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Inhibition of HIF-P4Hs leads to stabilisation of hypoxia-inducible factors (HIFs) and activation of the HIF pathway affecting multiple biological processes to rescue cells from hypoxia. As evidence from animal models suggests that HIF-P4H inhibitors could be used to treat metabolic disorders associated with insulin resistance, we examined whether roxadustat, an HIF-P4H inhibitor approved for the treatment of renal anaemia, would have an effect on glucose metabolism in primary human myotubes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Primary skeletal muscle cell cultures, established from biopsies of\n                      <jats:italic>vastus lateralis<\/jats:italic>\n                      muscle from men with normal glucose tolerance (NGT) (\n                      <jats:italic>n<\/jats:italic>\n                      =5) or type 2 diabetes (\n                      <jats:italic>n<\/jats:italic>\n                      =8), were treated with roxadustat. Induction of HIF target gene expression was detected with quantitative real-time PCR. Glucose uptake and glycogen synthesis were investigated with radioactive tracers. Glycolysis and mitochondrial respiration rates were measured with a Seahorse analyser.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Exposure to roxadustat stabilised nuclear HIF1\u03b1 protein expression in human myotubes. Treatment with roxadustat led to induction of HIF target gene mRNAs for\n                      <jats:italic>GLUT1<\/jats:italic>\n                      (also known as\n                      <jats:italic>SLC2A1<\/jats:italic>\n                      ),\n                      <jats:italic>HK2<\/jats:italic>\n                      ,\n                      <jats:italic>MCT4<\/jats:italic>\n                      (also known as\n                      <jats:italic>SLC16A4<\/jats:italic>\n                      ) and\n                      <jats:italic>HIF-P4H-2<\/jats:italic>\n                      (also known as\n                      <jats:italic>PHD2<\/jats:italic>\n                      or\n                      <jats:italic>EGLN1<\/jats:italic>\n                      ) in myotubes from donors with NGT, with a blunted response in myotubes from donors with type 2 diabetes. mRNAs for\n                      <jats:italic>LDHA<\/jats:italic>\n                      ,\n                      <jats:italic>PDK1<\/jats:italic>\n                      and\n                      <jats:italic>GBE1<\/jats:italic>\n                      were induced to a similar degree in myotubes from donors with NGT or type 2 diabetes. Exposure of myotubes to roxadustat led to a 1.4-fold increase in glycolytic rate in myotubes from men with NGT (\n                      <jats:italic>p<\/jats:italic>\n                      =0.0370) and a 1.7-fold increase in myotubes from donors with type 2 diabetes (\n                      <jats:italic>p<\/jats:italic>\n                      =0.0044), with no difference between the groups (\n                      <jats:italic>p<\/jats:italic>\n                      =0.1391). Exposure to roxadustat led to a reduction in basal mitochondrial respiration in both groups (\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.01). Basal glucose uptake rates were similar in myotubes from donors with NGT (20.2 \u00b1 2.7 pmol mg\n                      <jats:sup>\u22121<\/jats:sup>\n                      min\n                      <jats:sup>\u22121<\/jats:sup>\n                      ) and type 2 diabetes (25.3 \u00b1 4.4 pmol mg\n                      <jats:sup>\u22121<\/jats:sup>\n                      min\n                      <jats:sup>\u22121<\/jats:sup>\n                      ,\n                      <jats:italic>p<\/jats:italic>\n                      =0.4205). Treatment with roxadustat enhanced insulin-stimulated glucose uptake in myotubes from donors with NGT (1.4-fold vs insulin-only condition,\n                      <jats:italic>p<\/jats:italic>\n                      =0.0023). The basal rate of glucose incorporation into glycogen was lower in myotubes from donors with NGT (233 \u00b1 12.4 nmol g\n                      <jats:sup>\u22121<\/jats:sup>\n                      h\n                      <jats:sup>\u22121<\/jats:sup>\n                      ) than in myotubes from donors with type 2 diabetes (360 \u00b1 40.3 nmol g\n                      <jats:sup>\u22121<\/jats:sup>\n                      h\n                      <jats:sup>\u22121<\/jats:sup>\n                      ,\n                      <jats:italic>p<\/jats:italic>\n                      =0.0344). Insulin increased glycogen synthesis by 1.9-fold (\n                      <jats:italic>p<\/jats:italic>\n                      =0.0025) in myotubes from donors with NGT, whereas roxadustat did not affect their basal or insulin-stimulated glycogen synthesis. Insulin increased glycogen synthesis by 1.7-fold (\n                      <jats:italic>p<\/jats:italic>\n                      =0.0031) in myotubes from donors with type 2 diabetes. While basal glycogen synthesis was unaffected by roxadustat, pretreatment with roxadustat enhanced insulin-stimulated glycogen synthesis in myotubes from donors with type 2 diabetes (\n                      <jats:italic>p<\/jats:italic>\n                      =0.0345).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>Roxadustat increases glycolysis and inhibits mitochondrial respiration in primary human myotubes regardless of diabetes status. Roxadustat may also improve insulin action on glycogen synthesis in myotubes from donors with type 2 diabetes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-024-06185-6","type":"journal-article","created":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T09:02:03Z","timestamp":1717059723000},"page":"1943-1954","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Activation of the hypoxia-inducible factor pathway by roxadustat improves glucose metabolism in human primary myotubes from men"],"prefix":"10.1007","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7613-4238","authenticated-orcid":false,"given":"Selina","family":"M\u00e4kinen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7956-9811","authenticated-orcid":false,"given":"Sreesha","family":"Sree","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4303-9277","authenticated-orcid":false,"given":"Tuulia","family":"Ala-Nisula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1137-1790","authenticated-orcid":false,"given":"Henric","family":"Kultalahti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2827-8229","authenticated-orcid":false,"given":"Peppi","family":"Koivunen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7870-070X","authenticated-orcid":false,"given":"Heikki A.","family":"Koistinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,30]]},"reference":[{"key":"6185_CR1","doi-asserted-by":"publisher","first-page":"798","DOI":"10.3390\/cells12050798","volume":"12","author":"A Yfantis","year":"2023","unstructured":"Yfantis A, Mylonis I, Chachami G et al (2023) Transcriptional response to hypoxia: the role of HIF-1-associated co-regulators. 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Aatsinki, E. Lehtim\u00e4ki and A. Kokko (Biocenter Oulu, University of Oulu, Oulu, Finland) for expert technical assistance.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The data that support the findings of this study are not openly available due to reasons of sensitivity.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"Open Access funding provided by University of Helsinki (including Helsinki University Central Hospital). The authors acknowledge the following funding sources: Finnish Cultural Foundation (HAK, SS); Finska L\u00e4kares\u00e4llskapet (HAK); Helsinki University Hospital (funding from hospital administration and governmental subsidy for research [HAK]); Jalmari and Rauha Ahokas Foundation (HAK); Liv och H\u00e4lsa Foundation (HAK); Jane and Aatos Erkko Foundation (PK); Sigrid Jus\u00e9lius Foundation (PK); and Research Council of Finland (grants 127093 and 258753 to HAK, grant 339900 to PK). The study funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"SM, SS, PK and HAK designed the study. HAK and SM collected the muscle biopsies. SM, SS, TA-N, HK, PK and HAK acquired, analysed and interpreted the data. SM, SS and HAK drafted the article, which was reviewed and edited critically for important intellectual content by TA-N, HK and PK. SM and HAK revised the article with input from all authors. All authors read and approved the final version for publication. HAK is the guarantor of this work and, as such, has full access to all the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}