Restoration of SERCA ATPase prevents oxidative stress-related muscle atrophy and weakness
Molecular targets to reduce muscle weakness and atrophy due to oxidative stress have been elusive. Here we show that activation of Sarcoplasmic Reticulum (SR) Ca2+ ATPase (SERCA) with CDN1163, a novel small molecule allosteric SERCA activator, ameliorates the muscle impairment in the CuZnSOD deficie...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-01-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231718307365 |
| _version_ | 1828377700371267584 |
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| author | Rizwan Qaisar Shylesh Bhaskaran Rojina Ranjit Kavithalakshmi Sataranatarajan Pavithra Premkumar Kendra Huseman Holly Van Remmen |
| author_facet | Rizwan Qaisar Shylesh Bhaskaran Rojina Ranjit Kavithalakshmi Sataranatarajan Pavithra Premkumar Kendra Huseman Holly Van Remmen |
| author_sort | Rizwan Qaisar |
| collection | DOAJ |
| description | Molecular targets to reduce muscle weakness and atrophy due to oxidative stress have been elusive. Here we show that activation of Sarcoplasmic Reticulum (SR) Ca2+ ATPase (SERCA) with CDN1163, a novel small molecule allosteric SERCA activator, ameliorates the muscle impairment in the CuZnSOD deficient (Sod1-/-) mouse model of oxidative stress. Sod1-/- mice are characterized by reduced SERCA activity, muscle weakness and atrophy, increased oxidative stress and mitochondrial dysfunction. Seven weeks of CDN1163 treatment completely restored SERCA activity and reversed the 23% reduction in gastrocnemius mass and 22% reduction in specific force in untreated Sod1-/- versus wild type mice. These changes were accompanied by restoration of autophagy protein markers to the levels found in wild-type mice. CDN1163 also reversed the increase in mitochondrial ROS generation and oxidative damage in muscle tissue from Sod1-/- mice. Taken together our findings suggest that the pharmacological restoration of SERCA is a promising therapeutic approach to counter oxidative stress-associated muscle impairment. Keywords: CDN1163, Skeletal muscle, CuZnSod1, SERCA, Oxidative stress |
| first_indexed | 2024-04-14T08:16:10Z |
| format | Article |
| id | doaj.art-1109ff0a1f05410a8f10d187f34502b4 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-14T08:16:10Z |
| publishDate | 2019-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-1109ff0a1f05410a8f10d187f34502b42022-12-22T02:04:24ZengElsevierRedox Biology2213-23172019-01-01206874Restoration of SERCA ATPase prevents oxidative stress-related muscle atrophy and weaknessRizwan Qaisar0Shylesh Bhaskaran1Rojina Ranjit2Kavithalakshmi Sataranatarajan3Pavithra Premkumar4Kendra Huseman5Holly Van Remmen6Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USAAging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USAAging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USAAging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USAAging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USAAging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USAAging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Oklahoma City VA Medical Center, Oklahoma City, OK 73104, USA; Corresponding author at: Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA.Molecular targets to reduce muscle weakness and atrophy due to oxidative stress have been elusive. Here we show that activation of Sarcoplasmic Reticulum (SR) Ca2+ ATPase (SERCA) with CDN1163, a novel small molecule allosteric SERCA activator, ameliorates the muscle impairment in the CuZnSOD deficient (Sod1-/-) mouse model of oxidative stress. Sod1-/- mice are characterized by reduced SERCA activity, muscle weakness and atrophy, increased oxidative stress and mitochondrial dysfunction. Seven weeks of CDN1163 treatment completely restored SERCA activity and reversed the 23% reduction in gastrocnemius mass and 22% reduction in specific force in untreated Sod1-/- versus wild type mice. These changes were accompanied by restoration of autophagy protein markers to the levels found in wild-type mice. CDN1163 also reversed the increase in mitochondrial ROS generation and oxidative damage in muscle tissue from Sod1-/- mice. Taken together our findings suggest that the pharmacological restoration of SERCA is a promising therapeutic approach to counter oxidative stress-associated muscle impairment. Keywords: CDN1163, Skeletal muscle, CuZnSod1, SERCA, Oxidative stresshttp://www.sciencedirect.com/science/article/pii/S2213231718307365 |
| spellingShingle | Rizwan Qaisar Shylesh Bhaskaran Rojina Ranjit Kavithalakshmi Sataranatarajan Pavithra Premkumar Kendra Huseman Holly Van Remmen Restoration of SERCA ATPase prevents oxidative stress-related muscle atrophy and weakness Redox Biology |
| title | Restoration of SERCA ATPase prevents oxidative stress-related muscle atrophy and weakness |
| title_full | Restoration of SERCA ATPase prevents oxidative stress-related muscle atrophy and weakness |
| title_fullStr | Restoration of SERCA ATPase prevents oxidative stress-related muscle atrophy and weakness |
| title_full_unstemmed | Restoration of SERCA ATPase prevents oxidative stress-related muscle atrophy and weakness |
| title_short | Restoration of SERCA ATPase prevents oxidative stress-related muscle atrophy and weakness |
| title_sort | restoration of serca atpase prevents oxidative stress related muscle atrophy and weakness |
| url | http://www.sciencedirect.com/science/article/pii/S2213231718307365 |
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