Inducible deletion of raptor and mTOR from adult skeletal muscle impairs muscle contractility and relaxation

Skeletal muscle weakness has been associated with different pathological conditions, including sarcopenia and muscular dystrophy, and is accompanied by altered mammalian target f rapamycin (mTOR) signalling. We wanted to elucidate the functional role of mTOR in muscle contractility. Most loss-of-function studies for mTOR signalling have used the drug rapamycin to inhibit some of the signalling downstream of mTOR. However, given that rapamycin does not inhibit all mTOR signalling completely, we generated a double knockout for mTOR and fur the scaffold protein of mTORC1, raptor, in skeletal muscle. We found that double knockout in mice results in a more severe phenotype compared with deletion of raptor or mTOR alone. Indeed, these animals display muscle weakness, increased fibre denervation and a slower muscle relaxation following tetanic stimulation. This is accompanied by a shift towards slow-twitch fibres and changes in the expression levels of calcium-related genes, such as Sercul and Casq1. Double knockout mice show a decrease in calcium decay kinetics after tetanus in vivo, suggestive of a reduced calcium reuptake. In addition, RNA sequencing analysis revealed that many downregulated genes, such as Tcap and Fhod3, arc linked to sarcomere organization. These results suggest a key role Fhod3 mTOR signalling in maintaining proper fibre relaxation in skeletal muscle.

Automated summary

This study reveals the functional role of mTOR in muscle contractility. Double knockout of mTOR and raptor in skeletal muscle leads to severe muscle weakness and slower muscle relaxation. The altered mTOR signaling results in increased fiber denervation, changes in gene expression related to calcium, and a shift towards slow-twitch fibers.