Overexpression of manganese superoxide dismutase mitigates ACL injury-induced muscle atrophy, weakness and oxidative damage

Christine M. Latham; Peyton J. Balawender; Nicholas T. Thomas; Alexander R. Keeble; Camille R. Brightwell; Ahmed Ismaeel; Yuan Wen; Jean L. Fry; Patrick G. Sullivan; Darren L. Johnson; Brian Noehren; Allison M. Owen; Christopher S. Fry

doi:10.1016/j.freeradbiomed.2023.12.037

Overexpression of manganese superoxide dismutase mitigates ACL injury-induced muscle atrophy, weakness and oxidative damage

Christine M. Latham, Peyton J. Balawender, Nicholas T. Thomas, Alexander R. Keeble, Camille R. Brightwell, Ahmed Ismaeel, Yuan Wen, Jean L. Fry, Patrick G. Sullivan, Darren L. Johnson, Brian Noehren, Allison M. Owen, Christopher S. Fry

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

Oxidative stress has been implicated in the etiology of skeletal muscle weakness following joint injury. We investigated longitudinal patient muscle samples following knee injury (anterior cruciate ligament tear). Following injury, transcriptomic analysis revealed downregulation of mitochondrial metabolism-related gene networks, which were supported by reduced mitochondrial respiratory flux rates. Additionally, enrichment of reactive oxygen species (ROS)-related pathways were upregulated in muscle following knee injury, and further investigation unveiled marked oxidative damage in a progressive manner following injury and surgical reconstruction. We then investigated whether antioxidant protection is effective in preventing muscle atrophy and weakness after knee injury in mice that overexpress Mn-superoxide dismutase (MnSOD^+/−). MnSOD^+/− mice showed attenuated oxidative damage, atrophy, and muscle weakness compared to wild type littermate controls following ACL transection surgery. Taken together, our results indicate that ROS-related damage is a causative mechanism of muscle dysfunction after knee injury, and that mitochondrial antioxidant protection may hold promise as a therapeutic target to prevent weakness and development of disability.

Original language	English
Pages (from-to)	191-198
Number of pages	8
Journal	Free Radical Biology and Medicine
Volume	212
DOIs	https://doi.org/10.1016/j.freeradbiomed.2023.12.037
State	Published - Feb 20 2024

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Inc.

Funding

Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health ( NIH ) under Award Numbers R01 AR072061 (CSF), R01 AR071398 (BN), and K99 AR081367 (YW). This project was also supported by grants P20GM103436 and UL1TR001998 from the NIH . The content is solely the authors’ responsibility and does not necessarily represent the views of the NIH. Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH) under Award Numbers R01 AR072061 (CSF), R01 AR071398 (BN), and K99 AR081367 (YW). This project was also supported by grants P20GM103436 and UL1TR001998 from the NIH. The content is solely the authors’ responsibility and does not necessarily represent the views of the NIH.The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christopher Fry reports financial support was provided by University of Kentucky. Christopher Fry reports a relationship with University of Kentucky that includes: funding grants.

Funders	Funder number
National Institutes of Health (NIH)	R01 AR071398, UL1TR001998, P20GM103436, R01 AR072061, K99 AR081367
National Institutes of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases
University of Kentucky

Keywords

Anterior cruciate ligament
Knee injury
Mitochondria
Quadriceps
Reactive oxygen species
Skeletal muscle

ASJC Scopus subject areas

Biochemistry
Physiology (medical)

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10.1016/j.freeradbiomed.2023.12.037

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Latham, C. M., Balawender, P. J., Thomas, N. T., Keeble, A. R., Brightwell, C. R., Ismaeel, A., Wen, Y., Fry, J. L., Sullivan, P. G., Johnson, D. L., Noehren, B., Owen, A. M., & Fry, C. S. (2024). Overexpression of manganese superoxide dismutase mitigates ACL injury-induced muscle atrophy, weakness and oxidative damage. Free Radical Biology and Medicine, 212, 191-198. https://doi.org/10.1016/j.freeradbiomed.2023.12.037

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title = "Overexpression of manganese superoxide dismutase mitigates ACL injury-induced muscle atrophy, weakness and oxidative damage",

abstract = "Oxidative stress has been implicated in the etiology of skeletal muscle weakness following joint injury. We investigated longitudinal patient muscle samples following knee injury (anterior cruciate ligament tear). Following injury, transcriptomic analysis revealed downregulation of mitochondrial metabolism-related gene networks, which were supported by reduced mitochondrial respiratory flux rates. Additionally, enrichment of reactive oxygen species (ROS)-related pathways were upregulated in muscle following knee injury, and further investigation unveiled marked oxidative damage in a progressive manner following injury and surgical reconstruction. We then investigated whether antioxidant protection is effective in preventing muscle atrophy and weakness after knee injury in mice that overexpress Mn-superoxide dismutase (MnSOD+/−). MnSOD+/− mice showed attenuated oxidative damage, atrophy, and muscle weakness compared to wild type littermate controls following ACL transection surgery. Taken together, our results indicate that ROS-related damage is a causative mechanism of muscle dysfunction after knee injury, and that mitochondrial antioxidant protection may hold promise as a therapeutic target to prevent weakness and development of disability.",

