ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Molecular and Cellular Pathology
This article is part of the Research TopicMolecular Mechanisms and Cellular Processes in Aging and Age-Related DiseasesView all 3 articles
Sirt1 Coordinates the Mitochondrial UPR and Myocellular Proteostasis to Preserve Muscle Integrity During Muscle Atrophy in Zebrafish
Provisionally accepted
- National Tsing Hua University, Hsinchu City, Taiwan
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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 – or sarcopenia. In atrophic muscle mitochondrial dysfunction and proteostasis impairment frequently occur together, suggesting 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. In this study, we have shown that the muscle atrophic stress induced by dexamethasone treatment activates the mitochondrial unfolded protein response (UPRmt) in zebrafish. The UPRmt is part of the activity of a cell stress regulator, Sirt1, to promote mitochondrial function and preserve muscle integrity during muscle atrophy. Interestingly, suppressing the UPRmt 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 mitochondrial fatty acid oxidation exacerbates the dexamethasone-induced proteotoxicity. Collectively, our findings have uncovered a previously uncharacterized regulatory mechanism linking the UPRmt 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.
Keywords: Mitochondrial dysfunction, Mitochondrial homeostasis, muscle atrophy, myocellular proteostasis, proteostasis, SIRT1, UPRmt
Received: 05 Dec 2025; Accepted: 09 Feb 2026.
Copyright: © 2026 Lin, Chen, Chang, Hung, Lee and Hsin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yi-Fan Lin
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