{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T17:54:16Z","timestamp":1777312456091,"version":"3.51.4"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000844","name":"European Space Agency","doi-asserted-by":"publisher","award":["4000128599\/19\/NL\/PG"],"award-info":[{"award-number":["4000128599\/19\/NL\/PG"]}],"id":[{"id":"10.13039\/501100000844","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Program of Research and Projects of Significant National Interest","award":["2022MHT25A"],"award-info":[{"award-number":["2022MHT25A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Scientific evidence has demonstrated the involvement of irisin, a molecule produced by muscle contraction, in preventing the onset of musculoskeletal decline. We previously demonstrated that the expression of irisin and its muscle-derived precursor FNDC5 is affected by unloading in skeletal muscle of hindlimb-unloaded (HU) mice. Studies in the HU mouse model showed that treatment with irisin prevents muscle wasting and atrophy. In parallel, human studies documented a strong association between irisin\/FNDC5 and muscle function. Therefore, the scientific community is committed to determining whether irisin may represent a promising clinical strategy for preventing and treating disorders caused by muscle inactivity, such as those affecting bedridden or elderly patients. In translational research from mice to humans, there are very few in vivo studies conducted on large animals. The sheep model is an excellent model for studying the musculoskeletal system due to its anatomical characteristics, which share similarities with humans, allowing for the reproduction of mechanical load distribution on the limbs. To provide translational knowledge on the progression of muscle atrophy, we evaluated the impact of unloading on the expression of FNDC5 and functional proteins of skeletal muscle in sheep. Our findings revealed a reduction of FNDC5 in the quadriceps muscle after 2\u00a0wk of immobilization. The FNDC5 decrease is accompanied by a reduction of myosin isoforms MyHC1 and MyHC2x, and an increase in muscle fibrosis. Importantly, FNDC5 expression positively correlated with expression of myosins, implying that the irisin\/FNDC5 system is a driving force for muscle function in this large animal model.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziag057","type":"journal-article","created":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T12:49:21Z","timestamp":1774702161000},"source":"Crossref","is-referenced-by-count":0,"title":["Impact of mechanical unloading on the irisin precursor, FNDC5, in skeletal muscle of sheep as a large animal experimental model"],"prefix":"10.1093","volume":"10","author":[{"given":"Clelia","family":"Suriano","sequence":"first","affiliation":[{"name":"Department of Translational Biomedicine and Neuroscience, University of Bari , 70124 Bari ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Onofrio Daniele","family":"Terrevoli","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area, University of Bari , 70124 Bari ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Staffieri","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area, University of Bari , 70124 Bari ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Lacitignola","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area, University of Bari , 70124 Bari ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Crovace","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area, University of Bari , 70124 Bari ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa","family":"Pellicani","sequence":"additional","affiliation":[{"name":"Department of Translational Biomedicine and Neuroscience, University of Bari , 70124 Bari ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michela","family":"Taurino","sequence":"additional","affiliation":[{"name":"Department of Translational Biomedicine and Neuroscience, University of Bari , 70124 Bari ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9970-3539","authenticated-orcid":false,"given":"Silvia","family":"Colucci","sequence":"additional","affiliation":[{"name":"Department of Translational Biomedicine and Neuroscience, University of Bari , 70124 Bari ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Grano","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area, University of Bari , 70124 Bari ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto Maria","family":"Crovace","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, University of Sassari , 07100 Sassari ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8501-5399","authenticated-orcid":false,"given":"Graziana","family":"Colaianni","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area, University of Bari , 70124 Bari ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"2026042713192436700_ref1","doi-asserted-by":"publisher","first-page":"235","DOI":"10.3389\/fphys.2018.00235","article-title":"Muscle