I’m somewhat astonished that people on that forum did not realize that rapamycin blocks mTOR whose name is literally Target Of Rapamycin.
No mTOR =>
- no or reduced skeletal muscle protein synthesis
- no or reduced connective tissue and tendon protein synthesis (collagen)
Obviously complete blockages are only achieved at high concentration but lower concentrations will be enough to blunt the effects which is why people taking rapamycin in that study did get an effect but blunted compared to placebo.
The good news is that rapacymin enhance the effect of endurance training though.
That’s why I only take rapamycin during my deload/assimilation/rest weeks and I don’t do any strength training while my rapamycin level are above 2 or 3 ng/ml.
I asked Gemini pro to give me the reference studies from reputable authors (i.e. Keith Baar for tendons) on that topic.
The molecular regulation of both muscle and connective tissue (tendon) relies heavily on the mechanistic Target of Rapamycin Complex 1 (mTORC1) signaling pathway. Research by leading figures in musculoskeletal physiology has demonstrated that rapamycin—a potent and specific mTORC1 inhibitor—significantly blunts the synthetic response of these tissues to primary stimuli like exercise and growth factors.
1. Skeletal Muscle Protein Synthesis (MPS)
In skeletal muscle, mTORC1 is the primary “hub” for integrating mechanical and nutritional signals to initiate translation. Foundational human studies by Blake B. Rasmussen and Micah J. Drummond have established that rapamycin administration effectively “blocks” the expected rise in protein synthesis following resistance exercise.
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Human In Vivo Evidence: In a seminal study, Drummond et al. (2009) demonstrated that when humans were given rapamycin (12 mg) prior to a bout of resistance exercise, the typical 50–100% increase in mixed muscle protein synthesis was almost entirely abolished. The study showed that rapamycin specifically blocked the phosphorylation of downstream targets like S6K1 and the formation of the eIF4F complex, which are critical for initiating protein translation (Drummond et al., 2009).
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Blood Flow Restriction (BFR): Further research by Gundermann et al. (2014) (also from the Rasmussen group) showed that the stimulatory effect of BFR exercise on muscle protein synthesis is also inhibited by rapamycin, confirming that the mTORC1-dependent synthetic block applies across various exercise modalities (Gundermann et al., 2014).
2. Connective Tissue and Tendon Protein Synthesis
While less studied than muscle, connective tissue synthesis—specifically collagen production in tendons—is also highly sensitive to mTORC1 inhibition. Key work from Keith Baar, a leading authority in functional connective tissue biology, has utilized human-engineered ligament models to quantify these effects.
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Inhibition of Collagen Synthesis: Research by El Essawy and Baar (2023) demonstrated that rapamycin treatment in engineered human ligaments decreased procollagen synthesis by 55% and total collagen content by 36% (El Essawy & Baar, 2023). Crucially, the study found that while growth factors like IGF-1 normally stimulate collagen production, these increases are blocked by rapamycin, indicating that the anabolic response of tendon fibroblasts is predominantly mTORC1-mediated (El Essawy & Baar, 2023).
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Fibrosis and Tenocytes: Complementary research by Zheng et al. (2018) found that rapamycin significantly reduces collagen synthesis in human tenocytes and fibroblasts. By activating autophagy and inhibiting the mTOR signaling pathway, rapamycin was shown to suppress the excessive extracellular matrix (ECM) production typically seen in peritendinous fibrosis (Zheng et al., 2018).
Mechanistic Summary Table
| Tissue Type |
Key Reputable Authors |
Primary Finding |
Reference |
| Skeletal Muscle |
Drummond, M. J. & Rasmussen, B. B. |
Rapamycin blocks the contraction-induced increase in human MPS. |
(Drummond et al., 2009) |
| Tendon / Ligament |
El Essawy, E. S. & Baar, K. |
Rapamycin decreases procollagen synthesis by 55% in human ligaments. |
(El Essawy & Baar, 2023) |
| Fibroblasts |
Zheng, W. & Fan, C. |
Rapamycin reduces collagen synthesis and ECM production in tenocytes. |
(Zheng et al., 2018) |
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References
Drummond, M. J., Fry, C. S., Glynn, E. L., Dreyer, H. C., Dhanani, S., Timmerman, K. L., Volpi, E., & Rasmussen, B. B. (2009). Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis. The Journal of Physiology , 587 (7), 1535–1546. https://doi.org/10.1113/jphysiol.2008.163816 Cited by: 598
El Essawy, E. S., & Baar, K. (2023). Rapamycin insensitive regulation of engineered ligament structure and function by IGF-1. Journal of Applied Physiology, 135(4), 833–839. https://doi.org/10.1152/japplphysiol.00593.2022 Cited by: 7
Gundermann, D. M., Walker, D. K., Reidy, P. T., Borack, M. S., Dickinson, J. M., Volpi, E., & Rasmussen, B. B. (2014). Activation of mTORC1 signaling and protein synthesis in human muscle following blood flow restriction exercise is inhibited by rapamycin. American Journal of Physiology-Endocrinology and Metabolism, 306(10), E1198-E1204. https://doi.org/10.1152/ajpendo.00600.2013 Cited by: 181
Zheng, W., Qian, Y., Chen, S., Ruan, H., & Fan, C. (2018). Rapamycin Protects Against Peritendinous Fibrosis Through Activation of Autophagy. Frontiers in Pharmacology, 9. https://doi.org/10.3389/fphar.2018.00402 Cited by: 52
raising weights every 3-4 months. Almost doubling my ability… and I can still equally lift …if not out lift most of the younger gym bros.
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And both groups did make gains - but the placebo group gained more. (Plus, as we both know, this is the “noob gain” phase when you start any exercise program. It’s pretty different to what happens 6+ month later.)