Can a Drug Mimic Exercise in Aging Muscle? What a Small Human-Cell Study Really Found

Edited and Approved by Stephen C. Rose, PhD, MS

Imagine a medicine that could switch on some of the molecular programs normally activated by exercise. For an older person confined by pain, injury, or illness, that possibility is genuinely important. A 2025 pilot study moved the idea one careful step forward: researchers compared muscle from active and inactive older women, then treated muscle-forming cells from the inactive group with an experimental compound called SLU-PP-332 [1].

The headline needs an immediate guardrail. The compound was not given to the women. It was added to cells growing in laboratory dishes after the cells had been isolated from surgical biopsies. The study therefore offers early mechanistic evidence, not proof that a drug can preserve strength, prevent falls, or replace exercise in people.

Why researchers are interested in ERRs

SLU-PP-332 activates proteins called estrogen-related receptors, or ERRs. Despite the name, these are not the classical estrogen receptors and the compound is not estrogen therapy. ERRs are nuclear receptors: proteins inside cells that help regulate which genes are turned on. In skeletal muscle, ERR-alpha and ERR-gamma help coordinate mitochondrial energy production, blood-vessel support, muscle-fiber identity, and repair. They work with other regulators, including PGC-1-alpha, to help muscle adapt to changing energy demands [2].

Mitochondria are the cell's energy-processing structures. During prolonged inactivity, mitochondrial function can deteriorate while reactive oxygen species increase. Reactive oxygen species are chemically active molecules that are useful in controlled amounts but can damage proteins, fats, and DNA when production overwhelms antioxidant defenses. These changes can contribute to the loss of muscle fibers during disuse [3]. That biology makes ERRs an attractive target: activating them might restore part of the energy and stress-response program that quiet muscle has lost.

What the researchers actually did

The study enrolled 20 women undergoing hip replacement for osteoarthritis. Their average age was about 78. Ten reported at least 30 minutes of moderate activity, mainly brisk walking or bicycling, three times a week; ten reported no regular structured activity. During surgery, researchers collected muscle tissue and compared fiber size, handgrip strength, hip function, pain, and several molecular markers between the groups [1].

They also isolated myoblasts from participants. Myoblasts are immature muscle cells that can multiply and fuse into long, contractile myotubes, an early laboratory model of muscle-fiber formation. Cells from the inactive women were exposed to SLU-PP-332. This created two linked but distinct experiments: an observational comparison of active and inactive women, and an ex vivo intervention in cultured cells. Ex vivo means the cells came from people but were studied outside the body.

The compound did not appear from nowhere. Earlier research found that SLU-PP-332 activated all three ERR subtypes, increased mitochondrial respiration in mouse muscle cells, shifted mouse muscle toward a more oxidative profile, and improved treadmill endurance in mice [4]. A separate mouse study reported increased energy expenditure and fatty-acid oxidation, with improved metabolic measures in models of obesity [5]. Those results made human-derived muscle cells a logical next test, but mouse performance and cells in a dish remain far from a safe, effective medicine for older adults.

What the active and inactive groups showed

The active women had larger muscle fibers, stronger handgrip, better hip-function scores, and less reported pain than the inactive women. Their muscle tissue also showed a pattern consistent with better cellular energy regulation: lower levels of NOX4, an enzyme that can contribute to oxidative stress, and higher levels of SIRT1, PGC-1-alpha, ERR-alpha, and FNDC5. FNDC5 is a protein involved in muscle signaling and is the precursor of the signaling molecule irisin [1].

These differences are biologically coherent, but they do not prove that activity caused every difference. The groups contained only ten women each, activity was self-reported, and all participants had severe enough hip osteoarthritis to need surgery. Pain could reduce activity; better muscle function could make activity easier; medication, nutrition, health history, or other unmeasured differences could affect both. This comparison is best viewed as a signal that matched known exercise biology, not a randomized exercise trial.

What changed after the cells received SLU-PP-332

In cultured myoblasts from inactive women, SLU-PP-332 lowered NOX4 and raised SIRT1, PGC-1-alpha, ERR-alpha, and FNDC5. It also increased Akt and Bcl-2, proteins associated with cell survival. Laboratory measures suggested less oxidative stress, less cellular senescence, lower cytotoxicity, and more reduced glutathione, one of the cell's major antioxidant defenses. Treated cells formed more abundant myotubes and expressed more myosin heavy chain, a key contractile protein [1].

The overall pattern is encouraging: the experimental compound pushed inactive-donor cells toward several features seen in the active group. Yet the study measured markers and cell behavior, not the strength of an intact human muscle. A myotube in a dish has no nerves, blood flow, immune system, hormonal environment, liver metabolism, or real-world mechanical load. A treatment can look beneficial in that simplified setting and still fail because the body absorbs it poorly, breaks it down quickly, sends it to the wrong tissues, or experiences harmful off-target effects.

