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Significance Tuberous sclerosis complex (TSC) is a genetic disease characterized by tumor formation in multiple organs. The identification of dysregulated cellular processes in TSC is necessary for the selection of possible therapeutic interventions. The current models place impaired mTORC1 signaling at the core of TSC pathogenesis. In this study, we identify an mTORC1-independent pathway that drives excess glycogen storage in TSC via impaired autophagic degradation of glycogen caused by defects in the autophagy-lysosome system. Importantly, we find that the combined use of mTORC1 and Akt pharmacological inhibitors restore glycogen homeostasis. Our findings uncouple mTORC1-dependent from mTORC1-independent processes that are dysregulated in TSC and pinpoint multiple pharmacologically actionable entry points that could be leveraged to develop a therapeutic treatment.

Abnormal glycogen storage in tuberous sclerosis complex caused by impairment of mTORC1-dependent and -independent signaling pathways