{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:47:10Z","timestamp":1760060830817,"version":"build-2065373602"},"reference-count":31,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"SBI Pharmaceuticals Co., Ltd."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>5-aminolevulinic acid (5-ALA) is a heme precursor involved in mitochondrial activation. A clinical study suggested that 5-ALA supplementation alleviates fatigue in healthy individuals who experience chronic physical tiredness. However, the detailed mechanisms are unknown. Therefore, we investigated the mechanism underlying the antifatigue effect of 5-ALA using fatigue mouse models. C57BL\/6N mice were orally administered 5-ALA hydrochloride or distilled water for 8 weeks. Fatigue mouse models were developed by housing the mice in a cage filled with water for 4 days. Fatigue was evaluated through running distance via a treadmill test. The decrease in the running distance in female mice significantly recovered after 5-ALA administration. 5-ALA administration ameliorated the decreased blood glucose levels in fatigue mouse models. These results suggest that 5-ALA improves fatigue-induced hypoglycemia by promoting the use of fatty acids. PpIX\u2019s concentration in the FCX of the fatigue mouse models significantly increased after 5-ALA treatment. Decreased levels of 3-methoxy-4-hydroxyphenylglycol and noradrenaline (NA) turnover ratio in the FCX recovered to non-fatigue levels after 5-ALA treatment. Therefore, the antifatigue effect of 5-ALA in mice could be related to the activation of the NA neuronal systems in the FCX and the increase in energy production via glycogenesis activation from peripheral adipose tissue.<\/jats:p>","DOI":"10.3390\/life15091465","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T14:45:46Z","timestamp":1758206746000},"page":"1465","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Antifatigue Effects of 5-Aminolevulinic Acid Chronic Treatment on Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Chinatsu","family":"Ohmori","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacology, Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika-ku, Tokyo 125-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eiko","family":"Kumamoto","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika-ku, Tokyo 125-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoka","family":"Kasai","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika-ku, Tokyo 125-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kotaro","family":"Okano","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika-ku, Tokyo 125-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Urara","family":"Ota","sequence":"additional","affiliation":[{"name":"SBI Pharmaceuticals Co., Ltd., Tokyo 106-6013, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5965-301X","authenticated-orcid":false,"given":"Atsuko","family":"Kamiya","sequence":"additional","affiliation":[{"name":"SBI Pharmaceuticals Co., Ltd., Tokyo 106-6013, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitsugu","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"SBI Pharmaceuticals Co., Ltd., Tokyo 106-6013, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiwamu","family":"Takahashi","sequence":"additional","affiliation":[{"name":"SBI Pharmaceuticals Co., Ltd., Tokyo 106-6013, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiro","family":"Ishizuka","sequence":"additional","affiliation":[{"name":"SBI Pharmaceuticals Co., Ltd., Tokyo 106-6013, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazumi","family":"Yoshizawa","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika-ku, Tokyo 125-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Yamada","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika-ku, Tokyo 125-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akiyoshi","family":"Saitoh","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 6-3-1 Niijyuku, Katsushika-ku, Tokyo 125-8585, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/1756-0500-4-66","article-title":"The effect of 5-aminolevulinic acid on cytochrome c oxidase activity in mouse liver","volume":"4","author":"Ogura","year":"2011","journal-title":"BMC Res. Notes"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16004","DOI":"10.1038\/s41598-020-72763-4","article-title":"Reduction of fatigue and anger-hostility by the oral administration of 5-aminolevulinic acid phosphate: A randomized, double-blind, placebo-controlled, parallel study","volume":"10","author":"Higashikawa","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1152\/japplphysiol.00582.2015","article-title":"Impact of 5-aminolevulinic acid with iron supplementation on exercise efficiency and home-based walking training achievement in older women","volume":"120","author":"Masuki","year":"2016","journal-title":"J. Appl. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7151","DOI":"10.1038\/s41598-018-25452-2","article-title":"Effects of 5-aminolevulinic acid supplementation on home-based walking training achievement in middle-aged depressive women: Randomized, double-blind, crossover pilot study","volume":"8","author":"Suzuki","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/S0140-6736(89)92143-0","article-title":"Decline in skeletal muscle mitochondrial respiratory chain function: Possible factor in ageing","volume":"1","author":"Trounce","year":"1989","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1093\/oxfordjournals.bmb.a072558","article-title":"Physical and mental fatigue: Metabolic mechanisms and importance of plasma amino acids","volume":"48","author":"Newsholme","year":"1992","journal-title":"Br. Med. Bull."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/BF00511231","article-title":"Physical conditioning in rats influences the central and peripheral catecholamine responses to sustained exercise","volume":"71","author":"Pagliari","year":"1995","journal-title":"Eur. J. Appl. Physiol. Occup. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3383","DOI":"10.1113\/jphysiol.2011.203570","article-title":"Brain glycogen decreases during prolonged exercise","volume":"589","author":"Matsui","year":"2011","journal-title":"J. Physiol."