Why this is not an exercise replacement

Exercise is not one molecular switch. It challenges the heart and lungs, loads bones and tendons, improves balance and coordination, changes blood flow, affects immune and brain signaling, and gives muscle repeated mechanical reasons to remain strong. An ERR agonist might eventually reproduce selected metabolic signals, but it cannot be assumed to reproduce this whole-body network. The phrase exercise mimetic is useful in laboratory research and dangerously easy to overread in public discussion.

The distinction also matters clinically. Sarcopenia is not simply small muscles. Current consensus emphasizes low muscle strength, uses low muscle quantity or quality to confirm the diagnosis, and regards poor physical performance as a sign of severe disease [6]. This pilot study did not diagnose or treat sarcopenia, test walking speed, reduce falls, or show sustained improvements in strength. It studied older women with hip osteoarthritis and laboratory cells derived from a subset of them.

Meanwhile, exercise already has human outcome evidence. A network meta-analysis of 42 randomized trials involving 3,728 older adults with sarcopenia found that resistance exercise, often combined with aerobic or balance training and sometimes nutrition, improved patient-important outcomes such as quality of life, grip strength, gait speed, and chair-stand performance, with certainty varying by outcome [7]. For people who can exercise safely, an experimental molecule should not displace a treatment with direct human evidence.

Where the research could go next

The most compelling future use may not be a shortcut for healthy gym-goers. It could be an adjunct for people who cannot generate enough activity because of hospitalization, immobilization, neurologic disease, advanced frailty, or painful musculoskeletal conditions. Before that becomes plausible, researchers need replication in cells from more participants, including men and people with varied conditions. They also need animal studies focused on aging and disuse, followed by formal toxicology, pharmacokinetic work, dose finding, and carefully monitored human trials.

Those trials would need to measure more than molecular markers. The meaningful questions are whether treatment preserves muscle mass and strength, improves mobility, supports rehabilitation, reduces disability, and does so without unacceptable risks. Because ERRs regulate metabolism in multiple tissues, investigators must also watch for effects outside muscle. Long-term activation of a powerful gene-regulatory pathway deserves particular caution.

The bottom line

This pilot study identified a promising molecular target and showed that an ERR agonist could improve several stress, survival, and differentiation signals in muscle cells taken from inactive older women. That is a meaningful translational step beyond a standard mouse experiment. It is still preclinical evidence. No participant received SLU-PP-332, and the research tells us nothing yet about human dosing, safety, strength, mobility, falls, or longevity.

For now, the compound is best understood as a research tool that may help scientists learn how active muscle maintains its energy and repair programs. The exciting possibility is not that movement has been bottled. It is that a carefully targeted therapy might one day preserve part of muscle's capacity when movement is temporarily or permanently limited. That possibility deserves attention, but it also deserves the patience required to test it properly.

References

[1] Bonanni R, Falvino A, Matticari A, et al. Targeting ERRs to counteract age-related muscle atrophy associated with physical inactivity: a pilot study. Front Physiol. 2025;16:1616693. doi:10.3389/fphys.2025.1616693.

[2] Sopariwala D, Nguyen H, Narkar V. Estrogen-related receptor signaling in skeletal muscle fitness. Int J Sports Med. 2023;44(9):609-617. doi:10.1055/a-2035-8192.

[3] Hyatt H, Deminice R, Yoshihara T, Powers SK. Mitochondrial dysfunction induces muscle atrophy during prolonged inactivity: a review of the causes and effects. Arch Biochem Biophys. 2019;662:49-60. doi:10.1016/j.abb.2018.11.005.

[4] Billon C, Sitaula S, Banerjee S, et al. Synthetic ERRalpha/beta/gamma agonist induces an ERRalpha-dependent acute aerobic exercise response and enhances exercise capacity. ACS Chem Biol. 2023;18(4):756-771. doi:10.1021/acschembio.2c00720.

[5] Billon C, Schoepke E, Avdagic A, et al. A synthetic ERR agonist alleviates metabolic syndrome. J Pharmacol Exp Ther. 2024;388(2):232-240. doi:10.1124/jpet.123.001733.

[6] Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019;48(1):16-31. doi:10.1093/ageing/afy169.

[7] Shen Y, Shi Q, Nong K, et al. Exercise for sarcopenia in older people: a systematic review and network meta-analysis. J Cachexia Sarcopenia Muscle. 2023;14(3):1199-1211. doi:10.1002/jcsm.13225.