Elevated phospholipid hydroperoxide glutathione peroxidase (GPX4) expression modulates oxylipin formation and inhibits age-related skeletal muscle atrophy and weakness
Our previous studies support a key role for mitochondrial lipid hydroperoxides as important contributors to denervation-related muscle atrophy, including muscle atrophy associated with aging. Phospholipid hydroperoxide glutathione peroxidase 4 (GPX4) is an essential antioxidant enzyme that directly...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231723001623 |
| _version_ | 1797784895288770560 |
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| author | Agnieszka Czyżowska Jacob Brown Hongyang Xu Kavitha Sataranatarajan Michael Kinter Victoria J. Tyrell Valerie B. O'Donnell Holly Van Remmen |
| author_facet | Agnieszka Czyżowska Jacob Brown Hongyang Xu Kavitha Sataranatarajan Michael Kinter Victoria J. Tyrell Valerie B. O'Donnell Holly Van Remmen |
| author_sort | Agnieszka Czyżowska |
| collection | DOAJ |
| description | Our previous studies support a key role for mitochondrial lipid hydroperoxides as important contributors to denervation-related muscle atrophy, including muscle atrophy associated with aging. Phospholipid hydroperoxide glutathione peroxidase 4 (GPX4) is an essential antioxidant enzyme that directly reduces phospholipid hydroperoxides and we previously reported that denervation-induced muscle atrophy is blunted in a mouse model of GPX4 overexpression. Therefore, the goal of the present study was to determine whether GPX4 overexpression can reduce the age-related increase in mitochondrial hydroperoxides in skeletal muscle and ameliorate age-related muscle atrophy and weakness (sarcopenia). Male C57Bl6 WT and GPX4 transgenic (GPX4Tg) mice were studied at 3 to 5 and 23–29 months of age. Basal mitochondrial peroxide generation was reduced by 34% in muscle fibers from aged GPX4Tg compared to old WT mice. GPX4 overexpression also reduced levels of lipid peroxidation products: 4-HNE, MDA, and LOOHs by 38%, 32%, and 84% respectively in aged GPX4Tg mice compared to aged WT mice. Muscle mass was preserved in old GPX4 Tg mice by 11% and specific force generation was 21% higher in old GPX4Tg versus age matched male WT mice. Oxylipins from lipoxygenases (LOX) and cyclooxygenase (COX), as well as less abundant non-enzymatically generated isomers, were significantly reduced by GPX4 overexpression. The expression of cPLA2, 12/15-LOX and COX-2 were 1.9-, 10.5- and 3.4-fold greater in old versus young WT muscle respectively, and 12/15-LOX and COX-2 levels were reduced by 37% and 35%, respectively in muscle from old GPX4Tg mice. Our study suggests that lipid peroxidation products may play an important role in the development of sarcopenia, and their detoxification might be an effective intervention in preventing muscle atrophy. |
| first_indexed | 2024-03-13T00:46:24Z |
| format | Article |
| id | doaj.art-5ff81d932c6e4952806e59208fb00ab3 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-03-13T00:46:24Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-5ff81d932c6e4952806e59208fb00ab32023-07-09T04:21:48ZengElsevierRedox Biology2213-23172023-08-0164102761Elevated phospholipid hydroperoxide glutathione peroxidase (GPX4) expression modulates oxylipin formation and inhibits age-related skeletal muscle atrophy and weaknessAgnieszka Czyżowska0Jacob Brown1Hongyang Xu2Kavitha Sataranatarajan3Michael Kinter4Victoria J. Tyrell5Valerie B. O'Donnell6Holly Van Remmen7Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, United StatesAging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, United States; Oklahoma City VA Medical Center, Oklahoma City, OK, 73104, United StatesAging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, United StatesAging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, United StatesAging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, United StatesSystems Immunity Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, CF14 4XN, UKSystems Immunity Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, CF14 4XN, UKAging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, United States; Oklahoma City VA Medical Center, Oklahoma City, OK, 73104, United States; Corresponding author. Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK, 73104, United States.Our previous studies support a key role for mitochondrial lipid hydroperoxides as important contributors to denervation-related muscle atrophy, including muscle atrophy associated with aging. Phospholipid hydroperoxide glutathione peroxidase 4 (GPX4) is an essential antioxidant enzyme that directly reduces phospholipid hydroperoxides and we previously reported that denervation-induced muscle atrophy is blunted in a mouse model of GPX4 overexpression. Therefore, the goal of the present study was to determine whether GPX4 overexpression can reduce the age-related increase in mitochondrial hydroperoxides in skeletal muscle and ameliorate age-related muscle atrophy and weakness (sarcopenia). Male C57Bl6 WT and GPX4 transgenic (GPX4Tg) mice were studied at 3 to 5 and 23–29 months of age. Basal mitochondrial peroxide generation was reduced by 34% in muscle fibers from aged GPX4Tg compared to old WT mice. GPX4 overexpression also reduced levels of lipid peroxidation products: 4-HNE, MDA, and LOOHs by 38%, 32%, and 84% respectively in aged GPX4Tg mice compared to aged WT mice. Muscle mass was preserved in old GPX4 Tg mice by 11% and specific force generation was 21% higher in old GPX4Tg versus age matched male WT mice. Oxylipins from lipoxygenases (LOX) and cyclooxygenase (COX), as well as less abundant non-enzymatically generated isomers, were significantly reduced by GPX4 overexpression. The expression of cPLA2, 12/15-LOX and COX-2 were 1.9-, 10.5- and 3.4-fold greater in old versus young WT muscle respectively, and 12/15-LOX and COX-2 levels were reduced by 37% and 35%, respectively in muscle from old GPX4Tg mice. Our study suggests that lipid peroxidation products may play an important role in the development of sarcopenia, and their detoxification might be an effective intervention in preventing muscle atrophy.http://www.sciencedirect.com/science/article/pii/S2213231723001623 |
| spellingShingle | Agnieszka Czyżowska Jacob Brown Hongyang Xu Kavitha Sataranatarajan Michael Kinter Victoria J. Tyrell Valerie B. O'Donnell Holly Van Remmen Elevated phospholipid hydroperoxide glutathione peroxidase (GPX4) expression modulates oxylipin formation and inhibits age-related skeletal muscle atrophy and weakness Redox Biology |
| title | Elevated phospholipid hydroperoxide glutathione peroxidase (GPX4) expression modulates oxylipin formation and inhibits age-related skeletal muscle atrophy and weakness |
| title_full | Elevated phospholipid hydroperoxide glutathione peroxidase (GPX4) expression modulates oxylipin formation and inhibits age-related skeletal muscle atrophy and weakness |
| title_fullStr | Elevated phospholipid hydroperoxide glutathione peroxidase (GPX4) expression modulates oxylipin formation and inhibits age-related skeletal muscle atrophy and weakness |
| title_full_unstemmed | Elevated phospholipid hydroperoxide glutathione peroxidase (GPX4) expression modulates oxylipin formation and inhibits age-related skeletal muscle atrophy and weakness |
| title_short | Elevated phospholipid hydroperoxide glutathione peroxidase (GPX4) expression modulates oxylipin formation and inhibits age-related skeletal muscle atrophy and weakness |
| title_sort | elevated phospholipid hydroperoxide glutathione peroxidase gpx4 expression modulates oxylipin formation and inhibits age related skeletal muscle atrophy and weakness |
| url | http://www.sciencedirect.com/science/article/pii/S2213231723001623 |
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