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Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis

ABSTRACT: Muscle size is controlled by the PI3K-PKB/Akt-mTORC1-FoxO pathway, which integrates signals from growth factors, energy and amino acids to activate protein synthesis and inhibit protein breakdown. While mTORC1 activity is necessary for PKB/Akt-induced muscle hypertrophy, its constant activation alone induces muscle atrophy. Here we show that this paradox is based on mTORC1 activity promoting protein breakdown through the ubiquitin-proteasome system (UPS) by simultaneously inducing ubiquitin E3 ligase expression via feedback inhibition of PKB/Akt and proteasome biogenesis via Nuclear Factor Erythroid 2-Like 1 (Nrf1). Muscle growth was restored by reactivation of PKB/Akt, but not by Nrf1 knockdown, implicating ubiquitination as the limiting step. However, both PKB/Akt activation and proteasome depletion by Nrf1 knockdown led to an immediate disruption of proteome integrity with rapid accumulation of damaged material. These data highlight the physiological importance of mTORC1-mediated PKB/Akt inhibition and point to juxtaposed roles of the UPS in atrophy and proteome integrity.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Alexander Schmidt

LAB HEAD: Alexander Schmidt

PROVIDER: PXD034117 | Pride | 2022-10-28

REPOSITORIES: Pride

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Project description:Maintaining skeletal muscle mass is of high importance as muscle atrophy like during sarcopenia or cachexia lead to a decrease in independence and a higher risk of morbidity and mortality. A leading compound in the treatment against ageing and cancer is rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1). Whether the treatment with mTORC1 inhibitors would work at a cost of losing muscle mass is unclear, as most studies have been focusing on the role of mTORC1 specifically during hypertrophy. In order to answer this question we developed an inducible muscle specific knockout mouse model in which raptor can be ablated during adulthood to eliminate mTORC1 activity. We analysed the muscles after different time points and found that after 3 months the mice showed a fiber shift towards slower fiber types, a loss in oxidative capacity but only very few myopathic features. After 5 months the myopathic features became more apparent, however it did not largely affect the ex vivo muscle force. Surprisingly despite the myopathy we did not see a significant loss of muscle mass even after 5 months, that we hypothesised based on mTORC1s central role in protein synthesis. We assume that the myopathy after long-term mTORC1 inactivation is mostly a result of secondary effects through the loss of mitochondria, alterations in metabolism and in cytoskeletal components. In conclusion, during skeletal muscle maintenance mTORC1 is more essential for metabolic processes than it is for maintaining basal muscle mass.Maintaining skeletal muscle mass is of high importance as muscle atrophy like during sarcopenia or cachexia lead to a decrease in independence and a higher risk of morbidity and mortality. A leading compound in the treatment against ageing and cancer is rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1). Whether the treatment with mTORC1 inhibitors would work at a cost of losing muscle mass is unclear, as most studies have been focusing on the role of mTORC1 specifically during hypertrophy. In order to answer this question we developed an inducible muscle specific knockout mouse model in which raptor can be ablated during adulthood to eliminate mTORC1 activity. We analysed the muscles after different time points and found that after 3 months the mice showed a fiber shift towards slower fiber types, a loss in oxidative capacity but only very few myopathic features. After 5 months the myopathic features became more apparent, however it did not largely affect the ex vivo muscle force. Surprisingly despite the myopathy we did not see a significant loss of muscle mass even after 5 months, that we hypothesised based on mTORC1s central role in protein synthesis. We assume that the myopathy after long-term mTORC1 inactivation is mostly a result of secondary effects through the loss of mitochondria, alterations in metabolism and in cytoskeletal components. In conclusion, during skeletal muscle maintenance mTORC1 is more essential for metabolic processes than it is for maintaining basal muscle mass.

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	C16-02045.raw	Raw
	C16-02046.raw	Raw
	C16-02047.raw	Raw
	C16-02048.raw	Raw
	C16-02049.raw	Raw

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Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis

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