AIMS: This study utilized proteomics, biochemical and enzymatic assays, and bioinformatics tools that characterize protein alterations in hindlimb (gastrocnemius) and forelimb (triceps) muscles in an amyotrophic lateral sclerosis (ALS) (SOD1(G93A)) mouse model. The aim of this study was to identify the key molecular signatures involved in disease progression. RESULTS: Both muscle types have in common an early down-regulation of complex I. In the hindlimb, early increases in oxidative metabolism are associated with uncoupling of the respiratory chain, an imbalance of NADH/NAD(+), and an increase in reactive oxygen species (ROS) production. The NADH overflow due to complex I inactivation induces TCA flux perturbations, leading to citrate production, triggering fatty acid synthase (FAS), and lipid peroxidation. These early metabolic changes in the hindlimb followed by sustained and comparatively higher metabolic and cytoskeletal derangements over time precede and may catalyze the progressive muscle wasting in this muscle at the late stage. By contrast, in the forelimb, there is an early down-regulation of complexes I and II that is associated with the reduction of oxidative metabolism, which promotes metabolic homeostasis that is accompanied by a greater cytoskeletal stabilization response. However, these early compensatory systems diminish by a later time point. INNOVATION: The identification of potential early- and late-stage disease molecular signatures in an ALS model: muscle albumin, complex I, complex II, citrate synthase, FAS, and phosphoinositide 3-kinase functions as diagnostic markers and peroxisome proliferator-activated receptor γ co-activator 1α (PGC1α), Sema-3A, and Rho-associated protein kinase 1 (ROCK1) play the role of disease progression markers. CONCLUSION: The differing pattern of cellular metabolism and cytoskeletal derangements in the hind and forelimb identifies the potential dysmetabolism/hypermetabolism molecular signatures associated with disease progression, which may serve as diagnostic/disease progression markers in ALS patients.
AIMS: This study utilized proteomics, biochemical and enzymatic assays, and bioinformatics tools that characterize protein alterations in hindlimb (gastrocnemius) and forelimb (triceps) muscles in an amyotrophic lateral sclerosis (ALS) (SOD1(G93A)) mouse model. The aim of this study was to identify the key molecular signatures involved in disease progression. RESULTS: Both muscle types have in common an early down-regulation of complex I. In the hindlimb, early increases in oxidative metabolism are associated with uncoupling of the respiratory chain, an imbalance of NADH/NAD(+), and an increase in reactive oxygen species (ROS) production. The NADH overflow due to complex I inactivation induces TCA flux perturbations, leading to citrate production, triggering fatty acid synthase (FAS), and lipid peroxidation. These early metabolic changes in the hindlimb followed by sustained and comparatively higher metabolic and cytoskeletal derangements over time precede and may catalyze the progressive muscle wasting in this muscle at the late stage. By contrast, in the forelimb, there is an early down-regulation of complexes I and II that is associated with the reduction of oxidative metabolism, which promotes metabolic homeostasis that is accompanied by a greater cytoskeletal stabilization response. However, these early compensatory systems diminish by a later time point. INNOVATION: The identification of potential early- and late-stage disease molecular signatures in an ALS model: muscle albumin, complex I, complex II, citrate synthase, FAS, and phosphoinositide 3-kinase functions as diagnostic markers and peroxisome proliferator-activated receptor γ co-activator 1α (PGC1α), Sema-3A, and Rho-associated protein kinase 1 (ROCK1) play the role of disease progression markers. CONCLUSION: The differing pattern of cellular metabolism and cytoskeletal derangements in the hind and forelimb identifies the potential dysmetabolism/hypermetabolism molecular signatures associated with disease progression, which may serve as diagnostic/disease progression markers in ALSpatients.
Authors: Antoon J M Janssen; Frans J M Trijbels; Rob C A Sengers; Jan A M Smeitink; Lambert P van den Heuvel; Liesbeth T M Wintjes; Berendien J M Stoltenborg-Hogenkamp; Richard J T Rodenburg Journal: Clin Chem Date: 2007-03-01 Impact factor: 8.327
Authors: Jose-Luis Gonzalez de Aguilar; Christa Niederhauser-Wiederkehr; Benoît Halter; Marc De Tapia; Franck Di Scala; Philippe Demougin; Luc Dupuis; Michael Primig; Vincent Meininger; Jean-Philippe Loeffler Journal: Physiol Genomics Date: 2007-11-13 Impact factor: 3.107
Authors: Suh Young Jeong; Khizr I Rathore; Katrin Schulz; Prem Ponka; Paolo Arosio; Samuel David Journal: J Neurosci Date: 2009-01-21 Impact factor: 6.167
Authors: Julie D Atkin; Manal A Farg; Adam K Walker; Catriona McLean; Doris Tomas; Malcolm K Horne Journal: Neurobiol Dis Date: 2008-03-06 Impact factor: 5.996
Authors: Ying Si; Xianqin Cui; David K Crossman; Jiaying Hao; Mohamed Kazamel; Yuri Kwon; Peter H King Journal: Neurobiol Dis Date: 2018-02-24 Impact factor: 5.996