Activation of Akt–mTORC1 signalling reverts cancer‐dependent muscle wasting

Abstract

Background Cancer-related muscle wasting occurs in most cancer patients. An important regulator of adult muscle mass and function is the Akt-mTORC1 pathway. While Akt-mTORC1 signalling is important for adult muscle homeostasis, it is also a major target of numerous cancer treatments. Which role Akt-mTORC1 signalling plays during cancer cachexia in muscle is currently not known. Here, we aimed to determine how activation or inactivation of the pathway affects skeletal muscle during cancer cachexia. Methods We used inducible, muscle-specific Raptor ko (mTORC1) mice to determine the effect of reduced mTOR signalling during cancer cachexia. On the contrary, in order to understand if skeletal muscles maintain their anabolic capacity and if activation of Akt-mTORC1 signalling can reverse cancer cachexia, we generated mice in which we can inducibly activate Akt specifically in skeletal muscles. Results We found that mTORC1 signalling is impaired during cancer cachexia, using the Lewis lung carcinoma and C26 colon cancer model, and is accompanied by a reduction in protein synthesis rates of 57% (P < 0.01). Further reduction of mTOR signalling, as seen in Raptor ko animals, leads to a 1.5-fold increase in autophagic flux (P > 0.001), but does not further increase muscle wasting. On the other hand, activation of Akt-mTORC1 signalling in already cachectic animals completely reverses the 15-20% loss in muscle mass and force (P < 0.001). Interestingly, Akt activation only in skeletal muscle completely normalizes the transcriptional deregulation observed in cachectic muscle, despite having no effect on tumour size or spleen mass. In addition to stimulating muscle growth, it is also sufficient to prevent the increase in protein degradation normally observed in muscles from tumour-bearing animals. Conclusions Here, we show that activation of Akt-mTORC1 signalling is sufficient to completely revert cancer-dependent muscle wasting. Intriguingly, these results show that skeletal muscle maintains its anabolic capacities also during cancer cachexia, possibly giving a rationale behind some of the beneficial effects observed in exercise in cancer patients.

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

“…In the present study, we wanted to examine the role of mTOR in adult skeletal muscle performance and contractility. Many diseases that show alterations in mTOR signalling also result in muscle wasting and weakness (Geremia et al., 2022; Laplante & Sabatini, 2012; Weichhart, 2018; Zhang et al., 2011). In addition, abnormalities of muscle contractile dynamics, together with changes in calcium‐related protein expression and activity, have been associated with different muscle pathologies (Esposito et al., 2016; Fajardo et al., 2015; Goonasekera et al., 2011; Marty & Fauré, 2016; Middlekauff, 2010).…”

Impact of Cancer Cachexia on Cardiac and Skeletal Muscle: Role of Exercise Training

“…The mTOR protein forms two complexes: mTOR Complex-1 (mTORC1), responsible for protein synthesis, and mTOR Complex-2 (mTORC2), involved in processes of cytoskeleton organization, cell survival, and metabolism [ 40 , 41 ]. In cancer-induced cachexia, resistance exercise stimulates the activation of mTORC1 and attenuates AMPK activity, which may induce protein synthesis [ 42 ], and mechanisms that activate the AKT/mTORC1 pathway can reverse the loss of strength and muscle mass in animal models [ 43 ].…”

Cancer cachexia: Pathophysiology and association with cancer-related pain

“…Protein synthesis is decreased primarily through inhibition of various steps in the mTOR signaling pathway, inhibiting protein translation initiation and elongation ( Figure 1 ). Indeed, mTORC1 signaling is blunted in cachectic mice ( 44 ), and ~60% decrease in protein synthesis has been measured in both cachectic rats ( 45 ) and mice ( 44 ). Protein degradation is increased via upregulation of two major pathways – the autophagy lysosomal system (ALS), and the ubiquitin-mediated proteolysis system (UPS) ( Figure 1 ).…”