Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching
Abstract Background Excess reactive oxygen species (ROS) and muscle weakness occur in parallel in multiple pathological conditions. However, the causative role of skeletal muscle mitochondrial ROS (mtROS) on neuromuscular junction (NMJ) morphology and function and muscle weakness has not been direct...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2019-04-01
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| Series: | Journal of Cachexia, Sarcopenia and Muscle |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jcsm.12375 |
| _version_ | 1797203256007458816 |
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| author | Bumsoo Ahn Rojina Ranjit Pavithra Premkumar Gavin Pharaoh Katarzyna M. Piekarz Satoshi Matsuzaki Dennis R. Claflin Kaitlyn Riddle Jennifer Judge Shylesh Bhaskaran Kavithalakshmi Satara Natarajan Erika Barboza Benjamin Wronowski Michael Kinter Kenneth M. Humphries Timothy M. Griffin Willard M. Freeman Arlan Richardson Susan V. Brooks Holly Van Remmen |
| author_facet | Bumsoo Ahn Rojina Ranjit Pavithra Premkumar Gavin Pharaoh Katarzyna M. Piekarz Satoshi Matsuzaki Dennis R. Claflin Kaitlyn Riddle Jennifer Judge Shylesh Bhaskaran Kavithalakshmi Satara Natarajan Erika Barboza Benjamin Wronowski Michael Kinter Kenneth M. Humphries Timothy M. Griffin Willard M. Freeman Arlan Richardson Susan V. Brooks Holly Van Remmen |
| author_sort | Bumsoo Ahn |
| collection | DOAJ |
| description | Abstract Background Excess reactive oxygen species (ROS) and muscle weakness occur in parallel in multiple pathological conditions. However, the causative role of skeletal muscle mitochondrial ROS (mtROS) on neuromuscular junction (NMJ) morphology and function and muscle weakness has not been directly investigated. Methods We generated mice lacking skeletal muscle‐specific manganese‐superoxide dismutase (mSod2KO) to increase mtROS using a cre‐Lox approach driven by human skeletal actin. We determined primary functional parameters of skeletal muscle mitochondrial function (respiration, ROS, and calcium retention capacity) using permeabilized muscle fibres and isolated muscle mitochondria. We assessed contractile properties of isolated skeletal muscle using in situ and in vitro preparations and whole lumbrical muscles to elucidate the mechanisms of contractile dysfunction. Results The mSod2KO mice, contrary to our prediction, exhibit a 10–15% increase in muscle mass associated with an ~50% increase in central nuclei and ~35% increase in branched fibres (P < 0.05). Despite the increase in muscle mass of gastrocnemius and quadriceps, in situ sciatic nerve‐stimulated isometric maximum‐specific force (N/cm2), force per cross‐sectional area, is impaired by ~60% and associated with increased NMJ fragmentation and size by ~40% (P < 0.05). Intrinsic alterations of components of the contractile machinery show elevated markers of oxidative stress, for example, lipid peroxidation is increased by ~100%, oxidized glutathione is elevated by ~50%, and oxidative modifications of myofibrillar proteins are increased by ~30% (P < 0.05). We also find an approximate 20% decrease in the intracellular calcium transient that is associated with specific force deficit. Excess superoxide generation from the mitochondrial complexes causes a deficiency of succinate dehydrogenase and reduced complex‐II‐mediated respiration and adenosine triphosphate generation rates leading to severe exercise intolerance (~10 min vs. ~2 h in wild type, P < 0.05). Conclusions Increased skeletal muscle mtROS is sufficient to elicit NMJ disruption and contractile abnormalities, but not muscle atrophy, suggesting new roles for mitochondrial oxidative stress in maintenance of muscle mass through increased fibre branching. |
| first_indexed | 2024-04-24T08:16:26Z |
| format | Article |
| id | doaj.art-bf068644f5f343948ea2be767d068283 |
| institution | Directory Open Access Journal |
| issn | 2190-5991 2190-6009 |
| language | English |
| last_indexed | 2024-04-24T08:16:26Z |
| publishDate | 2019-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj.art-bf068644f5f343948ea2be767d0682832024-04-17T03:56:35ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092019-04-0110241142810.1002/jcsm.12375Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branchingBumsoo Ahn0Rojina Ranjit1Pavithra Premkumar2Gavin Pharaoh3Katarzyna M. Piekarz4Satoshi Matsuzaki5Dennis R. Claflin6Kaitlyn Riddle7Jennifer Judge8Shylesh Bhaskaran9Kavithalakshmi Satara Natarajan10Erika Barboza11Benjamin Wronowski12Michael Kinter13Kenneth M. Humphries14Timothy M. Griffin15Willard M. Freeman16Arlan Richardson17Susan V. Brooks18Holly Van Remmen19Aging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City USAAging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City USAAging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City