{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:23:13Z","timestamp":1787314993807,"version":"build-2736575974"},"reference-count":57,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,2,17]],"date-time":"2022-02-17T00:00:00Z","timestamp":1645056000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Intrauterine growth restriction (IUGR) is a leading cause of neonatal morbidity and mortality in humans and domestic animals. Developmental adaptations of skeletal muscle in IUGR lead to increased risk of premature muscle loss and metabolic disease in later life. Here, we identified \u03b2\u2010Klotho (KLB), a fibroblast growth factor 21 (FGF21) co\u2010receptor, as a novel regulator of muscle development in IUGR. Using the pig as a naturally\u2010occurring disease model, we performed transcriptome\u2010wide profiling of fetal muscle (day 90 of pregnancy) from IUGR and normal\u2010weight (NW) littermates. We found that, alongside large\u2010scale transcriptional changes comprising multiple developmental, tissue injury and metabolic gene pathways, KLB was increased in IUGR muscle. Moreover, FGF21 concentrations were increased in plasma in IUGR fetuses. Using cultures of fetal muscle progenitor cells (MPCs), we showed reduced myogenic capacity of IUGR compared to NW muscle\n                      <jats:italic>in vitro<\/jats:italic>\n                      , as evidenced by differences in fusion indices and myogenic transcript levels, as well as mechanistic target of rapamycin (mTOR) activity. Moreover, transfection of MPCs with KLB small interfering RNA promoted myogenesis and mTOR activation, whereas treatment with FGF21 had opposite and dose\u2010dependent effects in porcine and also in human fetal MPCs. In conclusion, our results identify KLB as a novel and potentially critical mediator of impaired muscle development in IUGR, through conserved mechanisms in pigs and humans. Our data shed new light onto the pathogenesis of IUGR, a significant cause of lifelong ill\u2010health in humans and animals.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Intrauterine growth restriction (IUGR) is associated with large\u2010scale transcriptional changes in developmental, tissue injury and metabolic gene pathways in fetal skeletal muscle.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Levels of the fibroblast growth factor 21 (FGF21) co\u2010receptor, \u03b2\u2010Klotho (KLB) are increased in IUGR fetal muscle, and FGF21 concentrations are increased in IUGR fetal plasma.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>KLB mediates a reduction in muscle development through inhibition of mechanistic target of rapamycin signalling.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>These effects of KLB on muscle cells are conserved in pig and human, suggesting a vital role of this protein in the regulation of muscle development and function in mammals.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp281647","type":"journal-article","created":{"date-parts":[[2022,1,26]],"date-time":"2022-01-26T19:39:57Z","timestamp":1643225997000},"page":"1771-1790","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["KLB dysregulation mediates disrupted muscle development in intrauterine growth restriction"],"prefix":"10.1113","volume":"600","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8456-2152","authenticated-orcid":false,"given":"Yennifer","family":"Cortes\u2010Araya","sequence":"first","affiliation":[{"name":"Division of Functional Genetics and Development The Roslin Institute and Royal (Dick) School of Veterinary Studies University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Stenhouse","sequence":"additional","affiliation":[{"name":"Division of Functional Genetics and Development The Roslin Institute and Royal (Dick) School of Veterinary Studies University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mazdak","family":"Salavati","sequence":"additional","affiliation":[{"name":"Division of Functional Genetics and Development The Roslin Institute and Royal (Dick) School of Veterinary Studies University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan O.","family":"Dan\u2010Jumbo","sequence":"additional","affiliation":[{"name":"Division of Functional Genetics and Development The Roslin Institute and Royal (Dick) School of Veterinary Studies University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Ho","sequence":"additional","affiliation":[{"name":"Division of Functional Genetics and Development The Roslin Institute and Royal (Dick) School of Veterinary Studies University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl J.","family":"Ashworth","sequence":"additional","affiliation":[{"name":"Division of Functional Genetics and Development The Roslin Institute and Royal (Dick) School of Veterinary Studies University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Clark","sequence":"additional","affiliation":[{"name":"Division of Functional Genetics and Development The Roslin Institute and Royal (Dick) School of Veterinary Studies University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina L.","family":"Esteves","sequence":"additional","affiliation":[{"name":"Division of Functional Genetics and Development The Roslin Institute and Royal (Dick) School of Veterinary Studies University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0331-2996","authenticated-orcid":false,"given":"F. 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