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Sixteen men and women aged 50\u201360 were administered daily sildenafil\/tadalafil for 1\u2009month. We characterized molecular signatures of sildenafil\/tadalafil treatment via analyses and multi\u2010omics integration of the serum metabolome and skeletal muscle proteome and transcriptome. In serum, eicosanoids decreased and arginine biosynthesis pathway components increased following sildenafil\/tadalafil. In skeletal muscle following sildenafil, blood vessel development and immune response genes increased, indicating augmented angiogenesis and possible inflammation at proximate biopsy sites. Proteins related to telomere maintenance and protein folding increased, suggesting reduced cellular senescence and cellular stress or functional adaptations. In skeletal muscle following tadalafil, there were no differentially expressed genes, and despite reduction of many proteins there were no enriched biological processes. Notably, sildenafil resulted in a more cohesive and substantial molecular signal in skeletal muscle. Multi\u2010omics integration for both treatments revealed significant coexpression patterns. Phosphodiesterase\u20105 inhibitors showed systemic anti\u2010inflammatory effects, as indicated by reduced serum levels of pro\u2010inflammatory eicosanoids. However, this did not translate to immunohistochemical changes. Additional research is warranted to investigate PDE\u20105 inhibitor effects on various tissues, which can inform prospective applications for drug repurposing.<\/jats:p>","DOI":"10.14814\/phy2.71104","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:18:03Z","timestamp":1789985883000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Assessing the therapeutic potential of\n                    <scp>PDE<\/scp>\n                    \u20105 inhibitors in adults: Insights from a multi\u2010omics study"],"prefix":"10.14814","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0040-8693","authenticated-orcid":false,"given":"Kristen A.","family":"McGovern","sequence":"first","affiliation":[{"name":"Department of Internal Medicine The University of Texas Medical Branch (UTMB)  Galveston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Traver J.","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine The University of Texas Medical Branch (UTMB)  Galveston Texas USA"},{"name":"Department of Biological Sciences Ohio University  Athens Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik D.","family":"Marchant","sequence":"additional","affiliation":[{"name":"Department of Cellular and Integrative Physiology University of Texas Health Science Center at San Antonio  San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean P.","family":"Kilroe","sequence":"additional","affiliation":[{"name":"Department of Cellular and Integrative Physiology University of Texas Health Science Center at San Antonio  San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Durham","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine The University of Texas Medical Branch (UTMB)  Galveston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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