Mitochondrial-targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancer
Objective: Muscle loss with cancer causes weakness, worsens quality of life, and predicts reduced overall survival rates. Recently, muscle weakness was identified during early-stage cancer before atrophy develops. This discovery indicates that mechanisms independent of muscle loss must contribute to...
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| Language: | English |
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Elsevier
2025-09-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877825001188 |
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| author | Luca J. Delfinis Shahrzad Khajehzadehshoushtar Luke D. Flewwelling Nathaniel J. Andrews Madison C. Garibotti Shivam Gandhi Aditya N. Brahmbhatt Brooke A. Morris Bianca Garlisi Sylvia Lauks Caroline Aitken Leslie Ogilvie Stavroula Tsitkanou Jeremy A. Simpson Nicholas P. Greene Arthur J. Cheng Jim Petrik Christopher G.R. Perry |
| author_facet | Luca J. Delfinis Shahrzad Khajehzadehshoushtar Luke D. Flewwelling Nathaniel J. Andrews Madison C. Garibotti Shivam Gandhi Aditya N. Brahmbhatt Brooke A. Morris Bianca Garlisi Sylvia Lauks Caroline Aitken Leslie Ogilvie Stavroula Tsitkanou Jeremy A. Simpson Nicholas P. Greene Arthur J. Cheng Jim Petrik Christopher G.R. Perry |
| author_sort | Luca J. Delfinis |
| collection | DOAJ |
| description | Objective: Muscle loss with cancer causes weakness, worsens quality of life, and predicts reduced overall survival rates. Recently, muscle weakness was identified during early-stage cancer before atrophy develops. This discovery indicates that mechanisms independent of muscle loss must contribute to progressive weakness. While mitochondrial stress responses are associated with early-stage ‘pre-cachexia’ weakness, a causal relationship has not been established. Methods and Results: Here, using a mouse model of metastatic ovarian cancer cachexia, we identified that the well-established mitochondrial-targeted plastoquinone SkQ1 partially prevents muscle weakness occurring before the development of atrophy in the diaphragm. Furthermore, SkQ1 improved force production during atrophy without preventing atrophy itself in the tibialis anterior and diaphragm. These findings indicate that atrophy-independent mechanisms of muscle weakness occur in different muscle types throughout ovarian cancer. Ovarian cancer reduced flexor digitorum brevis (FDB) whole muscle force production and myoplasmic free calcium ([Ca2+]i) during contraction in intact single muscle fibers, both of which were prevented by SkQ1. Remarkably, changes in mitochondrial reactive oxygen species and pyruvate metabolism were heterogeneous across time and between muscle types which highlights a considerable complexity in the relationships between mitochondria and muscle remodeling throughout ovarian cancer. Conclusions: These discoveries identify that muscle weakness can occur independent of atrophy throughout ovarian cancer in a manner that is linked to improved calcium handling. The findings also demonstrate that mitochondrial-targeted therapies exert a robust effect in preserving muscle force early during ovarian cancer during the pre-atrophy period and in late stages once cachexia has become severe. |
| format | Article |
| id | doaj-art-74d1896b7d494d4a9adef6f97380d42e |
| institution | DOAJ |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-74d1896b7d494d4a9adef6f97380d42e2025-08-20T02:58:27ZengElsevierMolecular Metabolism2212-87782025-09-019910221110.1016/j.molmet.2025.102211Mitochondrial-targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancerLuca J. Delfinis0Shahrzad Khajehzadehshoushtar1Luke D. Flewwelling2Nathaniel J. Andrews3Madison C. Garibotti4Shivam Gandhi5Aditya N. Brahmbhatt6Brooke A. Morris7Bianca Garlisi8Sylvia Lauks9Caroline Aitken10Leslie Ogilvie11Stavroula Tsitkanou12Jeremy A. Simpson13Nicholas P. Greene14Arthur J. Cheng15Jim Petrik16Christopher G.R. Perry17School of Kinesiology & Health Science, Muscle Health Research Centre, York University, Toronto, ON, M3J 1P3, CanadaSchool of Kinesiology & Health Science, Muscle Health Research Centre, York University, Toronto, ON, M3J 1P3, CanadaSchool of Kinesiology & Health Science, Muscle Health Research Centre, York University, Toronto, ON, M3J 1P3, CanadaSchool of Kinesiology & Health Science, Muscle Health Research Centre, York University, Toronto, ON, M3J 1P3, CanadaSchool of Kinesiology & Health Science, Muscle Health Research Centre, York University, Toronto, ON, M3J 1P3, CanadaSchool of Kinesiology & Health Science, Muscle Health Research Centre, York University, Toronto, ON, M3J 1P3, CanadaSchool of Kinesiology & Health Science, Muscle Health