Highlights 

  • Rapamycin treatment preserved the exercise-induced benefits of resistance-style wheel training in female mice, including greater endurance, grip strength, and muscle fiber growth, demonstrating that the drug does not block adaptations to resistance training.
  • Frequent rapamycin dosing impaired glucose tolerance more severely than once-weekly dosing, suggesting that dosing strategy influences metabolic side effects while leaving exercise-driven muscle and performance gains largely intact.

Rapamycin, a drug best known for its potential to extend lifespan, has often raised concerns among scientists because it blocks a key growth pathway in the body called mTOR (short for mechanistic target of rapamycin). mTOR is like a cellular “traffic controller” that tells cells when to grow, divide, or make proteins. Since exercise relies on this same pathway to build muscle, many assumed rapamycin would interfere with the benefits of resistance training.

A new study in Aging Cell shows that this may not be the case. In female mice, rapamycin did not block improvements in muscle size, strength, or endurance after eight weeks of a high-volume exercise program called progressive weighted wheel running (PoWeR), where mice run on wheels made gradually heavier to mimic human resistance training.

Rapamycin Retains Muscle and Strength Gains from Exercise

The team studied how rapamycin affected the way exercise reshapes the body in 5-month-old female mice. Whether the drug was given often or just once a week, the mice still gained the key benefits of their training program, which included running longer, gripping harder, and building bigger muscle fibers.

Looking closer at the muscles themselves, rapamycin did not prevent growth in two muscles that usually respond strongly to exercise: the soleus, which helps with endurance activities like steady running, and the flexor digitorum longus, which powers quick, forceful movements. Mice that received rapamycin several times a week did show slightly smaller hearts and soleus muscles compared to untreated controls, but these changes did not reduce their overall exercise performance.

(Elliehausen et al., 2025 | Aging Cell) Rapamycin does not block muscle fiber growth from exercise. The left panel (C) shows that PoWeR training enlarged Type IIA fibers in the soleus muscle, with similar gains whether or not mice received rapamycin. The right panel (D) shows the flexor digitorum longus (FDL), where exercise increased Type I and Type IIA fiber size across all groups. Overall, rapamycin-treated mice still experienced normal muscle fiber growth after training.

Metabolic Side Effects Are Reduced with Intermittent Dosing

Where rapamycin showed drawbacks was in glucose metabolism, the way the body handles sugar. Normally, exercise improves glucose control and makes muscles more sensitive to insulin, the hormone that moves sugar out of the blood and into cells. But both dosing schedules of rapamycin reduced this benefit.

The frequent schedule made glucose control much worse, while the once-weekly schedule caused only a mild disruption. This suggests that how often rapamycin is taken matters, and less frequent dosing may allow the body to hold on to more of exercise’s metabolic benefits.

(Elliehausen et al., 2025 | Aging Cell) Rapamycin impairs glucose tolerance during exercise training. The left panel shows blood glucose levels over two hours after a glucose injection in sedentary or exercised (PoWeR) mice treated with vehicle, rapamycin three times per week, or rapamycin once per week. Rapamycin-treated mice cleared glucose more slowly than vehicle controls. The right panel shows the total glucose burden (area under the curve), which was highest in the frequent dosing group and moderately elevated in the intermittent group.

Muscle Signaling Pathways Depend on Rapamycin Frequency

To understand why, the researchers looked at phosphorylation, a process where cells attach small chemical tags called phosphate groups onto proteins to turn them “on” or “off.” One of the key proteins tagged this way is rpS6, a signal that muscle cells are in growth mode.

Frequent rapamycin kept rpS6 turned off even after exercise, while intermittent dosing allowed rpS6 to switch back on between doses. This pattern helps explain why intermittent dosing interfered less with the benefits of training. Namely, rapamycin blocks the signal for muscle growth.

Why Female Mice?

The researchers chose female mice because past work shows rapamycin tends to extend lifespan more strongly in females than in males. Female mice also run more consistently in voluntary exercise setups like wheels, making them a good model for this type of study.

Balancing Longevity and Metabolism 

The findings suggest that rapamycin and exercise are not fundamentally at odds. Female mice given the drug were still able to build muscle and endurance through training, challenging the long-held assumption that rapamycin would block these benefits because of its effects on the mTOR pathway. At the same time, the drug did blunt some of the exercise-related improvements in blood sugar control, particularly when taken frequently, though once-weekly dosing lessened this effect.

Taken together, the results suggest that rapamycin can be compatible with the physical benefits of exercise if the dosing schedule is carefully managed. For people considering rapamycin as a potential longevity therapy, these findings highlight the need to balance its anti-aging promise against its metabolic downsides. While more research is needed, especially in older animals, males, and eventually human trials, this work points toward the possibility of combining rapamycin with regular physical activity in ways that extend healthspan while minimizing unwanted side effects.