{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:44:25Z","timestamp":1787237065527,"version":"build-2736575974"},"reference-count":42,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,18]],"date-time":"2022-09-18T00:00:00Z","timestamp":1663459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["1R01 HL 116573"],"award-info":[{"award-number":["1R01 HL 116573"]}]},{"name":"NIH","award":["5T32HD098061-04"],"award-info":[{"award-number":["5T32HD098061-04"]}]},{"name":"NIH","award":["5T32HL007609-34"],"award-info":[{"award-number":["5T32HL007609-34"]}]},{"name":"NIH","award":["#R24HL123767"],"award-info":[{"award-number":["#R24HL123767"]}]},{"name":"NHLBI R24","award":["1R01 HL 116573"],"award-info":[{"award-number":["1R01 HL 116573"]}]},{"name":"NHLBI R24","award":["5T32HD098061-04"],"award-info":[{"award-number":["5T32HD098061-04"]}]},{"name":"NHLBI R24","award":["5T32HL007609-34"],"award-info":[{"award-number":["5T32HL007609-34"]}]},{"name":"NHLBI R24","award":["#R24HL123767"],"award-info":[{"award-number":["#R24HL123767"]}]},{"name":"Cardiovascular Medical Research and Education Fund (CMREF)","award":["1R01 HL 116573"],"award-info":[{"award-number":["1R01 HL 116573"]}]},{"name":"Cardiovascular Medical Research and Education Fund (CMREF)","award":["5T32HD098061-04"],"award-info":[{"award-number":["5T32HD098061-04"]}]},{"name":"Cardiovascular Medical Research and Education Fund (CMREF)","award":["5T32HL007609-34"],"award-info":[{"award-number":["5T32HL007609-34"]}]},{"name":"Cardiovascular Medical Research and Education Fund (CMREF)","award":["#R24HL123767"],"award-info":[{"award-number":["#R24HL123767"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pulmonary arterial hypertension (PAH) is a serious, progressive, and often fatal disease that is in urgent need of improved therapies that treat it. One of the remaining therapeutic challenges is the increasingly recognized skeletal muscle dysfunction that interferes with exercise tolerance. Here we report that in the adult rat Sugen\/hypoxia (SU\/Hx) model of severe pulmonary hypertension (PH), there is highly significant, almost 50%, decrease in exercise endurance, and this is associated with a 25% increase in the abundance of type II muscle fiber markers, thick sarcomeric aggregates and an increase in the levels of FoxO1 in the soleus (a predominantly type I fiber muscle), with additional alterations in the transcriptomic profiles of the diaphragm (a mixed fiber muscle) and the extensor digitorum longus (a predominantly Type II fiber muscle). In addition, soleus atrophy may contribute to impaired exercise endurance. Studies in L6 rat myoblasts have showed that myotube differentiation is associated with increased FoxO1 levels and type II fiber markers, while the inhibition of FoxO1 leads to increased type I fiber markers. We conclude that the formation of aggregates and a FoxO1-mediated shift in the skeletal muscle fiber-type specification may underlie skeletal muscle dysfunction in an experimental study of PH.<\/jats:p>","DOI":"10.3390\/ijms231810912","type":"journal-article","created":{"date-parts":[[2022,9,18]],"date-time":"2022-09-18T23:39:22Z","timestamp":1663544362000},"page":"10912","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Skeletal Muscle Dysfunction in Experimental Pulmonary Hypertension"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9712-2615","authenticated-orcid":false,"given":"Kosmas","family":"Kosmas","sequence":"first","affiliation":[{"name":"Department of Pediatric Newborn Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7318-0215","authenticated-orcid":false,"given":"Zoe","family":"Michael","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital and Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aimilia Eirini","family":"Papathanasiou","sequence":"additional","affiliation":[{"name":"Department of Pediatric Newborn Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fotios","family":"Spyropoulos","sequence":"additional","affiliation":[{"name":"Department of Pediatric Newborn Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elio","family":"Adib","sequence":"additional","affiliation":[{"name":"Department of Medicine, Pulmonary Division, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi","family":"Jasuja","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Christou","sequence":"additional","affiliation":[{"name":"Department of Pediatric Newborn Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1165\/rcmb.2012-0506OC","article-title":"Skeletal muscle dysfunction in idiopathic pulmonary arterial hypertension","volume":"50","author":"Batt","year":"2014","journal-title":"Am. 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