The hormone in question is insulin-like growth factor-1, or IGF-1, a small protein secreted largely by the liver that circulates in the blood and acts as a master anabolic signal for skeletal muscle. When IGF-1 binds to receptors on muscle fibers, it activates the AKT/mTOR pathway, an intracellular circuit that drives protein synthesis, cell growth, and repair. When that signal weakens, muscles tip toward atrophy, ramping up destruction machinery such as the E3 ubiquitin ligases Atrogin-1 and MuRF1, which tag contractile proteins for degradation. The Korean team’s central finding is that two commonly prescribed statins, lovastatin and atorvastatin, appear to disrupt this liver-to-muscle endocrine axis by first aging the liver.

Cellular senescence is a state in which a cell stops dividing but does not die, instead accumulating damage markers and secreting a cocktail of inflammatory and regulatory molecules known as the senescence-associated secretory phenotype, or SASP. In the new work, the researchers treated hepatocytes with lovastatin and atorvastatin and observed the classic fingerprints of senescence: increased activity of senescence-associated beta-galactosidase, an enzyme used as a standard histochemical marker of aged cells, and elevated expression of p21 and p16, two tumor-suppressor proteins that enforce the senescence program by halting the cell cycle. These changes were seen both in cultured liver cells and in liver tissue from animals exposed to the drugs, indicating that the phenomenon is not merely an artifact of the culture dish.

The most striking result came when the team catalogued what the senescent hepatocytes were secreting. Among the many components of the SASP, one factor stood out for moving in the wrong direction: IGF-1 was selectively and significantly reduced. In other words, rather than gaining inflammatory secretions, the statin-aged liver cells lost a key growth factor output. Because circulating IGF-1 is produced predominantly by the liver, a drop in hepatic IGF-1 expression translates directly into lower levels of the hormone in the bloodstream, potentially affecting tissues throughout the body that rely on it for maintenance and repair.

To test whether this hormonal shortfall actually harms muscle, the researchers set up a transwell coculture system, an experimental arrangement in which two cell types share a medium but are separated by a porous membrane, allowing soluble factors to pass while keeping the cells physically apart. When senescent AML12 mouse hepatocytes were cocultured with C2C12 myoblasts, the muscle cells’ ability to differentiate into myotubes was impaired, the resulting myotubes were thinner, and the muscle atrophy markers Atrogin-1 and MuRF1 were upregulated. Because the cells never touched, the effect must have been mediated by secreted factors — consistent with the idea that the senescent liver cells’ diminished IGF-1 output starves muscle of an essential growth signal.

The in vivo experiments reinforced the picture. The team exposed animals to a combination of lovastatin and ezetimibe, a cholesterol-absorption inhibitor that is often co-prescribed with statins to achieve greater low-density lipoprotein reduction. In the livers of these animals, the area staining positive for senescence-associated beta-galactosidase expanded, p21 and p16 expression rose, and circulating IGF-1 fell. Downstream, in the tibialis anterior muscle — a standard lower-leg muscle used in rodent studies of skeletal muscle physiology — the researchers measured a reduced average fiber cross-sectional area and a size distribution shifted toward smaller fibers, exactly what one expects when atrophy outpaces growth.

The molecular readout in the muscle told a coherent mechanistic story. AKT/mTOR pathway activation was diminished, meaning the anabolic circuit that IGF-1 normally engages had gone quiet, and the atrophy-associated proteins Atrogin-1 and MuRF1 were elevated, indicating that the ubiquitin-proteasome degradation machinery had been switched on. Together, these changes describe a muscle caught between reduced protein synthesis and increased protein breakdown — the biochemical definition of atrophy. The authors propose that this cascade constitutes a liver-to-muscle endocrine axis: statin-induced hepatic senescence suppresses IGF-1, and the resulting attenuation of IGF-1 signaling in muscle secondarily impairs myogenesis and promotes wasting.

The findings carry several important caveats and implications. First, the study was conducted in cell culture and in animal models, so the results will need to be confirmed in human studies before they can reshape clinical practice; the authors themselves frame the work as supporting a potential axis rather than proving it in patients. Second, the observation that ezetimibe was part of the in vivo regimen raises questions about how much of the hepatic effect is attributable to statin-specific inhibition of HMGCR, the enzyme that both statins target and that sits at the head of the mevalonate pathway, versus broader metabolic stress. HMGCR catalyzes a rate-limiting step in the production of mevalonate, from which cells synthesize not only cholesterol but also isoprenoid intermediates needed for protein prenylation — processes implicated in cell survival and stress responses. Blocking this pathway in hepatocytes may therefore trigger senescence through mechanisms that go well beyond cholesterol lowering itself.

For the millions of people who take statins, the study should not prompt anyone to stop their medication; the cardiovascular benefits of statins are firmly established, and statin-associated muscle symptoms, while real, affect a minority of users and are often manageable by adjusting dose or switching agents. But the research does suggest a new therapeutic frontier. If hepatic senescence is a driver of muscle complications, then drugs that clear senescent cells — so-called senolytics — or agents that dampen the senescence program might one day protect muscle in susceptible patients. Alternatively, restoring IGF-1 signaling, whether by supplementing the hormone, boosting its hepatic production, or activating AKT/mTOR downstream, could counteract the atrophy signal at its source. The authors explicitly propose targeting hepatic senescence or restoring IGF-1/AKT/mTOR activity as candidate strategies to mitigate statin-associated myopathy.

More broadly, the work adds to a growing appreciation that aging-like states induced in one organ can propagate systemically through endocrine signals. The liver, as the body’s metabolic factory and a major source of circulating growth factors, is uniquely positioned to broadcast its internal state to muscle, bone, and brain. A drug that quietly ages hepatocytes may therefore have consequences far beyond lipid numbers on a lab report. As the population on long-term statin therapy continues to grow — and as those patients themselves age — understanding how hepatic senescence reshapes the hormonal environment of muscle could prove essential not only for making statins safer but for preserving strength and independence in later life. The Korean team’s liver-muscle axis offers a testable framework for that effort, and it transforms a side effect long dismissed as a pharmacological mystery into a biological pathway that can, in principle, be measured, modeled, and targeted.

Subject of Research: Statin-induced hepatic senescence and reduced IGF-1 signaling driving skeletal muscle atrophy

Article Title: Hepatic senescence triggered by statins decreases systemic IGF-1 signaling to drive skeletal muscle atrophy

Article References: Kim, W.-K., Yeon, M., Yoo, Y., Shin, H.-B., Yang, Y. R., & Seo, Y.-K. (2026). Hepatic senescence triggered by statins decreases systemic IGF-1 signaling to drive skeletal muscle atrophy. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03399-y

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03399-y

Keywords: statins, hepatic senescence, IGF-1, skeletal muscle atrophy, AKT/mTOR signaling, SASP, Atrogin-1, MuRF1, HMGCR, liver-muscle axis, myopathy, cell senescence