atrophy induced by mechanical unloading: mechanisms and potential countermeasures","volume":"9","author":"Gao","year":"2018","journal-title":"Front Physiol"},{"issue":"1","key":"2026042713192436700_ref2","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/s41526-023-00251-w","article-title":"Time-dependent unloading effects on muscle and bone and involvement of FNDC5\/irisin axis","volume":"9","author":"Sanesi","year":"2023","journal-title":"NPJ Microgravity"},{"issue":"4","key":"2026042713192436700_ref3","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1210\/endrev\/bnab003","article-title":"Progress and challenges in the biology of FNDC5 and irisin","volume":"42","author":"Maak","year":"2021","journal-title":"Endocr Rev"},{"issue":"1","key":"2026042713192436700_ref4","doi-asserted-by":"publisher","first-page":"2811","DOI":"10.1038\/s41598-017-02557-8","article-title":"Irisin prevents and restores bone loss and muscle atrophy in hind-limb suspended mice","volume":"7","author":"Colaianni","year":"2017","journal-title":"Sci Rep"},{"issue":"1","key":"2026042713192436700_ref5","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1038\/s41467-017-01131-0","article-title":"Irisin is a pro-myogenic factor that induces skeletal muscle hypertrophy and rescues denervation-induced atrophy","volume":"8","author":"Reza","year":"2017","journal-title":"Nat Commun"},{"issue":"11","key":"2026042713192436700_ref6","doi-asserted-by":"publisher","first-page":"2266","DOI":"10.1111\/ggi.13030","article-title":"Circulating irisin levels as a predictive biomarker for sarcopenia: a cross-sectional community-based study","volume":"17","author":"Chang","year":"2017","journal-title":"Geriatr Gerontol Int"},{"key":"2026042713192436700_ref7","doi-asserted-by":"publisher","first-page":"886243","DOI":"10.3389\/fendo.2022.886243","article-title":"Irisin serum levels and skeletal muscle assessment in a cohort of Charcot-Marie-Tooth patients","volume":"13","author":"Colaianni","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"1","key":"2026042713192436700_ref8","doi-asserted-by":"publisher","first-page":"e22668","DOI":"10.1096\/fj.202201005RR","article-title":"Impact of 10-day bed rest on serum levels of irisin and markers of musculoskeletal metabolism","volume":"37","author":"Oranger","year":"2023","journal-title":"FASEB J"},{"issue":"3","key":"2026042713192436700_ref9","doi-asserted-by":"publisher","first-page":"2469","DOI":"10.3390\/ijms24032469","article-title":"Elevated expression of ADAM10 in skeletal muscle of patients with idiopathic inflammatory myopathies could be responsible for FNDC5\/irisin unbalance","volume":"24","author":"Zerlotin","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"9","key":"2026042713192436700_ref10","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.3390\/biology11091251","article-title":"The sheep as a large animal model for the investigation and treatment of human disorders","volume":"11","author":"Banstola","year":"2022","journal-title":"Biology (Basel)"},{"issue":"2","key":"2026042713192436700_ref11","doi-asserted-by":"publisher","first-page":"183","DOI":"10.3390\/genes11020183","article-title":"Comparative transcriptome analysis identifying the different molecular genetic markers related to production performance and meat quality in Longissimus dorsi tissues of MG \u00d7 STH and STH sheep","volume":"11","author":"Cheng","year":"2020","journal-title":"Genes (Basel)"},{"key":"2026042713192436700_ref12","doi-asserted-by":"publisher","first-page":"100968","DOI":"10.1016\/j.jshs.2024.100968","article-title":"BMAL1\/PGC1\u03b14-FNDC5\/irisin axis impacts distinct outcomes of time-of-day resistance exercise","volume":"14","author":"Guo","year":"2025","journal-title":"J Sport Health Sci"},{"issue":"1","key":"2026042713192436700_ref13","doi-asserted-by":"publisher","first-page":"43296","DOI":"10.1038\/srep43296","article-title":"Glucocorticoid receptor positively regulates transcription of FNDC5 in the liver","volume":"7","author":"Kim","year":"2017","journal-title":"Sci Rep"},{"issue":"1","key":"2026042713192436700_ref14","doi-asserted-by":"publisher","first-page":"55","DOI":"10.3233\/BPL-150019","article-title":"FNDC5\/irisin - their role in the nervous system and as a mediator for beneficial effects of exercise on the brain","volume":"1","author":"Wrann","year":"2015","journal-title":"Brain Plast"},{"issue":"42","key":"2026042713192436700_ref15","doi-asserted-by":"publisher","first-page":"30515","DOI":"10.1074\/jbc.M113.489716","article-title":"SIRT1 protein, by blocking the activities of transcription factors FoxO1 and FoxO3, inhibits muscle atrophy and promotes muscle growth","volume":"288","author":"Lee","year":"2013","journal-title":"J Biol Chem"},{"issue":"1","key":"2026042713192436700_ref16","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1007\/s11033-025-11315-3","article-title":"Molecular crosstalk for longevity: exercise and the AMPK\/SIRT1\/PGC-1\u03b1\/Irisin\/BDNF