keywords = "Anterior cruciate ligament, Knee injury, Mitochondria, Quadriceps, Reactive oxygen species, Skeletal muscle",

author = "Latham, \{Christine M.\} and Balawender, \{Peyton J.\} and Thomas, \{Nicholas T.\} and Keeble, \{Alexander R.\} and Brightwell, \{Camille R.\} and Ahmed Ismaeel and Yuan Wen and Fry, \{Jean L.\} and Sullivan, \{Patrick G.\} and Johnson, \{Darren L.\} and Brian Noehren and Owen, \{Allison M.\} and Fry, \{Christopher S.\}",

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doi = "10.1016/j.freeradbiomed.2023.12.037",

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Latham, CM, Balawender, PJ, Thomas, NT, Keeble, AR, Brightwell, CR, Ismaeel, A, Wen, Y , Fry, JL , Sullivan, PG , Johnson, DL , Noehren, B , Owen, AM & Fry, CS 2024, 'Overexpression of manganese superoxide dismutase mitigates ACL injury-induced muscle atrophy, weakness and oxidative damage', Free Radical Biology and Medicine, vol. 212, pp. 191-198. https://doi.org/10.1016/j.freeradbiomed.2023.12.037

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T1 - Overexpression of manganese superoxide dismutase mitigates ACL injury-induced muscle atrophy, weakness and oxidative damage

AU - Latham, Christine M.

AU - Balawender, Peyton J.

AU - Thomas, Nicholas T.

AU - Keeble, Alexander R.

AU - Brightwell, Camille R.

AU - Ismaeel, Ahmed

AU - Wen, Yuan

AU - Fry, Jean L.

AU - Sullivan, Patrick G.

AU - Johnson, Darren L.

AU - Noehren, Brian

AU - Owen, Allison M.

AU - Fry, Christopher S.

PY - 2024/2/20

Y1 - 2024/2/20

N2 - Oxidative stress has been implicated in the etiology of skeletal muscle weakness following joint injury. We investigated longitudinal patient muscle samples following knee injury (anterior cruciate ligament tear). Following injury, transcriptomic analysis revealed downregulation of mitochondrial metabolism-related gene networks, which were supported by reduced mitochondrial respiratory flux rates. Additionally, enrichment of reactive oxygen species (ROS)-related pathways were upregulated in muscle following knee injury, and further investigation unveiled marked oxidative damage in a progressive manner following injury and surgical reconstruction. We then investigated whether antioxidant protection is effective in preventing muscle atrophy and weakness after knee injury in mice that overexpress Mn-superoxide dismutase (MnSOD+/−). MnSOD+/− mice showed attenuated oxidative damage, atrophy, and muscle weakness compared to wild type littermate controls following ACL transection surgery. Taken together, our results indicate that ROS-related damage is a causative mechanism of muscle dysfunction after knee injury, and that mitochondrial antioxidant protection may hold promise as a therapeutic target to prevent weakness and development of disability.

AB - Oxidative stress has been implicated in the etiology of skeletal muscle weakness following joint injury. We investigated longitudinal patient muscle samples following knee injury (anterior cruciate ligament tear). Following injury, transcriptomic analysis revealed downregulation of mitochondrial metabolism-related gene networks, which were supported by reduced mitochondrial respiratory flux rates. Additionally, enrichment of reactive oxygen species (ROS)-related pathways were upregulated in muscle following knee injury, and further investigation unveiled marked oxidative damage in a progressive manner following injury and surgical reconstruction. We then investigated whether antioxidant protection is effective in preventing muscle atrophy and weakness after knee injury in mice that overexpress Mn-superoxide dismutase (MnSOD+/−). MnSOD+/− mice showed attenuated oxidative damage, atrophy, and muscle weakness compared to wild type littermate controls following ACL transection surgery. Taken together, our results indicate that ROS-related damage is a causative mechanism of muscle dysfunction after knee injury, and that mitochondrial antioxidant protection may hold promise as a therapeutic target to prevent weakness and development of disability.

KW - Anterior cruciate ligament

KW - Knee injury

KW - Mitochondria

KW - Quadriceps

KW - Reactive oxygen species

KW - Skeletal muscle

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Overexpression of manganese superoxide dismutase mitigates ACL injury-induced muscle atrophy, weakness and oxidative damage

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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