{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:45:43Z","timestamp":1782798343912,"version":"3.54.5"},"reference-count":109,"publisher":"The Endocrine Society","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100007438","name":"Familien Hede Nielsens Fond","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007438","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007605","name":"Aarhus University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007605","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","award":["NNF20OC0060610"],"award-info":[{"award-number":["NNF20OC0060610"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","award":["NNF22SA0079901"],"award-info":[{"award-number":["NNF22SA0079901"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011958","name":"Independent Research Fund Denmark","doi-asserted-by":"publisher","award":["2096-00165A"],"award-info":[{"award-number":["2096-00165A"]}],"id":[{"id":"10.13039\/501100011958","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011958","name":"Independent Research Fund Denmark","doi-asserted-by":"publisher","award":["0134-00130B"],"award-info":[{"award-number":["0134-00130B"]}],"id":[{"id":"10.13039\/501100011958","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Sygesikringen Danmark","award":["2022-0189"],"award-info":[{"award-number":["2022-0189"]}]},{"DOI":"10.13039\/100015223","name":"The Danish Diabetes and Endocrine Academy","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015223","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Klinefelter syndrome (KS) is characterized by hypogonadism, resulting in metabolic disturbances and altered body composition, including reduced muscle mass. Although testosterone replacement therapy (TRT) is a standard treatment, its effects on skeletal muscle remain incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Single-nucleus RNA sequencing was applied to vastus lateralis biopsies from patients with KS (n = 4), collected at the time of diagnosis and again after 1 year of TRT. Reference material was retrieved from age-matched male controls (n = 4). We profiled nuclear transcriptomes across 10 cell types residing within the skeletal muscle.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>At diagnosis, sex hormone measurements confirmed hypogonadism in the untreated KS group. One year of TRT effectively normalized serum testosterone and reduced LH and FSH levels. Furthermore, 3 in 4 KS patients gained muscle mass. We obtained transcriptomic data from 81 786 individual nuclei. At baseline, untreated KS muscle exhibited pervasive transcriptional reprograming with indications of changes to myogenic differentiation and heightened fibrotic, adipogenic, and inflammatory transcriptomic profiles. Pseudotime trajectory analysis indicated altered progression from muscle stem to progenitor states. After TRT, gene expression shifted toward gene-patterns linked to improved structural integrity, regeneration, and vascular remodeling. Nevertheless, a substantial KS-specific signature persisted including increased inflammatory signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In this exploratory pilot study, TRT was associated with a shift toward a more proregenerative skeletal muscle transcriptional environment in patients with KS, though only partially mitigating some of the adverse effects of long-standing hypogonadism and KS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/clinem\/dgag240","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T16:35:54Z","timestamp":1781627754000},"source":"Crossref","is-referenced-by-count":1,"title":["Single-nucleus RNA sequencing reveals testosterone replacement therapy-associated multicellular remodeling of skeletal muscle in hypogonadal men with Klinefelter syndrome"],"prefix":"10.1210","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1017-7702","authenticated-orcid":false,"given":"Emma B","family":"Hasselholm","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Aarhus University Hospital , 8200 Aarhus N ,","place":["Denmark"]},{"name":"Department of Clinical Medicine, Aarhus University , 8000 Aarhus ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1110-748X","authenticated-orcid":false,"given":"Lukas Ochsner","family":"Ridder","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Aarhus University Hospital , 8200 Aarhus N ,","place":["Denmark"]},{"name":"Department of Clinical Medicine, Aarhus University , 8000 Aarhus ,","place":["Denmark"]},{"name":"Department of Endocrinology, Aarhus University Hospital , 8200 Aarhus N ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3970-2408","authenticated-orcid":false,"given":"Agnete N\u00f8rgaard","family":"Schou","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Aarhus University Hospital , 8200 Aarhus N ,","place":["Denmark"]},{"name":"Department of Clinical Medicine, Aarhus University , 8000 Aarhus ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7627-7132","authenticated-orcid":false,"given":"Jakob","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University , 8000 Aarhus ,","place":["Denmark"]},{"name":"Steno Diabetes Center Aarhus, Aarhus University Hospital , 8200 Aarhus N 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,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3825-0000","authenticated-orcid":false,"given":"Jesper","family":"Just","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Aarhus University Hospital , 8200 Aarhus N ,","place":["Denmark"]},{"name":"Department of Clinical Medicine, Aarhus University , 8000 Aarhus ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5924-1720","authenticated-orcid":false,"given":"Claus H\u00f8jbjerg","family":"Gravholt","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Aarhus University Hospital , 8200 Aarhus N ,","place":["Denmark"]},{"name":"Department of Clinical Medicine, Aarhus University , 8000 Aarhus ,","place":["Denmark"]},{"name":"Department of Endocrinology, Aarhus University Hospital , 8200 Aarhus N 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