083, University of Angers, 49100 Angers, France"},{"name":"Department of Anesthesia and Critical Care, University Hospital of Angers, 49100 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3222","DOI":"10.1182\/blood-2011-04-346304","article-title":"Intravenous Iron for the Treatment of Fatigue in Nonanemic, Premenopausal Women with Low Serum Ferritin Concentration","volume":"118","author":"Krayenbuehl","year":"2011","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Favrat, B., Balck, K., Breymann, C., Hedenus, M., Keller, T., Mezzacasa, A., and Gasche, C. (2014). Evaluation of a Single Dose of Ferric Carboxymaltose in Fatigued, Iron-Deficient Women--PREFER a Randomized, Placebo-Controlled Study. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0094217"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1097\/EJA.0b013e32834ad97b","article-title":"Preoperative Iron Deficiency Increases Transfusion Requirements and Fatigue in Cardiac Surgery Patients: A Prospective Observational Study","volume":"28","author":"Piednoir","year":"2011","journal-title":"Eur. J. Anaesthesiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1186\/s13054-014-0542-9","article-title":"Prevalence of Iron Deficiency on ICU Discharge and Its Relation with Fatigue: A Multicenter Prospective Study","volume":"18","author":"Lasocki","year":"2014","journal-title":"Crit. Care Lond. Engl."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1093\/ajcn\/75.4.734","article-title":"Marginal Iron Deficiency without Anemia Impairs Aerobic Adaptation among Previously Untrained Women","volume":"75","author":"Brownlie","year":"2002","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1093\/ajcn\/66.2.334","article-title":"Iron Depletion without Anemia and Physical Performance in Young Women","volume":"66","author":"Zhu","year":"1997","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1123\/ijsnem.21.6.501","article-title":"Impact of Iron Depletion without Anemia on Performance in Trained Endurance Athletes at the Beginning of a Training Season: A Study of Female Collegiate Rowers","volume":"21","author":"DellaValle","year":"2011","journal-title":"Int. J. Sport Nutr. Exerc. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1152\/jappl.2000.88.3.1103","article-title":"Iron Supplementation Improves Endurance after Training in Iron-Depleted, Nonanemic Women","volume":"88","author":"Hinton","year":"2000","journal-title":"J. Appl. Physiol. (1985)"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.1093\/eurheartj\/ehq158","article-title":"Iron Deficiency: An Ominous Sign in Patients with Systolic Chronic Heart Failure","volume":"31","author":"Jankowska","year":"2010","journal-title":"Eur. Heart J."},{"key":"ref_10","first-page":"436","article-title":"Prevalence and Clinical Impact of Iron Deficiency and Anaemia among Outpatients with Chronic Heart Failure: The PrEP Registry","volume":"106","author":"Gremmler","year":"2017","journal-title":"Clin. Res. Cardiol. Off. J. Ger. Card. Soc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.ahj.2013.01.017","article-title":"Iron Deficiency in Chronic Heart Failure: An International Pooled Analysis","volume":"165","author":"Klip","year":"2013","journal-title":"Am. Heart J."},{"key":"ref_12","first-page":"203","article-title":"Iron Deficiency in Patients with Heart Failure with Preserved Ejection Fraction and Its Association with Reduced Exercise Capacity, Muscle Strength and Quality of Life","volume":"108","author":"Bekfani","year":"2019","journal-title":"Clin. Res. Cardiol. Off. J. Ger. Card. Soc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1016\/j.jacc.2007.07.029","article-title":"Intravenous Iron Reduces NT-pro-Brain Natriuretic Peptide in Anemic Patients with Chronic Heart Failure and Renal Insufficiency","volume":"50","author":"Toblli","year":"2007","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jacc.2007.09.036","article-title":"Effect of Intravenous Iron Sucrose on Exercise Tolerance in Anemic and Nonanemic Patients with Symptomatic Chronic Heart Failure and Iron Deficiency FERRIC-HF: A Randomized, Controlled, Observer-Blinded Trial","volume":"51","author":"Okonko","year":"2008","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1056\/NEJMoa0908355","article-title":"Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency","volume":"361","author":"Anker","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1093\/eurjhf\/hft099","article-title":"Intravenous Ferric Carboxymaltose in Iron-Deficient Chronic Heart Failure Patients with and without Anaemia: A Subanalysis of the FAIR-HF Trial","volume":"15","author":"Filippatos","year":"2013","journal-title":"Eur. J. Heart Fail."