Ribosome Biogenesis as a Putative Bottleneck to Skeletal Muscle Hypertrophy: Mechanisms, Human Evidence, and Practical Modulators

Muscle growth occurs primarily when mechanical tension is applied over a sustained period of time.

When scientists measure RNA in muscle tissue samples and adjust for muscle weight, they may miss increases in ribosomes because the fluid content of muscle cells expands during growth, making ribosome levels appear lower than they are.

People who gain more muscle from resistance training show a consistent increase in ribosomal RNA production over time, while those who gain little muscle do not, despite having normal activity in the mTORC1 signaling pathway. This suggests that the ability to produce more ribosomes, not initial signaling, determines muscle growth differences between individuals.

As people age, the production of ribosomes in skeletal muscle decreases due to reduced activity of RNA Polymerase I and diminished sensitivity of the nucleolus to mechanical signals, and this reduction occurs independently of mTORC1 signaling, leading to decreased muscle protein synthesis and muscle loss.

After muscle loss from inactivity, molecular changes in DNA methylation and retained muscle cell nuclei allow faster muscle regrowth during retraining.

In people who regularly lift weights, long-term muscle growth is linked to an increase in ribosomal RNA and larger nucleoli, not short-term changes in mTORC1 signaling, because protein synthesis capacity is determined by the total number of ribosomes, not how active they are at a given moment.