Document Information

PMID 17584954  (  )
Title Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production.
Abstract Reactive oxygen species (ROS), especially mitochondrial ROS, are postulated to play a significant role in muscle atrophy. We report a dramatic increase in mitochondrial ROS generation in three conditions associated with muscle atrophy: in aging, in mice lacking CuZn-SOD (Sod1(-/-)), and in the neurodegenerative disease, amyotrophic lateral sclerosis (ALS). ROS generation in muscle mitochondria is nearly threefold higher in 28- to 32-mo-old than in 10-mo-old mice and is associated with a 30% loss in gastrocnemius mass. In Sod1(-/-) mice, muscle mitochondrial ROS production is increased >100% in 20-mo compared with 5-mo-old mice along with a >50% loss in muscle mass. ALS G93A mutant mice show a 75% loss of muscle mass during disease progression and up to 12-fold higher muscle mitochondrial ROS generation. In a second ALS mutant model, H46RH48Q mice, ROS production is approximately fourfold higher than in control mice and is associated with a less dramatic loss (30%) in muscle mass. Thus ROS production is strongly correlated with the extent of muscle atrophy in these models. Because each of the models of muscle atrophy studied are associated to some degree with a loss of innervation, we were interested in determining whether denervation plays a role in ROS generation in muscle mitochondria isolated from hindlimb muscle following surgical sciatic nerve transection. Seven days post-denervation, muscle mitochondrial ROS production increased nearly 30-fold. We conclude that enhanced generation of mitochondrial ROS may be a common factor in the mechanism underlying denervation-induced atrophy. Science Center at San Antonio, Barshop Institute for Longevity and Aging Studies, 15355 Lambda Drive, San Antonio, TX 78245-3207, USA. physiology

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Targets by SciMiner Summary

HUGO ID Symbol Target Name #Occur ActualStr
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))41Sod1 | superoxide dismutase |
16731FBXO32F-box protein 323MAFbx | Atrogin-1 | atrogin 1 |
2422CScitrate synthase1citrate synthase |
7794NFKB1nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105)1NF-kappaB |
4141GAPDHglyceraldehyde-3-phosphate dehydrogenase1glyceraldehyde 3 phosphate dehydrogenase |
1991CKBcreatine kinase, brain1creatine kinase |
21148RNF123ring finger protein 1231ubiquitin ligase |
399ALBalbumin1serum albumin |
31395COX8Bcytochrome c oxidase, subunit 8B pseudogene1cytochrome c oxidase |

 

