{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:52:28Z","timestamp":1790718748553,"version":"4.1.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2014,1,1]],"date-time":"2014-01-01T00:00:00Z","timestamp":1388534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Despite improvements in survival with disease-targeted therapies, the majority of patients with pulmonary arterial hypertension (PAH) have persistent exercise intolerance that results from impaired cardiac function and skeletal muscle dysfunction. Our intent was to understand the molecular mechanisms mediating skeletal muscle dysfunction in PAH. A total of 12 patients with PAH and 10 matched control subjects were assessed. Patients with PAH demonstrated diminished exercise capacity (lower oxygen uptake max, lower anaerobic threshold and higher minute ventilation\/CO2) compared with control subjects. Quadriceps muscle cross-sectional area was significantly smaller in patients with PAH. The vastus lateralis muscle was biopsied to enable muscle fiber morphometric assessment and to determine expression levels\/activation of proteins regulating (1) muscle mass, (2) mitochondria biogenesis and shaping machinery, and (3) excitation\u2013contraction coupling. Patients with PAH demonstrated a decreased type I\/type II muscle fiber ratio, with a smaller cross-sectional area in the type I fibers. Diminished AKT and p70S6 kinase phosphorylation, with increased atrogin-1 and muscle RING-finger protein-1 transcript levels, were evident in the PAH muscle, suggesting engagement of cellular signaling networks stimulating ubiquitin-proteasome\u2013mediated proteolysis of muscle, with concurrent depression of networks mediating muscle hypertrophy. Although there were no differences in expression\/activation of proteins associated with mitochondrial biogenesis or fission (MTCO2 [cytochrome C oxidase subunit II]\/succinate dehydrogenase flavoprotein subunit A, mitochondrial transcription factor A, nuclear respiratory factor-1\/dynamin-related protein 1 phosphorylation), protein levels of a positive regulator of mitochondrial fusion, Mitofusin2, were significantly lower in patients with PAH. Patients with PAH demonstrated increased phosphorylation of ryanodine receptor 1 receptors, suggesting that altered sarcoplasmic reticulum Ca++ sequestration may impair excitation\u2013contraction coupling in the PAH muscle. These data suggest that muscle dysfunction in PAH results from a combination of muscle atrophy and intrinsically impaired contractility.<\/jats:p>","DOI":"10.1165\/rcmb.2012-0506oc","type":"journal-article","created":{"date-parts":[[2013,8,23]],"date-time":"2013-08-23T13:07:57Z","timestamp":1377263277000},"page":"74-86","source":"Crossref","is-referenced-by-count":130,"title":["Skeletal Muscle Dysfunction in Idiopathic Pulmonary Arterial Hypertension"],"prefix":"10.1093","volume":"50","author":[{"given":"Jane","family":"Batt","sequence":"first","affiliation":[{"name":"Keenan Research Center, Li Ka Shing Knowledge Institute, St. Michael\u2019s Hospital, Toronto, Ontario, Canada; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samar Shadly","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Division of Respirology, Department of Medicine, Toronto General Hospital, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy","family":"Correa","sequence":"additional","affiliation":[{"name":"Division of Respirology, Department of Medicine, Toronto General Hospital, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Bain","sequence":"additional","affiliation":[{"name":"Division of Respirology, Department of Medicine, Toronto General Hospital, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Granton","sequence":"additional","affiliation":[{"name":"Division of Respirology, Department of Medicine, Toronto General Hospital, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,1,1]]},"reference":[{"key":"2026030623202823600_bib1","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1378\/chest.09-1140","article-title":"Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry","volume":"137","author":"Badesch","year":"2010","journal-title":"Chest"},{"key":"2026030623202823600_bib2","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/s11136-005-3513-4","article-title":"The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR): a measure of health-related quality of life and quality of life for patients with pulmonary hypertension","volume":"15","author":"McKenna","year":"2006","journal-title":"Qual Life Res"},{"key":"2026030623202823600_bib3","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1183\/09031936.04.00095804","article-title":"Respiratory muscle dysfunction in idiopathic pulmonary arterial hypertension","volume":"25","author":"Meyer","year":"2005","journal-title":"Eur Respir J"},{"key":"2026030623202823600_bib4","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1016\/j.rmed.2007.06.014","article-title":"Skeletal muscle dysfunction in patients with idiopathic pulmonary arterial hypertension","volume":"101","author":"Bauer","year":"2007","journal-title":"Respir Med"},{"key":"2026030623202823600_bib5","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1161\/CIRCULATIONAHA.106.618397","article-title":"Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension","volume":"114","author":"Mereles","year":"2006","journal-title":"Circulation"},{"key":"2026030623202823600_bib6","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1136\/thx.2009.117168","article-title":"Peripheral muscle dysfunction in idiopathic pulmonary arterial hypertension","volume":"65","author":"Mainguy","year":"2010","journal-title":"Thorax"},{"key":"2026030623202823600_bib7","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.1093\/eurheartj\/ehp297","article-title":"Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT)","volume":"30","author":"Gali\u00e8","year":"2009","journal-title":"Eur Heart J"},{"key":"2026030623202823600_bib8","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1161\/CIRCULATIONAHA.106.184461","article-title":"Assessment of functional capacity in clinical and research settings: a scientific statement from the American Heart Association Committee on Exercise, Rehabilitation, and Prevention of the Council on Clinical Cardiology and the Council on Cardiovascular Nursing","volume":"116","author":"Arena","year":"2007","journal-title":"Circulation"},{"key":"2026030623202823600_bib9","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1097\/01.hjr.0000209812.05573.04","article-title":"Statement on cardiopulmonary exercise testing in chronic heart failure due to left ventricular dysfunction: recommendations for performance and interpretation. 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