Sirt1 coordinates the mitochondrial UPR and myocellular proteostasis to preserve muscle integrity during muscle atrophy in zebrafish

We have demonstrated that muscle atrophic stress induced by dexamethasone treatment activates the UPR^mt in zebrafish. The UPR^mt is part of the activity of a cell stress regulator, Sirt1, to promote mitochondrial function and preserve muscle integrity during muscle atrophy. Notably, suppressing the UPR^mt via Sirt1 inhibition leads to protein aggregation and the ultimate loss of muscle mass, indicating a link between mitochondrial function and proteostasis. We have further shown that mitochondrial metabolism plays a role in proteostasis regulation, as pharmacological inhibition of the mFAO exacerbates dexamethasone-induced proteotoxicity. Collectively, our findings have uncovered a previously uncharacterized regulatory mechanism linking UPR^mt signaling to myocellular proteostasis, and highlight the activity of Sirt1, which coordinates these two key cell quality control mechanisms, in muscle preservation during muscle atrophy.