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The role of mTORC1 in muscle proteostasis

Research Project
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01.07.2019
 - 30.06.2020

Skeletal muscle accounts for up to 50% of the entire body weight in humans. It is essential for locomotion and breathing and it affects whole-body metabolism. Preservation of muscle mass is thus critical to maintain body function and health. Current views indicate that muscle mass is controlled by the tight balance between protein synthesis and protein degradation, called proteostasis. Perturbation of this balance by extrinsic factors, as for example seen in cachexia (i.e., muscle loss as a secondary consequence of e.g. cancer, AIDS, or cardiac and kidney disease) or in sarcopenia (i.e., loss of muscle mass and function as a consequence of aging), is a main cause of loss of life quality and increased mortality. Thus, a better molecular understanding of muscle proteostasis is of fundamental importance to develop possible treatment strategies to counteract the above diseases. Proteostasis is thought to be controlled (1) by the mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1) by regulating protein synthesis (Laplante and Sabatini, 2012) and (2) by forkhead box O (FoxO) transcription factors by regulating expression of the proteins involved in protein degradation (Milan et al., 2015; Zhao et al., 2007). Thus, inhibition of mTORC1 and/or activation of FoxO would cause muscle loss (atrophy), whereas activation of mTORC1 and/or inhibition of FoxO would result in muscle gain (hypertrophy). Consistent with this notion, genetic inactivation of mTORC1 by muscle-specific depletion of the mTORC1-essential component raptor causes muscle atrophy (Bentzinger et al., 2008). However and in striking contrast to the expected outcome of muscle gain, sustained activation of mTORC1 in muscle by knockout of its upstream inhibitor Tsc1 (TSCmKO mice) also results in atrophy, severe myopathy and early death (Bentzinger et al., 2013; Castets et al., 2013). This phenotype is observed despite the marked increase in protein synthesis. Hence, the mechanisms involved in muscle atrophy in TSCmKO mice remains unresolved. Marco Kaiser investigated the mechanisms that may underlie this phenotype during his Ph.D. thesis. In particular, he investigated the role of the most important protein degradation pathway of cells, which is the ubiquitin-proteasome system (UPS). His work has shown that sustained activation of mTORC1 in muscles of TSCmKO mice indeed leads to a significant increase in the expression of all the proteasomal subunits and increased UPS activity. Marco also observed an increase in the activity of the proteasome in lysates of TSCmKO muscles using an in vitro assay. Interestingly, the same increase in proteasome activity was observed in "inducible-TSCmKO" (iTSCmKO) mice upon acute muscle-specific deletion of Tsc1 for 3 weeks. This increase in proteasome activity was, at least in part, reversed by short-term treatment of the TSCmKO mice with the mTORC1-inhibitor rapamycin. Marco also discovered that increased UPS activity was accompanied by a concomitant increase of the transcription factor "nuclear factor, erythroid-derived 2,-like 1" (Nfe2l1, also called Nrf1). Moreover, he found evidence that Nrf1 may regulate the UPS in TSCmKO mice. We now aim to establish that this increase in UPS activity is the mechanism that causes muscle atrophy in TSCmKO mice and to test the functional role of Nrf1 in the regulation of the UPS. To do this, we will perturb the function of the UPS by bortezomib (BTZ) and by knocking down Nrf1 by shRNA in skeletal muscle in vivo. We hope that these experiments will firmly establish that mTORC1 activation is the main driver of protein degradation in skeletal muscle and that Nrf1 is the main regulator of this pathway. These experiments are important to better understand the control of muscle mass and to eventually develop new therapeutic agents that could slow-down the massive muscle wasting observed in cachexia and sarcopenia.

Funding

The role of mTORC1 in muscle proteostasis

Foundations / Associations (GrantsTool), 07.2019-06.2020 (12)
PI : Rüegg, Markus A..

Members (2)

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Markus A. Rüegg

Principal Investigator
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Marco Kaiser

Project Member