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Differential Expression of Genes Involved in the Degeneration and Regeneration Pathways in Mouse Models for Muscular Dystrophies

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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.

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Abbreviations

α- and β-DG:

Alpha and beta dystroglycan

α, β-, γ-, δ- and ε-SG:

Alpha, beta, gamma, delta and epsilon sarcoglycans

CMD:

Congenital muscular dystrophy

DGC:

Dystroglycan complex

DMD:

Duchenne muscular dystrophy

FKRP:

Fukutin-related protein

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

LGMD:

Limb-girdle muscular dystrophy

MRF:

Muscle regulatory factor

NMD:

Neuromuscular disorders

PCOL:

Pro-collagen 1α2

TGF:

Transforming growth factor

TGF-β1:

Transforming growth factor beta 1

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Acknowledgments

The authors would like to thank the following researchers for scientific and technical support: Dra. Mayana Zatz, Dra. Helga C. Silva, Lydia Yamamoto and Marta Canovas. We would also like to thank Dr. Paulo Otto for the statistical analyses, Dr. Peter Pearson for the English revision, and Ms. Claudia Mori and IPEN for taking care of the mice. This work was supported by Fundação de Amparo a Pesquisa do Estado de São Paulo—Centro de Pesquisa, Inovação e Difusão (FAPESP-CEPID), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Instituto Nacional de Ciência e Tecnologia (INCT), FINEP, and Associação Brasileira de Distrofia Muscular (ABDIM).

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Authors and Affiliations

  1. Human Research Genome Center, Bioscience Institute, University of São Paulo, R. do Matão, travessa 13, no. 106, São Paulo, SP, CEP 05508-090, Brazil

    P. C. G. Onofre-Oliveira, A. L. F. Santos, P. M. Martins, D. Ayub-Guerrieri & M. Vainzof

  2. Centro de Estudos do Genoma Humano, IB-USP, R. do Matão, 277, sala 220, São Paulo, SP, CEP 05508-900, Brazil

    M. Vainzof

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  1. P. C. G. Onofre-Oliveira
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  2. A. L. F. Santos
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  3. P. M. Martins
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Correspondence to M. Vainzof.

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Onofre-Oliveira, P.C.G., Santos, A.L.F., Martins, P.M. et al. Differential Expression of Genes Involved in the Degeneration and Regeneration Pathways in Mouse Models for Muscular Dystrophies. Neuromol Med 14, 74–83 (2012). https://doi.org/10.1007/s12017-012-8172-3

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