The research team, based at the University of Texas Medical Branch, enrolled sixteen adults between the ages of 50 and 60 in a randomized, double-blind crossover trial. Each participant took sildenafil at 50 milligrams per day or tadalafil at 10 milligrams per day for four weeks, along with a visually identical placebo for another four weeks, in an order determined by random assignment. Neither the volunteers nor the investigators knew which pill was being taken at any point. The crossover design meant that every participant served as their own control, allowing the researchers to compare molecular measurements taken before drug exposure with those taken after a month of active treatment within the same person, a powerful approach for filtering out individual biological noise.

What set this study apart was the sheer breadth of molecular sampling. At each study visit, participants provided fasting blood samples and underwent needle biopsies of the vastus lateralis, the large quadriceps muscle on the side of the thigh. Those tissue and blood samples were then subjected to four complementary analytical approaches: transcriptomics to measure gene activity, proteomics to quantify the proteins actually being produced, metabolomics to track lipid signaling molecules and amino acid pathways in plasma, and immunohistochemistry to count inflammatory immune cells embedded in the muscle. The researchers also used liquid chromatography-tandem mass spectrometry to verify that participants had genuine drug in their bloodstream, confirming that sildenafil and tadalafil concentrations fell within ranges previously reported for these doses.

The most consistent signal emerged from the blood. After four weeks of treatment with either drug, levels of eicosanoids, bioactive lipid messengers derived from polyunsaturated fatty acids, shifted in a direction associated with reduced inflammation. Sildenafil treatment lowered 12-hydroxyeicosatetraenoic acid, a product of the 12-lipoxygenase enzyme that has been linked to oxidative stress, endothelial dysfunction, neuroinflammation, and cancer metastasis, and also reduced 5-HETE, a related mediator implicated in tumor progression and Alzheimer’s disease. Tadalafil produced similar reductions in 12-HETE and 13-HODE, another lipid mediator associated with cognitive impairment, while simultaneously raising levels of protectin D1, an anti-inflammatory docosanoid derived from docosahexaenoic acid that is known to be produced by macrophages at sites of tissue injury.

Both drugs also appeared to rev up the body’s arginine biosynthesis machinery. Sildenafil increased plasma L-arginine by roughly 1.55-fold, while tadalafil raised citrulline and argininosuccinate, two intermediates of the citrulline-nitric oxide cycle that feeds the raw material for nitric oxide production. The authors propose several possible explanations: the drugs may suppress arginase, an enzyme that competes with nitric oxide synthase for arginine; they may dial down inducible nitric oxide synthase, the inflammatory form of the enzyme; or they may improve the health of small intestinal enterocytes, the cells responsible for manufacturing citrulline in the first place. Whatever the mechanism, the shift suggests these drugs do not merely prolong nitric oxide signaling but may actively expand the substrate supply that fuels it.

Inside the muscle, the two drugs told strikingly different stories. Sildenafil produced a broad transcriptional response, with 101 genes upregulated and 23 downregulated after four weeks. The enriched gene ontology terms clustered around cell adhesion, cell motility, immune system processes, extracellular matrix organization, and blood vessel and bone development, patterns that the authors note resemble the molecular signature of long-term aerobic exercise training. Proteomic analysis reinforced this picture: 136 proteins increased after sildenafil treatment, including components of the protein folding machinery that govern the unfolded protein response, a cellular quality-control system also activated during exercise adaptation. Notably, proteins involved in telomere maintenance and DNA biosynthesis also rose, hinting at possible effects on cellular aging, since telomere length in skeletal muscle is positively associated with physical activity and inversely related to age-related disease.

Tadalafil, despite remaining active in the body far longer than sildenafil, left almost no coherent mark on the muscle transcriptome, with no differentially expressed genes detected at all, and produced a proteomic response dominated by downregulated proteins with few shared functional themes. The researchers find this asymmetry puzzling and raise the possibility that some of sildenafil’s muscular effects may be off-target. The two drugs are structurally dissimilar and cross-react with other phosphodiesterase enzymes to different degrees: sildenafil inhibits PDE-1 and PDE-6 more strongly, while tadalafil inhibits PDE-11, an enzyme found in skeletal muscle whose physiological role remains poorly understood. The discrepancy underscores how little is still known about why these chemically distinct molecules diverge once they leave the bloodstream.

To weave the three omics layers together, the team applied a multiblock statistical integration method called DIABLO, which selects the variables from each dataset that best discriminate between pre- and post-treatment states. For the sildenafil group, the most influential gene was SPTLC2, a subunit of the enzyme that initiates sphingolipid biosynthesis and has been linked to both aging and exercise adaptation; the most influential protein was PHKA1, a regulator of glycogen breakdown whose reduction could reflect the drugs’ known ability to enhance muscle glucose uptake; and the top metabolite was L-arginine itself. For tadalafil, the leading gene was MCUB, a negative regulator of the mitochondrial calcium uniporter whose downregulation could theoretically increase mitochondrial calcium uptake, a change associated with muscle hypertrophy in animal models and reduced by aging.

Not every result supported the repurposing enthusiasm. Immunohistochemical counts of M1 and M2 macrophages in the muscle biopsies showed no significant change with either drug, meaning the systemic anti-inflammatory signal in the blood was not mirrored by a measurable shift in the local immune environment of the tissue. The authors caution that repeated biopsies taken close to previous sampling sites may have introduced local inflammation that obscured treatment effects, and they acknowledge that the small sample size of eight participants per drug group limits statistical power. Functional measures of strength, endurance, and self-reported fatigue likewise showed no significant improvement over the four-week window, despite earlier work from the same group showing that just eight days of sildenafil increased muscle protein synthesis in healthy men.

Even with those caveats, the study offers a compelling molecular map of what these widely prescribed drugs do beyond their famous vascular effects. The convergence of reduced pro-inflammatory lipid mediators, elevated arginine pathway substrates, and exercise-like gene expression patterns in muscle provides testable hypotheses for future trials targeting inflammation, sarcopenia, cognitive decline, and cancer-related fatigue. The authors call for larger studies with careful attention to sampling techniques and longer treatment durations to determine whether the molecular shifts documented here translate into meaningful clinical benefits for the growing population of healthy adults hoping to age well.

Subject of Research: Multi-omics analysis of the systemic and skeletal muscle effects of PDE-5 inhibitors in healthy middle-aged adults

Article Title: Assessing the therapeutic potential of PDE‐5 inhibitors in adults: Insights from a multi‐omics study

Article References: McGovern, K. A., Wright, T. J., Marchant, E. D., Kilroe, S. P., Durham, W. J., Dillon, E. L., Baum, M. M., Kinsky, M. P., Russell, W. K., Fry, C. S., Gongloor, P., Pyles, R. B., Urban, R. J., Rasmussen, B. B., & Sheffield‐Moore, M. (2026). Assessing the therapeutic potential of PDE ‐5 inhibitors in adults: Insights from a multi‐omics study. Physiological Reports, 14(18), Article e71104. https://doi.org/10.14814/phy2.71104

Image Credits: AI Generated

DOI: 10.14814/phy2.71104

Keywords: PDE-5 inhibitors, sildenafil, tadalafil, multi-omics, inflammation, eicosanoids, skeletal muscle, arginine biosynthesis, proteomics, transcriptomics, metabolomics, drug repurposing