Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia
<i>Objective</i>: Cachexia is a complex metabolic syndrome frequently occurring in cancer patients and exacerbated by chemotherapy. In skeletal muscle of cancer hosts, reduced oxidative capacity and low intracellular ATP resulting from abnormal mitochondrial function were described. <...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/4/850 |
| _version_ | 1797396209783013376 |
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| author | Riccardo Ballarò Patrizia Lopalco Valentina Audrito Marc Beltrà Fabrizio Pin Roberto Angelini Paola Costelli Angela Corcelli Andrea Bonetto Hazel H. Szeto Thomas M. O’Connell Fabio Penna |
| author_facet | Riccardo Ballarò Patrizia Lopalco Valentina Audrito Marc Beltrà Fabrizio Pin Roberto Angelini Paola Costelli Angela Corcelli Andrea Bonetto Hazel H. Szeto Thomas M. O’Connell Fabio Penna |
| author_sort | Riccardo Ballarò |
| collection | DOAJ |
| description | <i>Objective</i>: Cachexia is a complex metabolic syndrome frequently occurring in cancer patients and exacerbated by chemotherapy. In skeletal muscle of cancer hosts, reduced oxidative capacity and low intracellular ATP resulting from abnormal mitochondrial function were described. <i>Methods</i>: The present study aimed at evaluating the ability of the mitochondria-targeted compound SS-31 to counteract muscle wasting and altered metabolism in C26-bearing (C26) mice either receiving chemotherapy (OXFU: oxaliplatin plus 5-fluorouracil) or not. <i>Results</i>: Mitochondrial dysfunction in C26-bearing (C26) mice associated with alterations of cardiolipin fatty acid chains. Selectively targeting cardiolipin with SS-31 partially counteracted body wasting and prevented the reduction of glycolytic myofiber area. SS-31 prompted muscle mitochondrial succinate dehydrogenase (SDH) activity and rescued intracellular ATP levels, although it was unable to counteract mitochondrial protein loss. Progressively increased dosing of SS-31 to C26 OXFU mice showed transient (21 days) beneficial effects on body and muscle weight loss before the onset of a refractory end-stage condition (28 days). At day 21, SS-31 prevented mitochondrial loss and abnormal autophagy/mitophagy. Skeletal muscle, liver and plasma metabolomes were analyzed, showing marked energy and protein metabolism alterations in tumor hosts. SS-31 partially modulated skeletal muscle and liver metabolome, likely reflecting an improved systemic energy homeostasis. <i>Conclusions</i>: The results suggest that targeting mitochondrial function may be as important as targeting protein anabolism/catabolism for the prevention of cancer cachexia. With this in mind, prospective multi-modal therapies including SS-31 are warranted. |
| first_indexed | 2024-03-09T00:47:03Z |
| format | Article |
| id | doaj.art-d756f105502d425b98959b0695105262 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T00:47:03Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d756f105502d425b98959b06951052622023-12-11T17:27:48ZengMDPI AGCancers2072-66942021-02-0113485010.3390/cancers13040850Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced CachexiaRiccardo Ballarò0Patrizia Lopalco1Valentina Audrito2Marc Beltrà3Fabrizio Pin4Roberto Angelini5Paola Costelli6Angela Corcelli7Andrea Bonetto8Hazel H. Szeto9Thomas M. O’Connell10Fabio Penna11Department of Clinical and Biological Sciences, University of Torino, 10125 Torino, ItalyDipartimento di Scienze Mediche di Base, Neuroscienze e Organi di Senso, University of Bari Aldo Moro, 70121 Bari, ItalyMolecular Biotechnology Center, University of Torino, 10125 Torino, ItalyDepartment of Clinical and Biological Sciences, University of Torino, 10125 Torino, ItalyDepartment of Anatomy, Cell Biology and Physiology, Indiana University, Indianapolis, IN 46202, USASwansea University Medical School, Swansea University, Swansea SA2 8PP, UKDepartment of Clinical and Biological Sciences, University of Torino, 10125 Torino, ItalyDipartimento di Scienze Mediche di Base, Neuroscienze e Organi di Senso, University of Bari Aldo Moro, 70121 Bari, ItalyDepartment of Surgery, Indiana University, Indianapolis, IN 46202, USASocial Profit Network Research Lab, New York, NY 10016, USADepartment of Otolaryngology, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Clinical and Biological Sciences, University of Torino, 10125 Torino, Italy<i>Objective</i>: Cachexia is a complex metabolic syndrome frequently occurring in cancer patients and exacerbated by chemotherapy. In skeletal muscle of cancer hosts, reduced oxidative capacity and low intracellular ATP resulting from abnormal mitochondrial function were described. <i>Methods</i>: The present study aimed at evaluating the ability of the mitochondria-targeted compound SS-31 to counteract muscle wasting and altered metabolism in C26-bearing (C26) mice either receiving chemotherapy (OXFU: oxaliplatin plus 5-fluorouracil) or not. <i>Results</i>: Mitochondrial dysfunction in C26-bearing (C26) mice associated with alterations of cardiolipin fatty acid chains. Selectively targeting cardiolipin with SS-31 partially counteracted body wasting and prevented the reduction of glycolytic myofiber area. SS-31 prompted muscle mitochondrial succinate dehydrogenase (SDH) activity and rescued intracellular ATP levels, although it was unable to counteract mitochondrial protein loss. Progressively increased dosing of SS-31 to C26 OXFU mice showed transient (21 days) beneficial effects on body and muscle weight loss before the onset of a refractory end-stage condition (28 days). At day 21, SS-31 prevented mitochondrial loss and abnormal autophagy/mitophagy. Skeletal muscle, liver and plasma metabolomes were analyzed, showing marked energy and protein metabolism alterations in tumor hosts. SS-31 partially modulated skeletal muscle and liver metabolome, likely reflecting an improved systemic energy homeostasis. <i>Conclusions</i>: The results suggest that targeting mitochondrial function may be as important as targeting protein anabolism/catabolism for the prevention of cancer cachexia. With this in mind, prospective multi-modal therapies including SS-31 are warranted.https://www.mdpi.com/2072-6694/13/4/850cancer cachexiamuscle wastingmitochondriaSS-31metabolomicsliver |
| spellingShingle | Riccardo Ballarò Patrizia Lopalco Valentina Audrito Marc Beltrà Fabrizio Pin Roberto Angelini Paola Costelli Angela Corcelli Andrea Bonetto Hazel H. Szeto Thomas M. O’Connell Fabio Penna Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia Cancers cancer cachexia muscle wasting mitochondria SS-31 metabolomics liver |
| title | Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia |
| title_full | Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia |
| title_fullStr | Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia |
| title_full_unstemmed | Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia |
| title_short | Targeting Mitochondria by SS-31 Ameliorates the Whole Body Energy Status in Cancer- and Chemotherapy-Induced Cachexia |
| title_sort | targeting mitochondria by ss 31 ameliorates the whole body energy status in cancer and chemotherapy induced cachexia |
| topic | cancer cachexia muscle wasting mitochondria SS-31 metabolomics liver |
| url | https://www.mdpi.com/2072-6694/13/4/850 |
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