axis","volume":"53","author":"De Sousa","year":"2025","journal-title":"Mol Biol Rep"},{"key":"2026042713192436700_ref17","doi-asserted-by":"publisher","first-page":"32","DOI":"10.12703\/r\/11-32","article-title":"The role of mTORC1 in the regulation of skeletal muscle mass","volume":"11","author":"Bodine","year":"2022","journal-title":"Fac Rev"},{"issue":"314","key":"2026042713192436700_ref18","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2004809","article-title":"mTORC1 promotes denervation-induced muscle atrophy through a mechanism involving the activation of FoxO and E3 ubiquitin ligases","volume":"7","author":"Tang","year":"2014","journal-title":"Sci Signal"},{"issue":"9","key":"2026042713192436700_ref19","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1242\/dmm.019414","article-title":"The role of mTOR signaling in the regulation of protein synthesis and muscle mass during immobilization in mice","volume":"8","author":"You","year":"2015","journal-title":"Dis Model Mech"},{"issue":"5547","key":"2026042713192436700_ref20","doi-asserted-by":"publisher","first-page":"1704","DOI":"10.1126\/science.1065874","article-title":"Identification of ubiquitin ligases required for skeletal muscle atrophy","volume":"294","author":"Bodine","year":"2001","journal-title":"Science."},{"issue":"2","key":"2026042713192436700_ref21","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1139\/H09-137","article-title":"Little change in markers of protein breakdown and oxidative stress in humans in immobilization-induced skeletal muscle atrophy","volume":"35","author":"Glover","year":"2010","journal-title":"Appl Physiol Nutr Metab"},{"issue":"3","key":"2026042713192436700_ref22","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1111\/apha.12190","article-title":"Substantial skeletal muscle loss occurs during only 5 days of disuse","volume":"210","author":"Wall","year":"2014","journal-title":"Acta Physiol (Oxf)"},{"issue":"3","key":"2026042713192436700_ref23","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1007\/s00441-018-2955-2","article-title":"Skeletal muscle fibrosis: an overview","volume":"375","author":"Mahdy","year":"2019","journal-title":"Cell Tissue Res"},{"issue":"4","key":"2026042713192436700_ref24","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1152\/japplphysiol.00681.2022","article-title":"Muscle disuse as hindlimb unloading in early postnatal mice negatively impacts grip strength in adult mice: a pilot study","volume":"134","author":"Reidy","year":"2023","journal-title":"J Appl Physiol (1985)"},{"issue":"7","key":"2026042713192436700_ref25","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1002\/cbin.10725","article-title":"The role of TGF-\u03b21 during skeletal muscle regeneration","volume":"41","author":"Delaney","year":"2017","journal-title":"Cell Biol Int"},{"key":"2026042713192436700_ref26","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.biocel.2018.04.002","article-title":"Perivascular cell \u03b1v integrins as a target to treat skeletal muscle fibrosis","volume":"99","author":"Prazeres","year":"2018","journal-title":"Int J Biochem Cell Biol"},{"issue":"4","key":"2026042713192436700_ref27","first-page":"292","article-title":"Sheep model in orthopedic research: a literature review","volume":"51","author":"Martini","year":"2001","journal-title":"Comp Med"},{"issue":"20","key":"2026042713192436700_ref28","doi-asserted-by":"publisher","first-page":"4575","DOI":"10.1113\/jphysiol.2014.275545","article-title":"PGC1-\u03b1 over-expression prevents metabolic alterations and soleus muscle atrophy in hindlimb unloaded mice","volume":"592","author":"Cannavino","year":"2014","journal-title":"J Physiol"},{"issue":"4","key":"2026042713192436700_ref29","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1152\/japplphysiol.91578.2008","article-title":"Exercise in space: human skeletal muscle after 6 months aboard the International Space Station","volume":"106","author":"Trappe","year":"2009","journal-title":"J Appl Physiol (1985)"}],"container-title":["JBMR Plus"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jbmrplus\/advance-article-pdf\/doi\/10.1093\/jbmrpl\/ziag057\/67691582\/ziag057.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article-pdf\/10\/5\/ziag057\/67691582\/ziag057.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article-pdf\/10\/5\/ziag057\/67691582\/ziag057.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T17:19:27Z","timestamp":1777310367000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article\/doi\/10.1093\/jbmrpl\/ziag057\/8566168"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,31]]},"references-count":29,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,4,2]]}},"URL":"https:\/\/doi.org\/10.1093\/jbmrpl\/ziag057","relation":{},"ISSN":["2473-4039"],"issn-type":[{"value":"2473-4039","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,5]]},"published":{"date-parts":[[2026,3,31]]},"article-number":"ziag057"}}