Muscle-Restricted Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Knockout Partially Corrects Muscle Contractility After Spinal Cord Injury in Mice
Spinal cord injury (SCI) results in severe atrophy of skeletal muscle in paralyzed regions, and a decrease in the force generated by muscle per unit of cross-sectional area. Oxidation of skeletal muscle ryanodine 1 receptors (RyR1) reduces contractile force as a result of reduced binding of calstabi...
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Mary Ann Liebert
2024-11-01
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| Series: | Neurotrauma Reports |
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| Online Access: | https://www.liebertpub.com/doi/10.1089/neur.2023.0089 |
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| author | Carlos A. Toro Rita De Gasperi Abdurrahman Aslan Nicholas Johnson Mustafa M. Siddiq Christine Chow Wei Zhao Lauren Harlow Zachary Graham Xin-Hua Liu Junichi Sadoshima Ravi Iyengar Christopher P. Cardozo |
| author_facet | Carlos A. Toro Rita De Gasperi Abdurrahman Aslan Nicholas Johnson Mustafa M. Siddiq Christine Chow Wei Zhao Lauren Harlow Zachary Graham Xin-Hua Liu Junichi Sadoshima Ravi Iyengar Christopher P. Cardozo |
| author_sort | Carlos A. Toro |
| collection | DOAJ |
| description | Spinal cord injury (SCI) results in severe atrophy of skeletal muscle in paralyzed regions, and a decrease in the force generated by muscle per unit of cross-sectional area. Oxidation of skeletal muscle ryanodine 1 receptors (RyR1) reduces contractile force as a result of reduced binding of calstabin 1 to RyR1. One cause of RyR1 oxidation is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox4). We have previously shown that, in rats, RyR1 was oxidized and bound less to calstabin 1 at 56 days after SCI by spinal cord transection. Here, we used a conditional knockout (KO) mouse model of Nox4 in skeletal muscle to investigate the role of Nox4 in reduced muscle specific force after SCI. Peak twitch force of extensor digitorum longus muscles in control mice after SCI was reduced by 42% compared with sham-operated controls, but was increased by ∼43% in SCI Nox4 conditional KO mice compared with SCI controls, although it remained less than that for sham-operated controls. Unlike what was previously observed in rats after SCI, the expression of Nox4 was not increased in gastrocnemius muscle, and binding of calstabin 1 to RyR1 was not reduced in this muscle. The results suggest that Nox4 is directly involved in reduction in muscle twitch force after SCI, although further studies are needed to understand the mechanistic basis for this linkage. |
| format | Article |
| id | doaj-art-9b7a8b5dd1bb4decbb3b7052e1b2e22d |
| institution | OA Journals |
| issn | 2689-288X |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Mary Ann Liebert |
| record_format | Article |
| series | Neurotrauma Reports |
| spelling | doaj-art-9b7a8b5dd1bb4decbb3b7052e1b2e22d2025-08-20T02:31:48ZengMary Ann LiebertNeurotrauma Reports2689-288X2024-11-015130431610.1089/neur.2023.0089Muscle-Restricted Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Knockout Partially Corrects Muscle Contractility After Spinal Cord Injury in MiceCarlos A. Toro0Rita De Gasperi1Abdurrahman Aslan2Nicholas Johnson3Mustafa M. Siddiq4Christine Chow5Wei Zhao6Lauren Harlow7Zachary Graham8Xin-Hua Liu9Junichi Sadoshima10Ravi Iyengar11Christopher P. Cardozo12Spinal Cord Damage Research Center, James J Peters VA Medical Center, Departments of Icahn School of Medicine at Mount Sinai, Bronx, New York, USA.Spinal Cord Damage Research Center, James J Peters VA Medical Center, Departments of Icahn School of Medicine at Mount Sinai, Bronx, New York, USA.Spinal Cord Damage Research Center, James J Peters VA Medical Center, Departments of Icahn School of Medicine at Mount Sinai, Bronx, New York, USA.Spinal Cord Damage Research Center, James J Peters VA Medical Center, Departments of Icahn School of Medicine at Mount Sinai, Bronx, New York, USA.Pharmacological Science and Systems Biomedicine Institute, Icahn School of Medicine at Mount Sinai, Bronx, New York, USA.Spinal Cord Damage