Rapamycin does not compromise muscle endurance

rapamycin and mTOR

Rapamycin inhibits the mTOR pathway, crucial for muscle growth

The following study partly answers something I’ve long wondered about, whether the anti-aging drug rapamycin can compromise muscle endurance or performance: Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance

Rapamycin extends lifespan in mice, but can have a number of undesirable effects that may ultimately limit its utility in humans. The canonical target of rapamycin, and the one thought to account for its effects on lifespan, is the mammalian/mechanistic target of rapamycin, complex 1 (mTORC1). We have previously shown that at least some of the detrimental side effects of rapamycin are due to “off target” disruption of mTORC2, suggesting they could be avoided by more specific targeting of mTORC1. However, mTORC1 inhibitionper se can reduce the mRNA expression of mitochondrial genes and compromise the function of mitochondria in cultured muscle cells, implying that defects in bioenergetics might be an unavoidable consequence of targeting mTORC1 in vivo. Therefore, we tested whether rapamycin, at the same doses used to extend lifespan, affects mitochondrial function in skeletal muscle. While mitochondrial transcripts were decreased, particularly in the highly oxidative soleus muscle, we found no consistent change in mitochondrial DNA or protein levels. In agreement with the lack of change in mitochondrial components, rapamycin-treated mice had endurance equivalent to that of untreated controls, and isolated, permeabilized muscle fibers displayed similar rates of oxygen consumption. We conclude that the doses of rapamycin required to extend life do not cause overt mitochondrial dysfunction in skeletal muscle.

Rapamycin is perhaps the most promising anti-aging drug available, the other candidate being metformin, a diabetes drug. However, this doesn’t answer the question in mind as to whether rapamycin compromises muscle hypertrophy, size, and strength; that is, just because endurance performance and mitochondrial number and function are not compromised, it doesn’t mean that hypertrophy is not affected. There are good grounds for thinking that it may be, since rapamycin works (or appears to) by affecting mTOR (mammalian target of rapamycin), which is the main nutrient sensor that signals growth. It seems possible that rapamycin may leave enough mTOR activity in place so that hypertrophy is not affected, but this remains to be shown, as far as I know.

The fundamental growth-longevity tradeoff is still in place.


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