title: Molecular signatures of amyotrophic lateral sclerosis disease progression in hind and forelimb muscles of an SOD1(G93A) mouse model.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biomedical Sciences for Health, University of Milan, Segrate, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Capitanio
authors.forename: Michele
authors.initials: M
authors.lastname: Vasso
authors.forename: Antonia
authors.initials: A
authors.lastname: Ratti
authors.forename: Giuliano
authors.initials: G
authors.lastname: Grignaschi
authors.forename: Manuela
authors.initials: M
authors.lastname: Volta
authors.forename: Manuela
authors.initials: M
authors.lastname: Moriggi
authors.forename: Cristina
authors.initials: C
authors.lastname: Daleno
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Silani
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gelfi
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000378:metabolism; D005260:Female; D005552:Forelimb / Q000378:metabolism*; D006614:Hindlimb / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D040901:Proteomics; D017382:Reactive Oxygen Species / Q000378:metabolism; D040121:Semaphorin-3A / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D040121:Semaphorin-3A; D015534:Trans-Activators; D014157:Transcription Factors; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D002950:Citrate (si)-Synthase; D058539:Phosphatidylinositol 3-Kinase; C515854:Rock1 protein, mouse; D054460:rho-Associated Kinases; D042967:Electron Transport Complex I