Research Centre, York University, Toronto, ON, M3J 1P3, CanadaSchool of Kinesiology & Health Science, Muscle Health Research Centre, York University, Toronto, ON, M3J 1P3, CanadaDepartment of Biomedical Sciences, University of Guelph, Guelph, ON, N1G 2W1, CanadaDepartment of Biomedical Sciences, University of Guelph, Guelph, ON, N1G 2W1, CanadaDepartment of Biomedical Sciences, University of Guelph, Guelph, ON, N1G 2W1, CanadaDepartment of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, N1G 2W1, CanadaCachexia Research Laboratory, Department of Health, Human Performance and Recreation, College of Education and Health Professions, University of Arkansas, Fayetteville, AR, 71656, USADepartment of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, N1G 2W1, CanadaCachexia Research Laboratory, Department of Health, Human Performance and Recreation, College of Education and Health Professions, University of Arkansas, Fayetteville, AR, 71656, USASchool of Kinesiology & Health Science, Muscle Health Research Centre, York University, Toronto, ON, M3J 1P3, CanadaDepartment of Biomedical Sciences, University of Guelph, Guelph, ON, N1G 2W1, CanadaSchool of Kinesiology & Health Science, Muscle Health Research Centre, York University, Toronto, ON, M3J 1P3, Canada; Corresponding author. School of Kinesiology and Health Science, Muscle Health Research Centre, 341 Norman Bethune College, York University, 4700 Keele Street, Toronto, Ontario, M3J 1P3, Canada.Objective: Muscle loss with cancer causes weakness, worsens quality of life, and predicts reduced overall survival rates. Recently, muscle weakness was identified during early-stage cancer before atrophy develops. This discovery indicates that mechanisms independent of muscle loss must contribute to progressive weakness. While mitochondrial stress responses are associated with early-stage ‘pre-cachexia’ weakness, a causal relationship has not been established. Methods and Results: Here, using a mouse model of metastatic ovarian cancer cachexia, we identified that the well-established mitochondrial-targeted plastoquinone SkQ1 partially prevents muscle weakness occurring before the development of atrophy in the diaphragm. Furthermore, SkQ1 improved force production during atrophy without preventing atrophy itself in the tibialis anterior and diaphragm. These findings indicate that atrophy-independent mechanisms of muscle weakness occur in different muscle types throughout ovarian cancer. Ovarian cancer reduced flexor digitorum brevis (FDB) whole muscle force production and myoplasmic free calcium ([Ca2+]i) during contraction in intact single muscle fibers, both of which were prevented by SkQ1. Remarkably, changes in mitochondrial reactive oxygen species and pyruvate metabolism were heterogeneous across time and between muscle types which highlights a considerable complexity in the relationships between mitochondria and muscle remodeling throughout ovarian cancer. Conclusions: These discoveries identify that muscle weakness can occur independent of atrophy throughout ovarian cancer in a manner that is linked to improved calcium handling. The findings also demonstrate that mitochondrial-targeted therapies exert a robust effect in preserving muscle force early during ovarian cancer during the pre-atrophy period and in late stages once cachexia has become severe.http://www.sciencedirect.com/science/article/pii/S2212877825001188Ovarian cancer cachexiaMitochondriaSkeletal muscle |
| spellingShingle | Luca J. Delfinis Shahrzad Khajehzadehshoushtar Luke D. Flewwelling Nathaniel J. Andrews Madison C. Garibotti Shivam Gandhi Aditya N. Brahmbhatt Brooke A. Morris Bianca Garlisi Sylvia Lauks Caroline Aitken Leslie Ogilvie Stavroula Tsitkanou Jeremy A. Simpson Nicholas P. Greene Arthur J. Cheng Jim Petrik Christopher G.R. Perry Mitochondrial-targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancer Molecular Metabolism Ovarian cancer cachexia Mitochondria Skeletal muscle |
| title | Mitochondrial-targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancer |
| title_full | Mitochondrial-targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancer |
| title_fullStr | Mitochondrial-targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancer |
| title_full_unstemmed | Mitochondrial-targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancer |
| title_short | Mitochondrial-targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancer |
| title_sort | mitochondrial targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancer |
| topic | Ovarian cancer cachexia Mitochondria Skeletal muscle |
| url | http://www.sciencedirect.com/science/article/pii/S2212877825001188 |
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