USAAging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City USAAging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City USAAging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City USADepartment of Surgery, Section of Plastic Surgery University of Michigan Ann Arbor USAAging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City USADepartment of Molecular and Integrative Physiology University of Michigan Ann Arbor USAAging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City USAAging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City USAAging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City USADepartment of Physiology University of Oklahoma Health Sciences Center Oklahoma City USAAging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City USAAging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City USAAging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City USADepartment of Physiology University of Oklahoma Health Sciences Center Oklahoma City USADepartment of Physiology University of Oklahoma Health Sciences Center Oklahoma City USADepartment of Molecular and Integrative Physiology University of Michigan Ann Arbor USAAging and Metabolism Research Program Oklahoma Medical Research Foundation Oklahoma City USAAbstract Background Excess reactive oxygen species (ROS) and muscle weakness occur in parallel in multiple pathological conditions. However, the causative role of skeletal muscle mitochondrial ROS (mtROS) on neuromuscular junction (NMJ) morphology and function and muscle weakness has not been directly investigated. Methods We generated mice lacking skeletal muscle‐specific manganese‐superoxide dismutase (mSod2KO) to increase mtROS using a cre‐Lox approach driven by human skeletal actin. We determined primary functional parameters of skeletal muscle mitochondrial function (respiration, ROS, and calcium retention capacity) using permeabilized muscle fibres and isolated muscle mitochondria. We assessed contractile properties of isolated skeletal muscle using in situ and in vitro preparations and whole lumbrical muscles to elucidate the mechanisms of contractile dysfunction. Results The mSod2KO mice, contrary to our prediction, exhibit a 10–15% increase in muscle mass associated with an ~50% increase in central nuclei and ~35% increase in branched fibres (P < 0.05). Despite the increase in muscle mass of gastrocnemius and quadriceps, in situ sciatic nerve‐stimulated isometric maximum‐specific force (N/cm2), force per cross‐sectional area, is impaired by ~60% and associated with increased NMJ fragmentation and size by ~40% (P < 0.05). Intrinsic alterations of components of the contractile machinery show elevated markers of oxidative stress, for example, lipid peroxidation is increased by ~100%, oxidized glutathione is elevated by ~50%, and oxidative modifications of myofibrillar proteins are increased by ~30% (P < 0.05). We also find an approximate 20% decrease in the intracellular calcium transient that is associated with specific force deficit. Excess superoxide generation from the mitochondrial complexes causes a deficiency of succinate dehydrogenase and reduced complex‐II‐mediated respiration and adenosine triphosphate generation rates leading to severe exercise intolerance (~10 min vs. ~2 h in wild type, P < 0.05). Conclusions Increased skeletal muscle mtROS is sufficient to elicit NMJ disruption and contractile abnormalities, but not muscle atrophy, suggesting new roles for mitochondrial oxidative stress in maintenance of muscle mass through increased fibre branching.https://doi.org/10.1002/jcsm.12375Skeletal muscleMitochondriaMnSODReactive oxygen speciesFibre branchingHyperplasia |
| spellingShingle | Bumsoo Ahn Rojina Ranjit Pavithra Premkumar Gavin Pharaoh Katarzyna M. Piekarz Satoshi Matsuzaki Dennis R. Claflin Kaitlyn Riddle Jennifer Judge Shylesh Bhaskaran Kavithalakshmi Satara Natarajan Erika Barboza Benjamin Wronowski Michael Kinter Kenneth M. Humphries Timothy M. Griffin Willard M. Freeman Arlan Richardson Susan V. Brooks Holly Van Remmen Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching Journal of Cachexia, Sarcopenia and Muscle Skeletal muscle Mitochondria MnSOD Reactive oxygen species Fibre branching Hyperplasia |
| title | Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching |
| title_full | Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching |
| title_fullStr | Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching |
| title_full_unstemmed | Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching |
| title_short | Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching |
| title_sort | mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching |
| topic | Skeletal muscle Mitochondria MnSOD Reactive oxygen species Fibre branching Hyperplasia |
| url | https://doi.org/10.1002/jcsm.12375 |
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