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.

Quantitative Proteomic Analysis Reveals Metabolic Alterations, Calcium Dysregulation, and Increased Expression of Extracellular Matrix Proteins in Laminin α2 Chain–deficient Muscle

“…Similar metabolic crises and mitochondrial abnormalities have been reported in gene and/or proteome expression profiling of different types of muscular dystrophy, including Duchenne muscular dystrophy and sarcoglycanopathy (56,57), and biochemical studies unveiled limitations in glycolytic and tricarboxylic acid cycle pathways and defective regulation of energy metabolism in mdx mice (58,59). Also, metabolic defects in ␤-sarcoglycan-deficient mice have been reported (60).…”

Comparative transcriptome analysis of muscular dystrophy models Largemyd, Dmdmdx/Largemyd and Dmdmdx: what makes them different?

“…This could indicate an apparent response mechanism to reinforce the links between the ECM and the cytoskeleton, protecting the muscular fibers against contraction damages. 20 A higher expression of Gpnmb (osteoactivin) in dystrophic mice 35 and DMD patients 36 was previously described. Osteoactivin is implicated in the differentiation and function of many cell types.…”

“…For Large myd − / − (27,35,156) and Dmd mdx /Large myd − / − (22,63,66), the number of exclusive DEGs increases with age ( Figure 1b).…”

Serum protein profiling in mice: Identification of Factor XIIIa as a potential biomarker for muscular dystrophy

“…The hDMD gene is integrated at an autosomal location, such that the mice carry either one or two copies of hDMD and show human dystrophin expression in muscle [11]. All these strains are functionally well characterized and were used in a series of gene expression profiling studies in our laboratory that shed light on the pathological mechanisms in muscular dystrophies [12,13]. We decided to use serum from a number of dystrophy models in an effort to reflect differences observed in the rate and extent of muscle breakdown in muscular dystrophy patients.…”