Nrf2 deficiency exacerbates age-related contractile dysfunction and loss of skeletal muscle mass

Ahn, Bumsoo; Pharaoh, Gavin; Premkumar, Pavithra; Huseman, Kendra; Ranjit, Rojina; Kinter, Michael; Szweda, Luke I.; Kiss, Tamás; Fülöp, Gábor; Tarantini, Stefano; Csiszár, Anna; Ungvári, Zoltán; Remmen, Holly Van

doi:10.1016/j.redox.2018.04.004

Cited by 78 publications

(75 citation statements)

References 65 publications

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“…Our data showed no differences in muscle mitochondrial oxygen consumption rate in LID mice at 24 months of age compared with age-matched controls, although muscle mass and OXPHOS capacity declined with age as expected. Consistent with previous reports [34], hydroperoxide production was unaffected with age or with reduced i Protein carbonylation (FITC conjugated) normalized to Coomassie gel staining in the cortex of 18-month GFP and LID mice (n = 7-9). Statistical significance for experiments with two groups determined by two-tailed student's t test (*p < 0.05), and statistical significance for experiments with three groups determined by ordinary one-way ANOVA with Tukey's multiple comparison test (*p < 0.05).…”

Section: Discussionsupporting

confidence: 90%

“…Thus, the age-related decline with OXPHOS capacity (GFP and LID mice) parallels a decline in gastrocnemius muscle mass. We previously reported no significant difference in hydroperoxide production capability in aged gastrocnemius fibers [34]. Analyzing hydroperoxide production as a percentage of oxygen consumed revealed no significant difference between groups, suggesting that decreased hydroperoxide production in 24-month GFP and LID mouse muscle fibers is a correlate of decreased OCR (Fig.…”

Section: Igf-1 Deficiency Does Not Alter Age-related Changes In Musclmentioning

confidence: 70%

“…We simultaneously probed oxygen consumption rate (OCR) and hydroperoxide production rate in permeabilized gastrocnemius muscle fibers, epididymal white adipose tissue (eWAT) biopsies, and isolated hippocampus mitochondria using HRR (OROBOROS Instruments, Innsbruck, Austria) and the O2K-Fluo LED2-Module Fluorescence-Sensor Green with the fluorogenic probe Amplex UltraRed as previously described [34,35]. Hydroperoxide groups, including hydrogen peroxide and lipid hydroperoxides, interact with Amplex UltraRed in a reaction catalyzed by horseradish peroxide to form the fluorescent compound resorufin [36].…”

Section: High-resolution Respirometry and Fluorometrymentioning

confidence: 99%

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Disparate Central and Peripheral Effects of Circulating IGF-1 Deficiency on Tissue Mitochondrial Function

et al. 2019

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Age-related decline in circulating levels of insulin-like growth factor (IGF)-1 is associated with reduced cognitive function, neuronal aging, and neurodegeneration. Decreased mitochondrial function along with increased reactive oxygen species (ROS) and accumulation of damaged macromolecules are hallmarks of cellular aging. Based on numerous studies indicating pleiotropic effects of IGF-1 during aging, we compared the central and peripheral effects of circulating IGF-1 deficiency on tissue mitochondrial function using an inducible liver IGF-1 knockout (LID). Circulating levels of IGF-1 (~75%) were depleted in adult male Igf1 f/f mice via AAV-mediated knockdown of hepatic IGF-1 at 5 months of age. Cognitive function was evaluated at 18 months using the radial arm water maze and glucose and insulin tolerance assessed. Mitochondrial function was analyzed in hippocampus, muscle, and visceral fat tissues using high-resolution respirometry O2K as well as redox status and oxidative stress in the cortex. Peripherally, IGF-1 deficiency did not significantly impact muscle mass or mitochondrial function. Aged LID mice were insulin resistant and exhibited~60% less adipose tissue but increased fat mitochondrial respiration (20%). The effects on fat metabolism were attributed to increases in growth hormone. Centrally, IGF-1 deficiency impaired hippocampal-dependent spatial acquisition as well as reversal learning in male mice. Hippocampal mitochondrial OXPHOS coupling efficiency and cortex ATP levels (~50%) were decreased and hippocampal oxidative stress (protein carbonylation and F 2-isoprostanes) was increased. These data suggest that IGF-1 is critical for regulating mitochondrial function, redox status, and spatial learning in the central nervous system but has limited impact on peripheral (liver and muscle) metabolism with age. Therefore, IGF-1 deficiency with age may increase sensitivity to damage in the brain and propensity for cognitive deficits. Targeting mitochondrial function in the brain may be an avenue for therapy of age-related impairment of cognitive function. Regulation of mitochondrial function and redox status by IGF-1 is essential to maintain brain function and coordinate hippocampal-dependent spatial learning. While a decline in IGF-1 in the periphery may be beneficial to avert cancer progression, diminished central IGF-1 signaling may mediate, in part, age-related cognitive dysfunction and cognitive pathologies potentially by decreasing mitochondrial function. Highlights Circulating IGF-1 deficiency: • Has pleiotropic effects on central and peripheral tissues. • Induces impairments in hippocampal learning and memory. • Decreases hippocampal mitochondrial oxygen coupling efficiency. • Increases stress response and oxidative damage in brain.

