Tadalafil, the long-acting phosphodiesterase type 5 inhibitor best known under the brand name Cialis, may do far more than improve blood flow. A new cell study from researchers at the University of Rome Foro Italico suggests that prolonged exposure to the drug can push skeletal muscle progenitor cells into a highly proliferative, regeneration-ready state, while simultaneously holding back their terminal differentiation. The findings, published in Molecular Biology Reports, add muscle biology to a growing list of tissues influenced by the nitric oxide and cyclic guanosine monophosphate signaling pathway that tadalafil modulates, and they raise questions that extend from the clinic for muscle-wasting diseases all the way to the anti-doping laboratory.
The research team, led by Cristina Antinozzi and Luigi Di Luigi, set out to address a gap in what is known about PDE5 inhibitors and muscle. Skeletal muscle regeneration depends on the activation, proliferation and eventual differentiation of myogenic progenitor cells, the satellite cells that sit dormant along muscle fibers until injury or exercise wakes them up. Nitric oxide signaling is known to be a key player in this process, and because PDE5 inhibitors prolong cGMP signaling downstream of nitric oxide, scientists have long suspected the drugs could influence how muscle repairs itself. What remained unclear was what happens when cells are exposed to tadalafil not for hours, but for days.
To find out, the researchers used C2C12 cells, a mouse myoblast cell line that is one of the workhorses of muscle biology research. When switched to low-serum conditions, these cells reliably exit the cell cycle, fuse together and form multinucleated myotubes, allowing scientists to track every stage of myogenesis in a dish. In the study, the cells were treated with 1 micromolar tadalafil for up to seven days, a prolonged exposure designed to mimic sustained pharmacological use rather than a single transient dose. The team then measured proliferation, cell viability, the activation of myogenic marker genes and the release of myokines, the signaling molecules that muscle cells secrete.
The first striking result was survival and growth. Tadalafil significantly increased cell proliferation and survival across all time points, reducing cell death throughout the treatment period. In practical terms, the drug appeared to keep the myoblast population expanding robustly instead of losing cells to apoptosis or stress. For a field where muscle-wasting disorders such as Duchenne muscular dystrophy and age-related sarcopenia are driven partly by the exhaustion and death of regenerative cells, any compound that keeps progenitor pools alive and dividing is of obvious therapeutic interest.
The myogenic program itself, however, showed a more nuanced response. Tadalafil enhanced the expression of early myogenic factors, the transcriptional switches that mark the beginning of the muscle-building program. Yet at the same time, it delayed terminal differentiation. Cells exposed to the drug for seven days produced fewer myosin heavy chain-positive multinucleated myotubes, the mature structures that represent the end point of myogenesis, and they maintained higher expression levels of Pax7 and Myf6, two markers associated with a less differentiated, more stem-like phenotype. In other words, tadalafil did not simply accelerate muscle formation; it appeared to keep the cells poised in an earlier, more regenerative state.
That combination, more proliferation plus delayed differentiation, is exactly the profile one would want from a drug intended to boost the regenerative capacity of muscle. Satellite cells that differentiate too quickly may rebuild a damaged fiber but fail to replenish the stem cell pool, whereas cells that self-renew can sustain repair over repeated rounds of injury. The Pax7 protein in particular is a master regulator of muscle stem cell self-renewal, and Myf6 has been implicated in maintaining the satellite cell niche. By sustaining expression of these factors, tadalafil seems to preserve the regenerative reserve rather than spend it, a mechanism the authors describe as promoting a highly proliferative state while preventing premature differentiation.
The molecular signature behind this shift offers further clues. The treated cells showed upregulation of Sirt3, the mitochondrial sirtuin deacetylase that governs mitochondrial fitness, oxidative stress resistance and metabolic adaptation, alongside increased IL6, an interleukin with well-documented roles as a muscle-derived myokine that can support regeneration. At the same time, the cells downregulated myostatin and TGF-beta, two of the most powerful brakes on muscle growth in the body. Myostatin inhibition is already a major strategy in the development of drugs for muscular dystrophy and other atrophic conditions, so its suppression under tadalafil treatment is a particularly meaningful signal. Reduced TGF-beta signaling likewise removes a barrier that normally restrains progenitor cell activation and progression through the myogenic program.
These results build on a body of earlier work by the same group and others. Previous studies had shown that tadalafil regulates lipid homeostasis in human skeletal muscle cells, improves lean mass and endothelial function in certain patients, and that nitric oxide and cGMP signaling sustain long-term muscle regeneration by controlling the fate of satellite cells. Clinical observations in boys with Duchenne muscular dystrophy have suggested that PDE5 inhibition can alleviate functional muscle ischemia, and recent epidemiological work has even associated PDE5 inhibitor use with reduced mortality and lower rates of cardiovascular disease and dementia. The new study adds a direct cellular mechanism: prolonged cGMP signaling appears to reprogram myogenic progenitors toward expansion and self-renewal while dialing down the anti-growth factors that would otherwise push them to mature and stop.
The therapeutic implications are considerable. If the same biology holds in human tissue, tadalafil or related compounds could serve as adjuvant pharmacological therapy for muscle-wasting disorders, helping patients with dystrophies, sarcopenia or disuse atrophy maintain a larger, healthier pool of regenerative cells. The drug is already widely prescribed, has a well-characterized safety profile and acts on a pathway that is naturally engaged by exercise itself, since muscle contraction increases nitric oxide production. A licensed medicine that amplifies an endogenous repair pathway is an attractive candidate for repurposing, and the authors explicitly point to this potential in their conclusions.
But the same mechanism that excites clinicians also alarms anti-doping authorities. A drug that increases progenitor cell proliferation, suppresses myostatin and TGF-beta, and keeps muscle in a regeneration-primed state is, on paper, a potential performance enhancer, capable of accelerating recovery from training damage and possibly supporting hypertrophy. The researchers themselves highlight this concern, noting that the potent improvement of the muscle regenerative machinery raises critical questions about misuse in sport and calling for evaluation by anti-doping agencies. As with any cell-culture study, important caveats remain: the work was done in a mouse cell line at a specific dose, and whether prolonged tadalafil exposure produces the same progenitor-sparing effect in living human muscle is not yet known. Still, the study marks a notable step in understanding how a familiar cardiovascular drug talks to the stem cells of the musculoskeletal system, and it ensures that both regenerative medicine specialists and sports regulators will be watching the next round of experiments closely.
Subject of Research: Effects of prolonged tadalafil exposure on myogenesis and myogenic marker activation in C2C12 skeletal muscle cells
Article Title: Prolonged tadalafil exposure promotes skeletal muscle myogenesis and regulates early myogenic markers activation in C2C12 cell lines
Article References: Antinozzi, C., & Di Luigi, L. (2026). Prolonged tadalafil exposure promotes skeletal muscle myogenesis and regulates early myogenic markers activation in C2C12 cell lines. Molecular Biology Reports, 53(1), Article 1701. https://doi.org/10.1007/s11033-026-12929-x
Image Credits: AI Generated
DOI: 10.1007/s11033-026-12929-x
Keywords: tadalafil, PDE5 inhibitors, myogenesis, C2C12 cells, satellite cells, muscle regeneration, myostatin, Pax7, Sirt3, interleukin-6, muscle-wasting disorders, doping
News Source: Drew Townsend. (October 11, 2026). Erectile Dysfunction Drug Tadalafil Keeps Muscle Stem Cells in a Powerful Regenerative State, Cell Study Finds. Scienmag.
