Key result
Double knockout of mTOR and raptor in skeletal muscle results in severe muscle weakness, increased fibre denervation, and slower muscle relaxation following tetanic stimulation in mice.
Why the study?
Skeletal muscle weakness is associated with altered mTOR signalling, but the functional role of mTOR in muscle contractility remained incompletely understood because rapamycin does not completely inhibit all mTOR signalling.
Does the inducible deletion of raptor and mTOR from adult skeletal muscle impair muscle contractility and relaxation in mice?
Does the inducible deletion of raptor and mTOR from adult skeletal muscle impair muscle contractility and relaxation in mice?
The combined loss of mTOR and raptor in skeletal muscle leads to severe contractile abnormalities and impaired calcium reuptake, demonstrating the critical role of mTOR signaling in muscle relaxation and function.
Muscle mTOR/raptor loss impairs function in mice; leaves open relevance to human myopathies or mTOR-targeted therapies.
Skeletal muscle weakness has been associated with different pathological conditions, including sarcopenia and muscular dystrophy, and is accompanied by altered mammalian target of 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 for 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 Serca1 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, are linked to sarcomere organization. These results suggest a key role for mTOR signalling in maintaining proper fibre relaxation in skeletal muscle. KEY POINTS: Skeletal muscle wasting and weakness have been associated with different pathological conditions, including sarcopenia and muscular dystrophy, and are accompanied by altered mammalian target of rapamycin (mTOR) signalling. Mammalian target of rapamycin plays a crucial role in the maintenance of muscle mass and functionality. We found that the loss of both mTOR and raptor results in contractile abnormalities, with severe muscle weakness and delayed relaxation following tetanic stimulation. These results are associated with alterations in the expression of genes involved in sarcomere organization and calcium handling and with an impairment in calcium reuptake after contraction. Taken together, these results provide a mechanistic insight into the role of mTOR in muscle contractility.
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Baraldo et al. (2022) studied Skeletal muscle weakness. Double knockout for mTOR and raptor vs. Deletion of raptor or mTOR alone was evaluated on Muscle contractility and relaxation. Double knockout of mTOR and raptor in skeletal muscle results in severe muscle weakness, increased fibre denervation, and slower muscle relaxation following tetanic stimulation in mice.
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