Key result
Administration of SS-31 to DOX-treated animals prevented DOX-induced proteolytic signaling through ALS and UPP in the heart, while in the diaphragm ALS was inhibited but UPP was unaffected.
Why the study?
The mechanisms by which amelioration of mitochondrial ROS emission preserves cardiorespiratory muscle function following doxorubicin treatment remain unknown.
Does the mitochondria-targeted peptide SS-31 prevent doxorubicin-induced pathological proteolytic signaling in cardiac and skeletal muscle?
Does the mitochondria-targeted peptide SS-31 prevent doxorubicin-induced pathological proteolytic signaling in cardiac and skeletal muscle?
Answers are grounded in this paper and cite their sources.
Doxorubicin-induced mitochondrial ROS production plays distinct, muscle-specific roles in regulating proteolytic signaling in the heart versus the diaphragm, which can be differentially modulated by the mitochondria-targeted peptide SS-31.
Doxorubicin (DOX) is a highly effective antineoplastic agent used in cancer treatment. Unfortunately, clinical use of DOX is limited due to the development of dose-dependent toxicity to cardiac and respiratory (i.e., diaphragm) muscles. After administration, DOX preferentially localizes to the inner mitochondrial membrane, where it promotes cellular toxicity via enhanced mitochondrial reactive oxygen species (ROS) production. Although recent evidence suggests that amelioration of mitochondrial ROS emission preserves cardiorespiratory muscle function following DOX treatment, the mechanisms responsible for this protection remain unknown. Therefore, we tested the hypothesis that DOX-induced mitochondrial ROS production is required to stimulate pathological signaling by the autophagy/lysosomal system (ALS), the ubiquitin-proteasome pathway (UPP), and the unfolded protein response (UPR). Cause and effect were determined by administration of the mitochondria-targeted peptide SS-31 to DOX-treated animals. Interestingly, while SS-31 abrogated aberrant ROS emission in cardiorespiratory muscles of DOX-treated animals, our results revealed muscle-specific regulation of effector pathways. In the heart, SS-31 prevented DOX-induced proteolytic signaling through the ALS and UPP. In contrast, ALS signaling was inhibited by SS-31 in the diaphragm, but the UPP was not affected. UPR signaling was activated in both muscles at eukaryotic translation initiation factor 2α (eIF2α) S51 in the heart and diaphragm of DOX-treated animals and was attenuated with SS-31 treatment in both tissues. However, downstream signaling of eIF2α (activating transcription factor 4 and CCAAT/enhancer-binding protein homologous protein) was diminished in the heart but upregulated in the diaphragm with DOX. Collectively, these results show that DOX-induced ROS production plays distinct roles in the regulation of cardiac and diaphragm muscle proteolysis.
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Montalvo et al. (2019) studied Doxorubicin-induced cardiorespiratory muscle toxicity. SS-31 vs. Doxorubicin alone was evaluated on Proteolytic signaling by the autophagy/lysosomal system (ALS), ubiquitin-proteasome pathway (UPP), and unfolded protein response (UPR). Administration of SS-31 to DOX-treated animals prevented DOX-induced proteolytic signaling through ALS and UPP in the heart, while in the diaphragm ALS was inhibited but UPP was unaffected.
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