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Section: Discussionsupporting

confidence: 90%

Section: Igf-1 Deficiency Does Not Alter Age-related Changes In Musclmentioning

confidence: 70%

Section: High-resolution Respirometry and Fluorometrymentioning

confidence: 99%

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Disparate Central and Peripheral Effects of Circulating IGF-1 Deficiency on Tissue Mitochondrial Function

et al. 2019

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“…We used targeted quantitative mass spectrometry to measure protein abundance as previously described …”

Section: Methodsmentioning

confidence: 99%

“…We used targeted quantitative mass spectrometry to measure protein abundance as previously described. 39 Determination of mitochondrial DNA copy number Absolute copy number of mitochondrial DNA (mtDNA) was quantified (copies per ng input DNA) by digital PCR based on a previously reported method. 40,41 Immunoblot and qPCR Standard procedures were used for western blots and qPCR.…”

Section: Quantification Of Protein Abundances By Selected Reaction Momentioning

confidence: 99%

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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Cancer cachexia in a mouse model of oxidative stress

Brown

Lawrence

Ahn

et al. 2020

J cachexia sarcopenia muscle

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Background Cancer is associated with muscle atrophy (cancer cachexia) that is linked to up to 40% of cancer-related deaths. Oxidative stress is a critical player in the induction and progression of age-related loss of muscle mass and weakness (sarcopenia); however, the role of oxidative stress in cancer cachexia has not been defined. The purpose of this study was to examine if elevated oxidative stress exacerbates cancer cachexia. Methods Cu/Zn superoxide dismutase knockout (Sod1KO) mice were used as an established mouse model of elevated oxidative stress. Cancer cachexia was induced by injection of one million Lewis lung carcinoma (LLC) cells or phosphate-buffered saline (saline) into the hind flank of female wild-type mice or Sod1KO mice at approximately 4 months of age. The tumour developed for 3 weeks. Muscle mass, contractile function, neuromuscular junction (NMJ) fragmentation, metabolic proteins, mitochondrial function, and motor neuron function were measured in wild-type and Sod1KO saline and tumour-bearing mice. Data were analysed by two-way ANOVA with Tukey-Kramer post hoc test when significant F ratios were determined and α was set at 0.05. Unless otherwise noted, results in abstract are mean ±SEM. Results Muscle mass and cross-sectional area were significantly reduced, in tumour-bearing mice. Metabolic enzymes were dysregulated in Sod1KO mice and cancer exacerbated this phenotype. NMJ fragmentation was exacerbated in tumour-bearing Sod1KO mice. Myofibrillar protein degradation increased in tumour-bearing wild-type mice (wild-type saline, 0.00847 ± 0.00205; wildtype LLC, 0.0211 ± 0.00184) and tumour-bearing Sod1KO mice (Sod1KO saline, 0.0180 ± 0.00118; Sod1KO LLC, 0.0490 ± 0.00132). Muscle mitochondrial oxygen consumption was reduced in tumour-bearing mice compared with saline-injected wild-type mice. Mitochondrial protein degradation increased in tumour-bearing wild-type mice (wild-type saline, 0.0204 ± 0.00159; wild-type LLC, 0.167 ± 0.00157) and tumour-bearing Sod1KO mice (Sod1KO saline, 0.0231 ± 0.00108; Sod1 KO LLC, 0.0645 ± 0.000631). Sciatic nerve conduction velocity was decreased in tumour-bearing wild-type mice (wild-type saline, 38.2 ± 0.861; wild-type LLC, 28.8 ± 0.772). Three out of eleven of the tumour-bearing Sod1KO mice did not survive the 3-week period following tumour implantation. Conclusions Oxidative stress does not exacerbate cancer-induced muscle loss; however, cancer cachexia may accelerate NMJ disruption.

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Nrf2 deficiency exacerbates age-related contractile dysfunction and loss of skeletal muscle mass

Abstract: Graphical abstract

Cited by 78 publications

References 65 publications

Disparate Central and Peripheral Effects of Circulating IGF-1 Deficiency on Tissue Mitochondrial Function

Disparate Central and Peripheral Effects of Circulating IGF-1 Deficiency on Tissue Mitochondrial Function

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

Cancer cachexia in a mouse model of oxidative stress

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