Metformin extends the lifespan of iMSUD mice by rescuing physiologic dysfunction and modulating mechanisms of mTORC1 activation

Abstract Background- Dysregulation of branched chain amino acid (BCAA) catabolism caused by mutations in the metabolizing enzyme-branched chain alpha-keto acid dehydrogenase (BCKDH) leads to the fatal newborn disorder Maple Syrup Urine Disease (MSUD) and is linked to chronic diseases such as type 2 diabetes. Results- Here we show that a MSUD mouse model with severely reduced BCKDH activity exhibits glucose intolerance, altered mTOR signaling, decreased levels of TCA cycle intermediates, reduced distribution of Type I skeletal muscle fibers and activated AMP-activated protein kinase (AMPK) signaling, all of which can be ameliorated by long term treatment with metformin, which enhances the survival of these mice. Treatment with metformin was correlated with increased serum-levels of growth/differentiation factor GDF15 (GFD15) and adiponectin. We also found that branched chain keto acid regulates leucine-mediated activation of mTORC1 by preventing the dissociation of sestrin2-gator complex in vitro. Conclusions- In summary, our study suggests metformin could be an effective therapeutic candidate for MSUD patients and maps the crosstalk between key pathways that maintain metabolic homeostasis in MSUD.