Image 1_Sirt1 coordinates the mitochondrial UPR and myocellular proteostasis to preserve muscle integrity during muscle atrophy in zebrafish.pdf

Introduction The decline of mitochondrial homeostasis and proteostasis, the two key cell quality control mechanisms, is the hallmark of aging and age-related diseases. One of the most notable examples is the age-related progressive loss of muscle mass, quality, and strength --a condition known as sarcopenia. In atrophic muscle, mitochondrial dysfunction and proteostasis impairment frequently occur together, indicating a potential association between the decline of mitochondrial homeostasis and proteostasis. However, the mechanism by which these two modes of cell quality control are coordinated remains poorly understood. Methods We employed dexamethasone-induced muscle atrophy models in both larval and adult zebrafish to investigate the role of cell stress responses in muscle maintenance. Mitochondrial stress was assessed by measuring the mitochondrial unfolded protein response (UPR mt ) activity using qRT-PCR and reporter analyses. Proteostasis impairment was evaluated by detecting insoluble polyubiquitinated protein aggregates via Western blotting. Muscle integrity was examined histologically in larval and adult tissues. We performed these assays in sirt1 loss of function conditions (genetic mutation and pharmacological inhibition). Furthermore, to elucidate the mechanism by which Sirt1 regulates proteostasis and muscle preservation, we inhibited the mitochondrial fatty acid oxidation (mFAO) using etomoxir. Results Inhibition of Sirt1 markedly exacerbated muscle deterioration and proteostasis impairment under dexamethasone-induced muscle atrophy in zebrafish. Mechanistically, Sirt1 is required for activation of the UPR mt , which in turn promotes expression of the mFAO gene cpt1b. Pharmacological inhibition of Cpt1 using etomoxir phenocopied the defects in muscle integrity and proteotoxic stress observed following Sirt1 inhibition. Importantly, enhancement of proteostasis via hormetic heat shock partially rescued the etomoxir-induced muscle defects. Discussion We have demonstrated that muscle atrophic stress ...