Gene profiling of skeletal muscle in an amyotrophic lateral sclerosis mouse model

• Published in: Physiological genomics Vol. 32; no. 2; pp. 207 - 218
• Main Authors: Gonzalez de Aguilar, Jose-Luis, Niederhauser-Wiederkehr, Christa, Halter, Benoit, De Tapia, Marc, Di Scala, Franck, Demougin, Philippe, Dupuis, Luc, Primig, Michael, Meininger, Vincent, Loeffler, Jean-Philippe
• Format: Journal Article
• Language: English
• Published: United States Am Physiological Soc 17-01-2008; American Physiological Society
• Subjects: Amyotrophic Lateral Sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Animals; Biochemistry, Molecular Biology; Cluster Analysis; Databases, Genetic; Disease Models, Animal; Gene Expression Profiling; Gene Expression Profiling - methods; Hindlimb; Humans; Life Sciences; Mice; Mice, Transgenic; Motor Neurons; Motor Neurons - metabolism; Muscle, Skeletal; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Atrophy; Muscular Atrophy - genetics; Neurons and Cognition; Oligonucleotide Array Sequence Analysis
• ISSN: 1094-8341; 1531-2267
• DOI: 10.1152/physiolgenomics.00017.2007

1 Institut National de la Santé et de la Recherche Médicale, U692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence, Strasbourg
2 Université Louis Pasteur, Faculté de Médecine, Unité Mixte de Recherche en Santé-692, Strasbourg, France
3 Biozentrum and Swiss Institute of Bioinformatics, Basel, Switzerland
4 Hôpital de la Pitié-Salpêtrière, Fédération des Maladies du Système Nerveux, Centre Référent Maladie Rare Sclérose Latérale Amyotrophique, Paris, France
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/EBP and DDIT4) and cell death (e.g., ankyrin repeat domain-1, CDKN1A, GADD45 , 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.
atrophy; axotomy; denervation; neuromuscular disease