title: Common pathological mechanisms in mouse models for muscular dystrophies.
abstract: Duchenne/Becker and limb-girdle muscular dystrophies share clinical symptoms like muscle weakness and wasting but differ in clinical presentation and severity. To get a closer view on the differentiating molecular events responsible for the muscular dystrophies, we have carried out a comparative gene expression profiling of hindlimb muscles of the following mouse models: dystrophin-deficient (mdx, mdx(3cv)), sarcoglycan-deficient (Sgca null, Sgcb null, Sgcg null, Sgcd null), dysferlin-deficient (Dysf null, SJL(Dysf)), sarcospan-deficient (Sspn null), and wild-type (C57Bl/6, C57Bl/10) mice. The expression profiles clearly discriminated between severely affected (dystrophinopathies and sarcoglycanopathies) and mildly or nonaffected models (dysferlinopathies, sarcospan-deficiency, wild-type). Dystrophin-deficient and sarcoglycan-deficient profiles were remarkably similar, sharing inflammatory and structural remodeling processes. These processes were also ongoing in dysferlin-deficient animals, albeit at lower levels, in agreement with the later age of onset of this muscular dystrophy. The inflammatory proteins Spp1 and S100a9 were up-regulated in all models, including sarcospan-deficient mice, which points, for the first time, at a subtle phenotype for Sspn null mice. In conclusion, we identified biomarker genes for which expression correlates with the severity of the disease, which can be used for monitoring disease progression. This comparative study is an integrating step toward the development of an expression profiling-based diagnostic approach for muscular dystrophies in humans.
authors.affiliation: Leiden University Medical Center, Center for Human and Clinical Genetics, Leiden, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Turk
authors.forename: E
authors.initials: E
authors.lastname: Sterrenburg
authors.forename: C G C
authors.initials: CG
authors.lastname: van der Wees
authors.forename: E J
authors.initials: EJ
authors.lastname: de Meijer
authors.forename: R X
authors.initials: RX
authors.lastname: de Menezes
authors.forename: S
authors.initials: S
authors.lastname: Groh
authors.forename: K P
authors.initials: KP
authors.lastname: Campbell
authors.forename: S
authors.initials: S
authors.lastname: Noguchi
authors.forename: G J B
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: J T
authors.initials: JT
authors.lastname: den Dunnen
authors.forename: P A C
authors.initials: PA
authors.lastname: 't Hoen
mesh_terms: D000818:Animals; D003599:Cytoskeleton / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D000073939:Dysferlin; D016189:Dystrophin / Q000172:deficiency; D005109:Extracellular Matrix / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007249:Inflammation / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency; D051379:Mice; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009136:Muscular Dystrophies / Q000145:classification / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D010641:Phenotype; D049031:Sarcoglycans / Q000172:deficiency; D012518:Sarcomeres / Q000378:metabolism
chemical_list: C114839:DYSF protein, human; D000073939:Dysferlin; D016189:Dystrophin; D008565:Membrane Proteins; D009124:Muscle Proteins; D049031:Sarcoglycans