#1

An increasing number of physically active adults are taking the mTOR inhibitor rapamycin off label with the goal of extending healthspan. However, frequent rapamycin dosing disrupts metabolic health during sedentary conditions and abates the anabolic response to exercise. Intermittent once weekly rapamycin dosing minimizes many negative metabolic side effects of frequent rapamycin in sedentary mice. However, it remains unknown how different rapamycin dosing schedules impact metabolic, physical, and skeletal muscle adaptations to voluntary exercise training. Therefore, we tested the hypothesis that intermittent rapamycin (2mg/kg; 1x/week) would avoid detrimental effects on adaptations to 8 weeks of progressive weighted wheel running (PoWeR) in adult female mice (5-month-old) by evading the sustained inhibitory effects on mTOR signaling by more frequent dosing schedules (2mg/kg; 3x/week). Frequent but not intermittent rapamycin suppressed skeletal muscle mTORC1 signaling in PoWeR trained mice. PoWeR improved maximal exercise capacity, absolute grip strength, and myofiber hypertrophy with no differences between vehicle or rapamycin treated mice. Conversely, frequent and intermittent rapamycin treated mice had impaired glucose tolerance and insulin sensitivity compared to vehicle treated mice after PoWeR; however, intermittent rapamycin reduced the impact on glucose intolerance versus frequent rapamycin. Collectively, these data in adult female mice suggest that 1) rapamycin is largely compatible with the physical and skeletal muscle benefits of PoWeR and 2) the detrimental effects of rapamycin on body composition and glucose metabolism in the context of voluntary exercise may be reduced by intermittent dosing.

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#2

Once weekly in mice translates to much longer in humans, no? IIRC the half-life in mice is much much shorter.

#3

Yes - I seem to remember the half life is less than 19 hours for mice. ChatGPT says 6 to 12 hours vs. approx. 60 hours for humans. But the dose used in the study is very high; 2mg/kg.

#4

Even if you translate the mouse dose by the usual factor (dividing by 10 or 12 or so), you still get a pretty high human weekly dose of around 12-14 mg/week.

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#5

This is not so high if you take into account how fast some people metabolize rapamycin and what blood levels are deemed therapeutic after 24,48 hours, etc.

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#6

That’s a great and very interesting study. Super comprehensive too, with functional tests not just biomarkers, which is awesome.

The Rapamycin was injected, which is kinda unusual! But at least it guaranteed no weirdness with absorption and bioavailability.

That said, you can really see the double-edged sword of Rapamycin. Arguably, the control (i.e. no drug) exercise strength group has the best metrics of everything - gained grip strength, hypertrophy etc. The continuous Rapa group were doing worse than untreated mice in a lot of tests. But, the intermittent Rapa group also did suffer some apparent negative effects like worse glucose tolerance even though they gained most of the exercise benefits. Also a bummer that exercise didn’t offset the glucose disposal problems.

So yet again we learn that the dose is key. If we take the 2 mg/kg, divide by 12.3 to correct for humans = 0.16 mg/kg, multiplied by 70kg average human = 11 mg. As for whether the mouse response to that dose is the same as a human, or what the blood concentration is, I have no idea. Hopefully they have blood samples stored and reviewers will ask for them to measure concentrations in the blood before the manuscript is accepted.

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