title: Gene profiling of skeletal muscle in an amyotrophic lateral sclerosis mouse model.
abstract: Muscle atrophy is a major hallmark of amyotrophic lateral sclerosis (ALS), the most frequent adult-onset motor neuron disease. To define the full set of alterations in gene expression in skeletal muscle during the course of the disease, we used the G86R superoxide dismutase-1 transgenic mouse model of ALS and performed high-density oligonucleotide microarrays. We compared these data to those obtained by axotomy-induced denervation. A major set of gene regulations in G86R muscles resembled those of surgically denervated muscles, but many others appeared specific to the ALS condition. The first significant transcriptional changes appeared in a subpopulation of mice before the onset of overt clinical symptoms and motor neuron death. These early changes affected genes involved in detoxification (e.g., ALDH3, metallothionein-2, and thioredoxin-1) and regeneration (e.g., BTG1, RB1, and RUNX1) but also tissue degradation (e.g., C/EBPdelta and DDIT4) and cell death (e.g., ankyrin repeat domain-1, CDKN1A, GADD45alpha, and PEG3). Of particular interest, metallothionein-1 and -2, ATF3, cathepsin-Z, and galectin-3 genes appeared, among others, commonly regulated in both skeletal muscle (our present data) and spinal motor neurons (as previously reported) of paralyzed ALS mice. The importance of these findings is twofold. First, they designate the distal part of the motor unit as a primary site of disease. Second, they identify specific gene regulations to be explored in the search for therapeutic strategies that could alleviate disease before motor neuron death manifests clinically.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence, Strasbourg, France. gonzalez@neurochem.ustrasbg.fr
authors.forename: Jose-Luis
authors.initials: JL
authors.lastname: Gonzalez de Aguilar
authors.forename: Christa
authors.initials: C
authors.lastname: Niederhauser-Wiederkehr
authors.forename: Benoît
authors.initials: B
authors.lastname: Halter
authors.forename: Marc
authors.initials: M
authors.lastname: De Tapia
authors.forename: Franck
authors.initials: F
authors.lastname: Di Scala
authors.forename: Philippe
authors.initials: P
authors.lastname: Demougin
authors.forename: Luc
authors.initials: L
authors.lastname: Dupuis
authors.forename: Michael
authors.initials: M
authors.lastname: Primig
authors.forename: Vincent
authors.initials: V
authors.lastname: Meininger
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Loeffler
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D016000:Cluster Analysis; D030541:Databases, Genetic; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods*; D006614:Hindlimb; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis