Role of superoxide–nitric oxide interactions in the accelerated age‐related loss of muscle mass in mice lacking Cu,Zn superoxide dismutase

Sakellariou, Giorgos K.; Pye, Deborah; Vasilaki, Aphrodite; Zibrik, Lea; Palomero, Jesús; Kabayo, Tabitha; McArdle, Francis; Remmen, Holly Van; Richardson, Arlan; Tidball, James G.; McArdle, Anne; Jackson, Malcolm J.

doi:10.1111/j.1474-9726.2011.00709.x

Cited by 64 publications

(109 citation statements)

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“…Studies using a combination of immunoblotting, high‐performance liquid chromatography and real‐time fluorescence microscopy methods have monitored specific intracellular RONS in single myofibres isolated from skeletal muscle of SOD1 −/− rodents. These studies carried out in resting and contracting skeletal muscle have demonstrated that genetic ablation of SOD1 does not induce the anticipated increase in cytosolic superoxide availability, but instead induced a substantial increase in peroxynitrite formation 30. These findings may provide important information of the RONS that are implicated in the processes of skeletal muscle ageing and highlight peroxynitrite formation as the important RONS mediator of the exacerbated neuromuscular ageing phenotype observed in the SOD1 −/− model.…”

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

confidence: 95%

“…Transgenic mice overexpressing nNOS isoform (nNOS Tg ) also exhibit increased peroxynitrite formation in skeletal muscle 30. However, this model is not associated with changes in skeletal muscle morphology and function, in contrast to the SOD1 −/− murine model 30.…”

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

confidence: 99%

“…Reactive oxygen and nitrogen species generation by myofibres has been detected and quantified by a variety of methods including high‐performance liquid chromatography techniques,30, 51 electron‐spin resonance spectroscopy (also known as electron paramagnetic resonance),52, 53 fluorescence‐based microscopic assays,54, 55 spectrophotometry,56, 57 chemiluminescence58, 59 and transfection methods including in vivo 60, 61 and in vitro. 62 It is widely accepted that superoxide and nitric oxide (NO) are the primary radical species generated by skeletal muscle 46, 63.…”

Section: Skeletal Muscle Produces Reactive Oxygen and Nitrogen Speciesmentioning

confidence: 99%

“…Evidence in skeletal muscle has shown in vivo intracellular generation of peroxynitrite in myofibres of transgenic murine models in which the levels of superoxide and/or NO were up‐regulated 30. The chemical reaction of superoxide with NO to generate peroxynitrite has a reaction rate ( k = 7 × 10 9 M −1 s −1 ),70 which is approximately three‐fold higher than the SOD catalysed conversion of superoxide to H 2 O 2 ( k = 2 × 10 9 M −1 s −1 ) as previously discussed.…”

Section: Chemistry Of Reactive Oxygen and Nitrogen Species Produced Bmentioning

confidence: 99%

“…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%

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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: 95%

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

confidence: 99%

Section: Skeletal Muscle Produces Reactive Oxygen and Nitrogen Speciesmentioning

confidence: 99%

Section: Chemistry Of Reactive Oxygen and Nitrogen Species Produced Bmentioning

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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Forum on aging and skeletal health: Summary of the proceedings of an ASBMR workshop

Khosla

Bellido

Drezner

et al. 2011

Journal of Bone and Mineral Research

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With the aging of the population, the scope of the problem of age-related bone loss and osteoporosis will continue to increase. As such, it is critical to obtain a better understanding of the factors determining the acquisition and loss of bone mass, from childhood to senescence. While there have been significant advances in recent years in our understanding of both the basic biology of aging and a clinical definition of age-related frailty, few of these concepts in aging research have been adequately evaluated for their relevance and application to skeletal aging or fracture prevention. The March 2011 “Forum on Aging and Skeletal Health”, sponsored by the NIH and ASBMR, sought to bring together leaders in aging and bone research to enhance communications among diverse fields of study so as to accelerate the pace of scientific advances needed to reduce the burden of osteoporotic fractures. This report summarizes the major concepts presented at this meeting and in each area, identifies key questions to help set the agenda for future research in skeletal aging.

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Oxidative stress‐induced dysregulation of excitation–contraction coupling contributes to muscle weakness

Qaisar

Bhaskaran

Premkumar

et al. 2018

J cachexia sarcopenia muscle

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BackgroundWe have previously shown that the deletion of the superoxide scavenger, CuZn superoxide dismutase, in mice (Sod1 −/− mice) results in increased oxidative stress and an accelerated loss of skeletal muscle mass and force that mirror the changes seen in old control mice. The goal of this study is to define the effect of oxidative stress and ageing on muscle weakness and the Excitation Contraction (EC) coupling machinery in age‐matched adult (8–10 months) wild‐type (WT) and Sod1 −/− mice in comparison with old (25–28 months) WT mice.Methods In vitro contractile assays were used to measure muscle contractile parameters. The activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump was measured using an NADH‐linked enzyme assay. Immunoblotting and immunofluorescence techniques were used to measure protein expression, and real‐time reverse transcription PCR was used to measure gene expression.ResultsThe specific force generated by the extensor digitorum longus muscle was reduced in the Sod1 −/− and old WT mice compared with young WT mice along with significant prolongation of time to peak force, increased half relaxation time, and disruption of intracellular calcium handling. The maximal activity of the SERCA calcium uptake pump was significantly reduced in gastrocnemius muscle from both old WT (≈14%) and adult Sod1 −/− (≈33%) mice compared with young WT mice along with increased expression of sarcolipin, a known inhibitor of SERCA activity. Protein levels of the voltage sensor and calcium uptake channel proteins dihydropyridine receptor α1 and SERCA2 were significantly elevated (≈45% and ≈57%, respectively), while the ratio of calstabin, a channel stabilizing protein, to ryanodine receptor was significantly reduced (≈21%) in Sod1 −/− mice compared with young WT mice. The changes in calcium handling were accompanied by substantially elevated levels of global protein carbonylation and lipid peroxidation.ConclusionsOur data suggest that the muscle weakness in Sod1 −/− and old WT mice is in part driven by reactive oxygen species‐mediated EC uncoupling and supports a role for reduced SERCA pump activity in compromised muscle function. The novel quantitative mechanistic data provided here can lead to potential therapeutic interventions of SERCA dysfunction for sarcopenia and muscle diseases.

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Role of superoxide–nitric oxide interactions in the accelerated age‐related loss of muscle mass in mice lacking Cu,Zn superoxide dismutase

Cited by 64 publications

References 51 publications

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

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

Forum on aging and skeletal health: Summary of the proceedings of an ASBMR workshop

Oxidative stress‐induced dysregulation of excitation–contraction coupling contributes to muscle weakness

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