title: Differential expression of genes involved in the degeneration and regeneration pathways in mouse models for muscular dystrophies.
abstract: The genetically determined muscular dystrophies are caused by mutations in genes coding for muscle proteins. Differences in the phenotypes are mainly the age of onset and velocity of progression. Muscle weakness is the consequence of myofiber degeneration due to an imbalance between successive cycles of degeneration/regeneration. While muscle fibers are lost, a replacement of the degraded muscle fibers by adipose and connective tissues occurs. Major investigation points are to elicit the involved pathophysiological mechanisms to elucidate how each mutation can lead to a specific degenerative process and how the regeneration is stimulated in each case. To answer these questions, we used four mouse models with different mutations causing muscular dystrophies, Dmd (mdx), SJL/J, Large (myd) and Lama2 (dy2J) /J, and compared the histological changes of regeneration and fibrosis to the expression of genes involved in those processes. For regeneration, the MyoD, Myf5 and myogenin genes related to the proliferation and differentiation of satellite cells were studied, while for degeneration, the TGF-β1 and Pro-collagen 1α2 genes, involved in the fibrotic cascade, were analyzed. The result suggests that TGF-β1 gene is activated in the dystrophic process in all the stages of degeneration, while the activation of the expression of the pro-collagen gene possibly occurs in mildest stages of this process. We also observed that each pathophysiological mechanism acted differently in the activation of regeneration, with distinctions in the induction of proliferation of satellite cells, but with no alterations in stimulation to differentiation. Dysfunction of satellite cells can, therefore, be an important additional mechanism of pathogenesis in the dystrophic muscle.
authors.affiliation: Human Research Genome Center, Bioscience Institute, University of São Paulo, R. do Matão, travessa 13, no. 106, São Paulo, SP CEP 05508-090, Brazil.
authors.forename: P C G
authors.initials: PC
authors.lastname: Onofre-Oliveira
authors.forename: A L F
authors.initials: AL
authors.lastname: Santos
authors.forename: P M
authors.initials: PM
authors.lastname: Martins
authors.forename: D
authors.initials: D
authors.lastname: Ayub-Guerrieri
authors.forename: M
authors.initials: M
authors.lastname: Vainzof
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D024042:Collagen Type I / Q000235:genetics; D004195:Disease Models, Animal; D000073939:Dysferlin; D016189:Dystrophin / Q000235:genetics; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000502:physiology*; D007797:Laminin / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D053580:Muscle Strength / Q000502:physiology; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D017570:MyoD Protein / Q000235:genetics; D051787:Myogenic Regulatory Factor 5 / Q000235:genetics; D018008:Myogenin / Q000235:genetics; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D012038:Regeneration / Q000502:physiology*; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics
chemical_list: D024042:Collagen Type I; C497505:Dysf protein, mouse; D000073939:Dysferlin; D016189:Dystrophin; D007797:Laminin; D008565:Membrane Proteins; C497418:Myf5 protein, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C503801:Myog protein, mouse; D051787:Myogenic Regulatory Factor 5; D018008:Myogenin; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C085339:apo-dystrophin 1; C102645:laminin alpha 2; C502747:Large1 protein, mouse; D017351:N-Acetylglucosaminyltransferases