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1161\/CIRCULATIONAHA.117.027497","article-title":"Effect of Ferric Carboxymaltose on Exercise Capacity in Patients With Chronic Heart Failure and Iron Deficiency","volume":"136","author":"Ponikowski","year":"2017","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1172\/JCI108489","article-title":"Iron Deficiency in the Rat. Physiological and Biochemical Studies of Muscle Dysfunction","volume":"58","author":"Finch","year":"1976","journal-title":"J. Clin. Investig."},{"key":"ref_19","first-page":"E418","article-title":"Muscle Mitochondrial Bioenergetics, Oxygen Supply, and Work Capacity during Dietary Iron Deficiency and Repletion","volume":"242","author":"Davies","year":"1982","journal-title":"Am. J. Physiol."},{"key":"ref_20","first-page":"E535","article-title":"Distinguishing Effects of Anemia and Muscle Iron Deficiency on Exercise Bioenergetics in the Rat","volume":"246","author":"Davies","year":"1984","journal-title":"Am. J. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2442","DOI":"10.1152\/jappl.1987.62.6.2442","article-title":"Effects of Iron Deficiency and Training on Mitochondrial Enzymes in Skeletal Muscle","volume":"62","author":"Willis","year":"1987","journal-title":"J. Appl. Physiol. (1985)"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1161\/01.RES.39.5.744","article-title":"The Effects of Iron Deficiency on the Respiratory Function and Cytochrome Content of Rat Heart Mitochondria","volume":"39","author":"Blayney","year":"1976","journal-title":"Circ. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.ijcard.2018.02.021","article-title":"Iron Deficiency without Anemia Is Responsible for Decreased Left Ventricular Function and Reduced Mitochondrial Complex I Activity in a Mouse Model","volume":"266","author":"Rineau","year":"2018","journal-title":"Int. J. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e004800","DOI":"10.1161\/CIRCHEARTFAILURE.117.004800","article-title":"Skeletal Muscle Abnormalities and Iron Deficiency in Chronic Heart FailureAn Exercise 31P Magnetic Resonance Spectroscopy Study of Calf Muscle","volume":"11","author":"Melenovsky","year":"2018","journal-title":"Circ. Heart Fail."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1161\/CIRCULATIONAHA.118.038516","article-title":"Effect of Iron Isomaltoside on Skeletal Muscle Energetics in Patients With Chronic Heart Failure and Iron Deficiency","volume":"139","author":"Amaral","year":"2019","journal-title":"Circulation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"R1347","DOI":"10.1152\/ajpregu.00687.2007","article-title":"Enhanced Muscle Fatigue Occurs in Male but Not Female ASIC3-\/- Mice","volume":"294","author":"Burnes","year":"2008","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1097\/CCM.0b013e31818103b9","article-title":"Phlebotomies or Erythropoietin Injections Allow Mobilization of Iron Stores in a Mouse Model Mimicking Intensive Care Anemia","volume":"36","author":"Lasocki","year":"2008","journal-title":"Crit. Care Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.mito.2009.05.001","article-title":"Development and Implementation of Standardized Respiratory Chain Spectrophotometric Assays for Clinical Diagnosis","volume":"9","author":"Medja","year":"2009","journal-title":"Mitochondrion"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"C47","DOI":"10.1152\/ajpcell.1981.241.1.C47","article-title":"Physiological and Biochemical Effects of Iron Deficiency on Rat Skeletal Muscle","volume":"241","author":"McLane","year":"1981","journal-title":"Am. J. