{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T23:57:20Z","timestamp":1768521440696,"version":"3.49.0"},"posted":{"date-parts":[[2025,3,28]]},"group-title":"Systems Biology","reference-count":35,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T00:00:00Z","timestamp":1743120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Pulmonary arterial hypertension (PAH) is a rare but debilitating condition that causes exercise intolerance and ultimately death. Skeletal muscle derangements contribute to depressed exercise capacity in PAH, but the mechanisms underlying muscle dysfunction including the changes in muscle biology based on fiber type are understudied.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We evaluated exercise capacity, muscle histopathology, mitochondrial density, mitochondrial proteomics, and metabolomics\/lipidomics of\n                    <jats:italic>quadriceps (<\/jats:italic>\n                    predominately fast fibers\n                    <jats:italic>)<\/jats:italic>\n                    and\n                    <jats:italic>soleus (<\/jats:italic>\n                    predominately slow fibers) muscles in the monocrotaline (MCT) rat model of PAH.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    MCT rats exhibited impaired exercise capacity. Surprisingly, there were divergent atrophic and metabolic remodeling in the\n                    <jats:italic>quadriceps<\/jats:italic>\n                    and\n                    <jats:italic>soleus<\/jats:italic>\n                    muscles of MCT rats. In the\n                    <jats:italic>quadriceps<\/jats:italic>\n                    , there was a mild atrophic response only in type II fibers. In contrast, both type I and II fibers atrophied in the\n                    <jats:italic>soleus<\/jats:italic>\n                    . Both muscles exhibited fibrotic infiltration, but mitochondrial density was reduced in the\n                    <jats:italic>quadriceps<\/jats:italic>\n                    only. Mitochondrial proteomics and tissue metabolomics\/lipidomics profiling demonstrated the two muscles exhibited distinct responses as the\n                    <jats:italic>quadriceps<\/jats:italic>\n                    had impairments in oxidative phosphorylation\/fat metabolism and storage of triacylglycerides. However, the\n                    <jats:italic>soleus<\/jats:italic>\n                    showed signs of proteasome deficiencies and alterations in phosphatidylcholine\/phosphatidylethanolamine homeostasis. Finally, profiling of metabolites\/lipids in the serum identified potential novel biomarkers of exercise intolerance in PAH including the dimethylarginine pathway, cysteine, and triacylglycerides.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our data suggests differential cachectic and metabolic responses occur in PAH-induced myopathy. We nominate mitochondrial biogenesis and proteasome activation as potential druggable targets for PAH-myopathy.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.03.27.644723","type":"posted-content","created":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T04:11:42Z","timestamp":1743221502000},"source":"Crossref","is-referenced-by-count":0,"title":["Proteomic and Metabolomic Profiling Nominates Druggable Targets and Biomarkers for Pulmonary Arterial Hypertension-Associated Myopathy and Exercise Intolerance"],"prefix":"10.64898","author":[{"given":"Phablo","family":"Abreu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Moon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8229-385X","authenticated-orcid":false,"given":"Jenna B.","family":"Mendelson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Todd","family":"Markowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"LeeAnn","family":"Higgins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Murray","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Candace","family":"Guerrero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Blake","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sasha Z.","family":"Prisco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0364-6742","authenticated-orcid":false,"given":"Kurt W.","family":"Prins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025040107001572000_2025.03.27.644723v1.1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.j5492"},{"key":"2025040107001572000_2025.03.27.644723v1.2","doi-asserted-by":"crossref","unstructured":"Malenfant S , Lebret M , Breton-Gagnon \u00c9 , et al.: Exercise intolerance in pulmonary arterial hypertension: insight into central and peripheral pathophysiological mechanisms. 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