Neuron‐specific expression of CuZnSOD prevents the loss of muscle mass and function that occurs in homozygous CuZnSOD‐knockout mice

Sakellariou, Giorgos K.; Davis, Carol; Shi, Yun; Ivannikov, Maxim V.; Zhang, Yiqiang; Vasilaki, Aphrodite; Macleod, Gregory T.; Richardson, Arlan; Remmen, Holly Van; Jackson, Malcolm J.; McArdle, Anne; Brooks, Susan V.

doi:10.1096/fj.13-240390

Cited by 77 publications

(111 citation statements)

References 36 publications

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“…The experimental work undertaken in this study revealed that sciatic nerve SOD1 content in SynTgSOD1 −/− was 20% of control WT mice. Partial rescue of SOD1 expression in motor neurons of the nerve rescue mice reversed all aspects of the accelerated neuromuscular ageing phenotype observed in the SOD1 −/− model including the multiple biochemical and physiological changes associated with the exacerbated ageing phenotype 29. Increased oxidative damage and compensatory up‐regulation of redox regulatory enzymes, stress responses and adaptive signalling pathways observed in muscle from SOD1 −/− mice30, 33 were not present in the neuron‐specific transgenic SynTgSOD1 −/− model.…”

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 89%

“…The impact of altered redox homeostasis in loss of neuromuscular integrity and function with ageing has been investigated in several murine models, which have undergone genetic modifications of redox signalling/homeostasis components 19, 23, 25, 29, 30, 31, 32, 33, 34, 240, 241, 242. Transgenic murine models have provided insight into the importance of RONS regulatory systems in lifespan and neuromuscular ageing, and it has been reported that SOD2 −/− ,243 GRX3 −/− ,244 GPX4 −/− ,245 TRX1 −/− ,246 TRX2 −/− ,247 TR1 −/− 248 and TR2 −/− 249 murine models are embryonically lethal.…”

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 99%

“…Right panels: merged images of presynaptic motor neurons and AChRs. Redrawn from Sakellariou et al 29. Original magnification: 60X (scale bar = 10 μm).…”

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 99%

“…To unravel whether the muscle decline and weakness shown in the SOD1 −/− model is initiated by defective redox signalling within motor neurons, a recent study generated a transgenic SOD1 −/− model in which human SOD1 was expressed under the control of the synapsin 1 promoter (SynTgSOD1 −/− ), termed ‘nerve rescue’ mice 29. The experimental work undertaken in this study revealed that sciatic nerve SOD1 content in SynTgSOD1 −/− was 20% of control WT mice.…”

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 99%

“…Increased oxidative damage and compensatory up‐regulation of redox regulatory enzymes, stress responses and adaptive signalling pathways observed in muscle from SOD1 −/− mice30, 33 were not present in the neuron‐specific transgenic SynTgSOD1 −/− model. Moreover, the accelerated degeneration in NMJ structure, including both presynaptic and postsynaptic NMJ features,23, 276 failure of neuromuscular transmission29, 278 and impaired in situ muscle‐force generation34, 277 that occur in the whole body SOD1 −/− model were completely rescued in the nerve rescue model 29…”

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 99%

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Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Sakellariou

Lightfoot

Earl

et al. 2017

J cachexia sarcopenia muscle

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Skeletal muscle is a major site of metabolic activity and is the most abundant tissue in the human body. Age‐related muscle atrophy (sarcopenia) and weakness, characterized by progressive loss of lean muscle mass and function, is a major contributor to morbidity and has a profound effect on the quality of life of older people. With a continuously growing older population (estimated 2 billion of people aged >60 by 2050), demand for medical and social care due to functional deficits, associated with neuromuscular ageing, will inevitably increase. Despite the importance of this ‘epidemic’ problem, the primary biochemical and molecular mechanisms underlying age‐related deficits in neuromuscular integrity and function have not been fully determined. Skeletal muscle generates reactive oxygen and nitrogen species (RONS) from a variety of subcellular sources, and age‐associated oxidative damage has been suggested to be a major factor contributing to the initiation and progression of muscle atrophy inherent with ageing. RONS can modulate a variety of intracellular signal transduction processes, and disruption of these events over time due to altered redox control has been proposed as an underlying mechanism of ageing. The role of oxidants in ageing has been extensively examined in different model organisms that have undergone genetic manipulations with inconsistent findings. Transgenic and knockout rodent studies have provided insight into the function of RONS regulatory systems in neuromuscular ageing. This review summarizes almost 30 years of research in the field of redox homeostasis and muscle ageing, providing a detailed discussion of the experimental approaches that have been undertaken in murine models to examine the role of redox regulation in age‐related muscle atrophy and weakness.

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Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 89%

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 99%

“…Right panels: merged images of presynaptic motor neurons and AChRs. Redrawn from Sakellariou et al 29. Original magnification: 60X (scale bar = 10 μm).…”

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 99%

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 99%

Section: Non‐enzymatic Key Antioxidants That Contribute To the Maintementioning

confidence: 99%

See 3 more Smart Citations

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Sakellariou

Lightfoot

Earl

et al. 2017

J cachexia sarcopenia muscle

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Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training

Bowen

Schuler

Adams

2015

Journal of Cachexia, Sarcopenia and Muscle

318

275

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Skeletal muscle provides a fundamental basis for human function, enabling locomotion and respiration. Transmission of external stimuli to intracellular effector proteins via signalling pathways is a highly regulated and controlled process that determines muscle mass by balancing protein synthesis and protein degradation. An impaired balance between protein synthesis and breakdown leads to the development of specific myopathies. Sarcopenia and cachexia represent two distinct muscle wasting diseases characterized by inflammation and oxidative stress, where specific regulating molecules associated with wasting are either activated (e.g. members of the ubiquitin-proteasome system and myostatin) or repressed (e.g. insulin-like growth factor 1 and PGC-1α). At present, no therapeutic interventions are established to successfully treat muscle wasting in sarcopenia and cachexia. Exercise training, however, represents an intervention that can attenuate or even reverse the process of muscle wasting, by exerting anti-inflammatory and anti-oxidative effects that are able to attenuate signalling pathways associated with protein degradation and activate molecules associated with protein synthesis. This review will therefore discuss the molecular mechanisms associated with the pathology of muscle wasting in both sarcopenia and cachexia, as well as highlighting the intracellular effects of exercise training in attenuating the debilitating loss of muscle mass in these specific conditions.

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Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching

Ahn

Ranjit

Premkumar

et al. 2019

J cachexia sarcopenia muscle

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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 (m Sod2 KO) 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 m Sod2 KO 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 /cm 2 ), 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.

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Neuron‐specific expression of CuZnSOD prevents the loss of muscle mass and function that occurs in homozygous CuZnSOD‐knockout mice

Cited by 77 publications

References 36 publications

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training

Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching

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