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 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.

One bout of endurance exercise does not change gene expression or proliferation in a C26 colon carcinoma in immunocompetent mice.

PURPOSE: Exercise typically reduces tumour growth, proliferation and improves outcomes. Many of these effects require exercise to change gene expression within a tumour, but whether exercise  actually affects gene expression within a tumour has not been investigated yet. The aim of this study was, therefore, to find out whether one bout of endurance exercise alters gene expression and proliferation in a C26 carcinoma in immunocompetent mice. METHODS: BALB/c were injected with C26 colon carcinoma cells. Once the tumours had formed, the mice either ran for 65 min with increasing intensity or rested before the tumour was dissected. The tumours were then analysed by RNA-Seq and stained for the proliferation marker KI67. RESULTS: One bout of running for 65 min did not systematically change gene expression in C26 carcinomas of BALB/c mice when compared to BALB/c mice that were rested. However, when analysed for sex, the expression of 17, mostly skeletal muscle-related genes was higher in the samples of the female mice taken post-exercise. Further histological analysis showed that this signal likely comes from the presence of muscle fibres from the panniculus carnosus muscle inside the tumours. Also, we found no differences in the positivity for the proliferation marker KI67 in the control and exercise C26 carcinomas. CONCLUSION: A bout of exercise did not systematically affect gene expression or proliferation in C26 carcinomas in immunocompetent BALB/c mice.