ABSTRACT
Duchenne muscle dystrophy results from the absence of dystrophin, a cytoskeletal protein of the muscle fibre. Dystrophin plays an essential role in the integrity of the membrane-associated protein complexes connected to the extracellular matrix. On chromosome 6 is located the gene of a protein presenting 80 % homology with dystrophin : utrophin, which is expressed at the neuromuscular junction. The review examines if utrophin can replace dystrophin and correct the structural and functional characteristics of the myopathy, and how the improvements can be quantitatively expressed. In transgenic mice, deficient in dystrophin, but overexpressing large quantities of utrophin, the latter is found on structures where dystrophin is normally located, histological signs of necrosis disappear and the recovery of functional disorders, specially affecting the mechanical properties of the muscle fibres, can be complete. The review examines also several ways of obtaining overexpression of utrophin in adult mdx mice, such as conditioned expression of the utrophin transgene (using a tetracycline-sensitive transactivator), transfection with viral vectors containing the utrophin cDNA (complete or truncated), actions on factor(s) controlling utrophin expression at the neuromuscular junction (heregulin, 4 N-acetylgalactosamine), and pharmacological ways of inducing expression (NO, arginine). Though partial improvements of the myopathy status have been obtained by these various approaches, they remain limited by their localized action and/or by the moderate level of utrophin expression obtained. Further researchs to overcome these limitations are urgently needed in order to transform the very promising effect of utrophin overexpression into a real treatment of Duchenne myopathy.
Subject(s)
Cytoskeletal Proteins/physiology , Genetic Therapy , Membrane Proteins/physiology , Muscular Dystrophy, Duchenne/therapy , Animals , Cytoskeletal Proteins/biosynthesis , Cytoskeletal Proteins/chemistry , Cytoskeletal Proteins/genetics , DNA, Complementary/genetics , Dystrophin/chemistry , Dystrophin/deficiency , Gene Expression Regulation/drug effects , Genetic Vectors/therapeutic use , Humans , Membrane Proteins/biosynthesis , Membrane Proteins/chemistry , Membrane Proteins/genetics , Mice , Mice, Inbred mdx , Mice, Knockout , Mice, Transgenic , Muscular Dystrophy, Animal/genetics , Muscular Dystrophy, Animal/therapy , Muscular Dystrophy, Duchenne/genetics , Neuregulin-1/therapeutic use , Nitric Oxide/physiology , Nitric Oxide Donors/therapeutic use , Recombinant Fusion Proteins/physiology , Sequence Homology, Amino Acid , Transcriptional Activation , UtrophinABSTRACT
Deletion of murine Smn exon 7, the most frequent mutation found in spinal muscular atrophy, has been directed to either both satellite cells, the muscle progenitor cells and fused myotubes, or fused myotubes only. When satellite cells were mutated, mutant mice develop severe myopathic process, progressive motor paralysis, and early death at 1 mo of age (severe mutant). Impaired muscle regeneration of severe mutants correlated with defect of myogenic precursor cells both in vitro and in vivo. In contrast, when satellite cells remained intact, mutant mice develop similar myopathic process but exhibit mild phenotype with median survival of 8 mo and motor performance similar to that of controls (mild mutant). High proportion of regenerating myofibers expressing SMN was observed in mild mutants compensating for progressive loss of mature myofibers within the first 6 mo of age. Then, in spite of normal contractile properties of myofibers, mild mutants develop reduction of muscle force and mass. Progressive decline of muscle regeneration process was no more able to counterbalance muscle degeneration leading to dramatic loss of myofibers. These data indicate that intact satellite cells remarkably improve the survival and motor performance of mutant mice suffering from chronic myopathy, and suggest a limited potential of satellite cells to regenerate skeletal muscle.
Subject(s)
Cell Differentiation/genetics , Muscle, Skeletal/growth & development , Muscular Atrophy, Spinal/genetics , Nerve Tissue Proteins/deficiency , Regeneration/genetics , Satellite Cells, Skeletal Muscle/metabolism , Animals , Animals, Newborn , Cell Death/genetics , Cell Division/genetics , Cells, Cultured , Cyclic AMP Response Element-Binding Protein , Disease Models, Animal , Female , Male , Mice , Mice, Mutant Strains , Movement Disorders/genetics , Movement Disorders/metabolism , Movement Disorders/pathology , Muscle Fibers, Skeletal/cytology , Muscle Fibers, Skeletal/metabolism , Muscle Fibers, Skeletal/pathology , Muscle Weakness/genetics , Muscle Weakness/metabolism , Muscle Weakness/pathology , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Muscular Atrophy, Spinal/metabolism , Muscular Atrophy, Spinal/therapy , Mutation/genetics , Necrosis , Nerve Tissue Proteins/genetics , Phenotype , RNA-Binding Proteins , SMN Complex Proteins , Satellite Cells, Skeletal Muscle/cytology , Stem Cells/cytology , Stem Cells/metabolismABSTRACT
This paper summarizes the various aspects of functional recovery obtained in dystrophin-deficient muscles of the mdx mice where utrophin was overexpressed. This includes preliminary results on tetracycline-controlled expression of utrophin. It is shown that overexpression of utrophin leads to major functional improvements and that full-length utrophin is more efficient than truncated utrophin, missing a part of the central rod-segment. A generalized way of presenting improvements obtained by any treatment in the form of a 'recovery score' is emphasized. The quantitative aspect of the replacement of dystrophin by utrophin is discussed.