},{"key":"ref_9","first-page":"747","article-title":"Tyrosine hydroxylase activity in discrete brain regions of depression model rats","volume":"44","author":"Komori","year":"1990","journal-title":"Jpn. J. Psychiatry Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S0091-3057(96)00341-3","article-title":"The effect of acute, chronic and chronic intermittent stress on the central noradrenergic system","volume":"57","author":"Hellriegel","year":"1997","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1001\/archpsyc.1986.01800100028005","article-title":"Cerebrospinal fluid amine metabolites. Relationships with behavioral measurements in depressed, manic, and healthy control subjects","volume":"43","author":"Redmond","year":"1986","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1097\/00131746-200407000-00005","article-title":"The role of monoamine oxidase inhibitors in current psychiatric practice","volume":"10","author":"Fiedorowicz","year":"2004","journal-title":"J. Psychiatr. Pract."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.neulet.2003.08.051","article-title":"Establishment and assessment of a rat model of fatigue","volume":"352","author":"Tanaka","year":"2003","journal-title":"Neurosci. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"177658","DOI":"10.1016\/j.ejphar.2025.177658","article-title":"5-Aminolevulinic acid improves spatial recognition memory in mice","volume":"15","author":"Komiya","year":"2025","journal-title":"Eur. J. Pharmacol."},{"key":"ref_15","first-page":"e54052","article-title":"The Treadmill Fatigue Test: A Simple, High-throughput Assay of Fatigue-like Behavior for the Mouse","volume":"31","author":"Dougherty","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"95","DOI":"10.21873\/cdp.10014","article-title":"Effect of Sucrose on Cisplatin-induced Fatigue-like Behavior in Mice: Comparison With Fructose and Glucose","volume":"1","author":"Yoshizawa","year":"2021","journal-title":"Cancer Diagn. Progn."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"826783","DOI":"10.3389\/fphar.2022.826783","article-title":"Disulfiram Produces Potent Anxiolytic-Like Effects Without Benzodiazepine Anxiolytics-Related Adverse Effects in Mice","volume":"13","author":"Saitoh","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"797","DOI":"10.3892\/mco.2015.549","article-title":"Plasma protoporphyrin IX following administration of 5-aminolevulinic acid as a potential tumor marker","volume":"3","author":"Ota","year":"2015","journal-title":"Mol. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1016\/j.mayocp.2021.07.004","article-title":"Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management","volume":"96","author":"Bateman","year":"2021","journal-title":"Mayo Clin. Proc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4236\/ijcm.2013.410A001","article-title":"The Role of 5-Aminolevulinic Acid (5-ALA) and Sleep","volume":"4","author":"Perez","year":"2013","journal-title":"Int. J. Clin. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1248\/bpb.b19-00009","article-title":"Myalgic Encephalomyelitis\/Chronic Fatigue Syndrome Induced by Repeated Forced Swimming in Mice","volume":"42","author":"Ohba","year":"2019","journal-title":"Biol. Pharm. Bull."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e20180957","DOI":"10.1590\/0001-3765201920180957","article-title":"Evaluation of a rat model of exercise-induced fatigue using treadmill running with progressively increasing load","volume":"91","author":"Hou","year":"2019","journal-title":"An. Da Acad. Bras. De Cienc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"111477","DOI":"10.1016\/j.isci.2024.111477","article-title":"Therapeutic potential of 5-aminolevulinic acid in metabolic disorders: Current insights and future directions","volume":"27","author":"Kuryata","year":"2024","journal-title":"iScience"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.3892\/etm.2021.10889","article-title":"5-Aminolevulinic acid combined with ferrous iron improves glucose tolerance in high-fat diet-fed mice via upregulation of glucose transporter 1","volume":"22","author":"Kuroda","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40360-016-0108-3","article-title":"5-aminolevulinic acid combined with ferrous ion reduces adiposity and improves glucose tolerance in diet-induced obese mice via enhancing mitochondrial function","volume":"18","author":"Ota","year":"2017","journal-title":"BMC Pharmacol. Toxicol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"229","DOI":"10.2217\/17460875.2.2.229","article-title":"Triacylglycerol metabolism in adipose tissue","volume":"2","author":"Ahmadian","year":"2007","journal-title":"Future Lipidol."},{"key":"ref_27","first-page":"16","article-title":"Norepinephrine dysfunction in depression","volume":"61","author":"Anand","year":"2000","journal-title":"J. Clin. Psychiatry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.psyneuen.2006.04.003","article-title":"Cortisol hypersecretion in unipolar major depression with melancholic and psychotic features: Dopaminergic, noradrenergic and thyroid correlates","volume":"31","author":"Duval","year":"2006","journal-title":"Psychoneuroendocrinology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4013","DOI":"10.1038\/s41598-017-03917-0","article-title":"Treatment of sarcopenia and glucose intolerance through mitochondrial activation by 5-aminolevulinic acid","volume":"7","author":"Fujii","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1016\/S0024-3205(98)00183-0","article-title":"Tyrosine hydroxylase gene expression in the locus coeruleus of depression-model rats and rats exposed to short-and long-term forced walking stress","volume":"62","author":"Wang","year":"1998","journal-title":"Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"14807","DOI":"10.1073\/pnas.192585799","article-title":"Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging","volume":"99","author":"Atamna","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/9\/1465\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:48:20Z","timestamp":1760035700000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/9\/1465"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,18]]},"references-count":31,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["life15091465"],"URL":"https:\/\/doi.org\/10.3390\/life15091465","relation":{},"ISSN":["2075-1729"],"issn-type":[{"type":"electronic","value":"2075-1729"}],"subject":[],"published":{"date-parts":[[2025,9,18]]}}}