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1093\/ajcn\/77.2.441","article-title":"Iron Supplementation Improves Progressive Fatigue Resistance during Dynamic Knee Extensor Exercise in Iron-Depleted, Nonanemic Women","volume":"77","author":"Brutsaert","year":"2003","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1093\/eurheartj\/ehu385","article-title":"Beneficial Effects of Long-Term Intravenous Iron Therapy with Ferric Carboxymaltose in Patients with Symptomatic Heart Failure and Iron Deficiency\u2020","volume":"36","author":"Ponikowski","year":"2015","journal-title":"Eur. Heart J."},{"key":"ref_32","first-page":"89","article-title":"Skeletal Muscle Fiber Types in C57BL6J Mice","volume":"21","author":"Augusto","year":"2004","journal-title":"J. Morphol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1126\/science.1113988","article-title":"Organization of Iron-Sulfur Clusters in Respiratory Complex I","volume":"309","author":"Hinchliffe","year":"2005","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1152\/jappl.1989.67.5.1868","article-title":"Iron Deficiency Decreases Gluconeogenesis in Isolated Rat Hepatocytes","volume":"67","author":"Klempa","year":"1989","journal-title":"J. Appl. Physiol. (1985)"},{"key":"ref_35","first-page":"E414","article-title":"Glucose Turnover and Oxidation Are Increased in the Iron-Deficient Anemic Rat","volume":"250","author":"Henderson","year":"1986","journal-title":"Am. J. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1146\/annurev.nutr.20.1.627","article-title":"Iron Regulatory Proteins and the Molecular Control of Mammalian Iron Metabolism","volume":"20","author":"Eisenstein","year":"2000","journal-title":"Annu. Rev. Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"13827","DOI":"10.1016\/S0021-9258(18)67094-2","article-title":"Perturbation of Mitochondrial Composition in Muscle by Iron Deficiency. Implications Regarding Regulation of Mitochondrial Assembly","volume":"261","author":"Cartier","year":"1986","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1042\/CS20040278","article-title":"Dietary Iron Deficiency Induces Ventricular Dilation, Mitochondrial Ultrastructural Aberrations and Cytochrome c Release: Involvement of Nitric Oxide Synthase and Protein Tyrosine Nitration","volume":"109","author":"Dong","year":"2005","journal-title":"Clin. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3349","DOI":"10.1113\/jphysiol.2012.230185","article-title":"Biomarkers of Mitochondrial Content in Skeletal Muscle of Healthy Young Human Subjects","volume":"590","author":"Larsen","year":"2012","journal-title":"J. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1002\/ejhf.592","article-title":"2016 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC). Developed with the Special Contribution of the Heart Failure Association (HFA) of the ESC","volume":"18","author":"Ponikowski","year":"2016","journal-title":"Eur. J. Heart Fail."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1093\/hmg\/ddp055","article-title":"Impairments in Motor Coordination without Major Changes in Cerebellar Plasticity in the Tc1 Mouse Model of Down Syndrome","volume":"18","author":"Galante","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1093\/ajcn\/59.4.908","article-title":"Functional Consequences of Iron Supplementation in Iron-Deficient Female Cotton Mill Workers in Beijing, China","volume":"59","author":"Li","year":"1994","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1139\/h2012-044","article-title":"Relationship between Physical Activity, Physical Performance, and Iron Status in Adult Women","volume":"37","author":"Crouter","year":"2012","journal-title":"Appl. Physiol. Nutr. Metab. Physiol. Appl. Nutr. Metab."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/4\/1056\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:40:26Z","timestamp":1760161226000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/4\/1056"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,24]]},"references-count":43,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["nu13041056"],"URL":"https:\/\/doi.org\/10.3390\/nu13041056","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,24]]}}}