Research Center, James J Peters VA Medical Center, Departments of Icahn School of Medicine at Mount Sinai, Bronx, New York, USA.Spinal Cord Damage Research Center, James J Peters VA Medical Center, Departments of Icahn School of Medicine at Mount Sinai, Bronx, New York, USA.Spinal Cord Damage Research Center, James J Peters VA Medical Center, Departments of Icahn School of Medicine at Mount Sinai, Bronx, New York, USA.Healthspan, Resilience, and Performance, Florida Institute for Human and Machine Cognition, Pensacola, Florida, USA.Spinal Cord Damage Research Center, James J Peters VA Medical Center, Departments of Icahn School of Medicine at Mount Sinai, Bronx, New York, USA.Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, USA.Pharmacological Science and Systems Biomedicine Institute, Icahn School of Medicine at Mount Sinai, Bronx, New York, USA.Spinal Cord Damage Research Center, James J Peters VA Medical Center, Departments of Icahn School of Medicine at Mount Sinai, Bronx, New York, USA.Spinal cord injury (SCI) results in severe atrophy of skeletal muscle in paralyzed regions, and a decrease in the force generated by muscle per unit of cross-sectional area. Oxidation of skeletal muscle ryanodine 1 receptors (RyR1) reduces contractile force as a result of reduced binding of calstabin 1 to RyR1. One cause of RyR1 oxidation is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox4). We have previously shown that, in rats, RyR1 was oxidized and bound less to calstabin 1 at 56 days after SCI by spinal cord transection. Here, we used a conditional knockout (KO) mouse model of Nox4 in skeletal muscle to investigate the role of Nox4 in reduced muscle specific force after SCI. Peak twitch force of extensor digitorum longus muscles in control mice after SCI was reduced by 42% compared with sham-operated controls, but was increased by ∼43% in SCI Nox4 conditional KO mice compared with SCI controls, although it remained less than that for sham-operated controls. Unlike what was previously observed in rats after SCI, the expression of Nox4 was not increased in gastrocnemius muscle, and binding of calstabin 1 to RyR1 was not reduced in this muscle. The results suggest that Nox4 is directly involved in reduction in muscle twitch force after SCI, although further studies are needed to understand the mechanistic basis for this linkage.https://www.liebertpub.com/doi/10.1089/neur.2023.0089muscle cKOmuscle contractilityNox4SCI mouse modelstransection SCI |
| spellingShingle | Carlos A. Toro Rita De Gasperi Abdurrahman Aslan Nicholas Johnson Mustafa M. Siddiq Christine Chow Wei Zhao Lauren Harlow Zachary Graham Xin-Hua Liu Junichi Sadoshima Ravi Iyengar Christopher P. Cardozo Muscle-Restricted Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Knockout Partially Corrects Muscle Contractility After Spinal Cord Injury in Mice Neurotrauma Reports muscle cKO muscle contractility Nox4 SCI mouse models transection SCI |
| title | Muscle-Restricted Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Knockout Partially Corrects Muscle Contractility After Spinal Cord Injury in Mice |
| title_full | Muscle-Restricted Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Knockout Partially Corrects Muscle Contractility After Spinal Cord Injury in Mice |
| title_fullStr | Muscle-Restricted Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Knockout Partially Corrects Muscle Contractility After Spinal Cord Injury in Mice |
| title_full_unstemmed | Muscle-Restricted Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Knockout Partially Corrects Muscle Contractility After Spinal Cord Injury in Mice |
| title_short | Muscle-Restricted Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 Knockout Partially Corrects Muscle Contractility After Spinal Cord Injury in Mice |
| title_sort | muscle restricted nicotinamide adenine dinucleotide phosphate oxidase 4 knockout partially corrects muscle contractility after spinal cord injury in mice |
| topic | muscle cKO muscle contractility Nox4 SCI mouse models transection SCI |
| url | https://www.liebertpub.com/doi/10.1089/neur.2023.0089 |
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