Targets by SciMiner Full list

HUGO ID Symbol Name ActualStr Score FlankingText
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7with muscle atrophy in aging in mice lacking CuZn-SOD ( Sod1 and in the neurodegenerative disease amyotrophic lateral sclerosis (ALS) ALS
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7In Sod1 mice muscle mitochondrial ROS production is increased >100% in 20-mo
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7is a knockout mouse lacking a major antioxidant enzyme CuZn-SOD Sod1 mice ( 67
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7In a recent study we reported that the Sod1 mice show a dramatic age-related loss of skeletal muscle mass
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7By 20 mo of age the Sod1 mice have lost nearly 50% of their hindlimb muscle mass
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7The Sod1 mice are also characterized by very high levels of oxidative
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7that occurs in the three conditions we studied (aging, aging Sod1 mice and ALS is largely the result of loss of
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7The Sod1 mice used in this study were generated by Dr Charles
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7The mice were maintained in the heterozygous state ( Sod1 and backcrossed with C57Bl/6J C57Bl 6J females (Jackson Jackson Laboratory
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7associated with significant loss of muscle mass age-related muscle atrophy Sod1 mice (a a mouse model of accelerated sarcopenia and two
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7of muscle atrophy is lowest higher in muscle from the Sod1 mice and increased nearly 10-fold in G93A ALS mutant mice
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7production and atrophy were higher in 20-mo-old than in 5-mo-old Sod1 mice and ROS generation was higher in the G93A compared
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7to denervation (caused caused by breakdown of neuromuscular junctions in Sod1 mice ( 25 57 70
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7Thus one common characteristic of the three models (aging, aging Sod1 mice and ALS mutant mice is alterations in innervation of
7794NFKB1nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105)NF-kappaB0.0NF-kappaB is known to play a role in muscle atrophy (
16731FBXO32F-box protein 32Atrogin-11.5lead to upregulation of the expression of ubiquitin ligase Atrogin-1/MAFbx Atrogin-1 MAFbx ( 53 and could therefore contribute to atrophy through
16731FBXO32F-box protein 32MAFbx1.5to upregulation of the expression of ubiquitin ligase Atrogin-1/MAFbx Atrogin-1 MAFbx ( 53 and could therefore contribute to atrophy through increased
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7on our experiments in young and old wild-type mice the Sod1 model and the ALS mouse models we cannot be certain
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7generation precedes or follows changes in innervation especially in the Sod1 mice and in the case of aging in which the
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.72 O 2 release was in fact lower in old Sod1 and late-stage G93A ALS skeletal muscle mitochondria conditions that are
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7Increased ROS generation in skeletal muscle mitochondria from Sod1 mice
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7of gastrocnemius muscle isolated from female wild-type (WT) WT and Sod1 mice at 5 and 20 mo of age
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7substrate in isolated muscle mitochondria from 8 WT and 8 Sod1 mice at 20 mo of age * P _lt_ 0.05
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7open bars represent 5-mo-old WT light shaded bars represent 5-mo-old Sod1 dark shaded bars represent 20-mo-old WT and solid bars represent
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7shaded bars represent 20-mo-old WT and solid bars represent 20-mo-old Sod1
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7in mitochondria from 5-mo-old WT ( n = 21 and Sod1 mice ( n = 10 and 20-mo-old WT ( n
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.710 and 20-mo-old WT ( n = 16 and old Sod1 mice ( n = 16 values in D are means
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7in H 2 O 2 release in muscle mitochondria from Sod1 mice compared with mitochondria from age-matched WT mice (ANOVA ANOVA
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7Skeletal muscle mitochondrial ROS production is increased in Sod1 null mice and is associated with the degree of muscle
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7In agreement with our previous report on Sod1 mice ( 57 the gastrocnemius mass was significantly decreased in
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7both young (5 5 mo and older (20 20 mo Sod1 mice compared with the age-matched wild-type mice ( Fig 2
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7was decreased ~36% in mitochondria isolated from muscle of 20-mo-old Sod1 mice compared with mitochondria from muscle of age-matched wild-type mice
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.71 ROS production was increased over 30% in mitochondria from Sod1 mice at as early as 5 mo of age compared
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7By 20 mo of age ROS production in mitochondria from Sod1 mice was threefold higher than in the age-matched wild-type mice
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.72 _amp_#183 min _amp_#183 mg protein in mitochondria from 5-mo-old Sod1 compared with 19.77 _amp_#177 1.78 pmol H 2 O 2
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7In 20-mo-old Sod1 mice the increase in ROS generation with the substrates glutamate
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7the substrate succinate was significantly lower in mitochondria from the Sod1 mice compared with wild-type controls especially in mitochondria from the
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7compared with wild-type controls especially in mitochondria from the 20-mo-old Sod1 mice ( Fig 2 D
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7the G93A mutants and in the 20-mo-old (late late stage Sod1 mice
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7the mitochondria from wild-type mice much higher than in the Sod1 mice or in old wild-type mice which had relatively less
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7As we had observed in mitochondria from the Sod1 mice ROS production with succinate as a substrate was lower
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7an even greater decrease than had been observed in the Sod1 mice approaching levels close to that measured in state 1
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))Sod12.7muscle mitochondria isolated from young and old wild-type mice 20-mo-old Sod1 mice and the two ALS mouse models is illustrated in
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0mitochondria; reactive oxygen species; amyotrophic lateral sclerosis; copper zinc superoxide dismutase
399ALBalbuminserum albumin1.0the resulting pellet was washed once in modified chappell perry buffer with 0.5% bovine serum albumin and once in modified chappell perry buffer without bovine serum albumin.
2422CScitrate synthasecitrate synthase1.0mple genes encoding the mitochondrial respiratory chain and the tca cycle are significantly downregulated following denervation 48 60 66 and the levels of cytochrome c oxidase succinate dehydrogenase citrate synthase and cardiolipin are significantly lowered 8 14 days after denervation 18 82 .
31395COX8Bcytochrome c oxidase, subunit 8B pseudogenecytochrome c oxidase1.0for example genes encoding the mitochondrial respiratory chain and the tca cycle are significantly downregulated following denervation 48 60 66 and the levels of cytochrome c oxidase succinate dehydrogenase citrate synthase and cardiolipin are significantly lowered 8 14 days after denervation 18 82 .
4141GAPDHglyceraldehyde-3-phosphate dehydrogenaseglyceraldehyde 3 phosphate dehydrogenase1.0in fact increased ros production following denervation is mirrored by decreases in surface hydrophobicity and enzymatic activity of glyceraldehyde 3 phosphate dehydrogenase and creatine kinase 64 possibly due to increased oxidative damage 63 .
1991CKBcreatine kinase, braincreatine kinase1.0in fact increased ros production following denervation is mirrored by decreases in surface hydrophobicity and enzymatic activity of glyceraldehyde 3 phosphate dehydrogenase and creatine kinase 64 possibly due to increased oxidative damage 63 .
21148RNF123ring finger protein 123ubiquitin ligase1.0mitochondrial ros has also been shown to lead to upregulation of the expression of ubiquitin ligase atrogin 1/mafbx 53 and could therefore contribute to atrophy through increased degradation of proteins by the 26s proteasome system.
16731FBXO32F-box protein 32atrogin 11.0mitochondrial ros has also been shown to lead to upregulation of the expression of ubiquitin ligase atrogin 1/mafbx 53 and could therefore contribute to atrophy through increased degradation of proteins by the 26s proteasome system.