Omentum acts as a regulatory organ controlling skeletal muscle repair of mdx mice diaphragm
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Duchenne muscular dystrophy is a lethal X-linked muscle wasting disease due to mutations of the dystrophin gene leading to distinct susceptibility to degeneration and fibrosis among skeletal muscles. This study aims at verifying whether intense mdx diaphragm remodeling could be attributed to influences from the omentum, a lymphohematopoietic tissue rich in progenitor cells and trophic factors. Mdx omentum produces growth factors HGF and FGF and increased amounts of VEGF with pleiotropic actions upon muscular progenitors and myoblast differentiation. Histology revealed that the absence of the omentum reduced inflammation and collagen deposition in the diaphragm. The diaphragm from omentectomized mdx mice presents impaired repair with a predominance of collagen type I deposition, decreased muscle regeneration and a reduction in collagen type IV and indication of altered basal lamina integrity in the diaphragm. Omentectomy further reduced inflammatory infiltration and NFκ-B activation but a change in the pattern of muscle inflammation with low numbers of the F4/80+CD206+ M-2 macrophage subset. Although omentectomized mice had high levels of Pax7, myogenin and TNF-α, the percentage of myofibers undergoing regeneration was low thus suggesting that a lack of the omentum halts the muscle differentiation program. Such results support that omentum exerts a regulatory function inducing an inflammatory process that favors regeneration and inhibits fibrosis selectively in the diaphragm muscle thus being a potential site for therapeutic interventions in DMD.
KeywordsOmentum mdx Macrophages Fibrosis Diaphragm Muscle regeneration
We are grateful to Nina Cortez and Diogo G. Garcia for technical assistance and Giselle M. Faria with the statistical analysis.
This study was financed in part by FAPERJ (Fundação de Amparo a Pesquisa do Rio de Janeiro), PROPPI (UFF) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.
- Hirai K, Takemori N, Namiki M (1994) Erythropoiesis in mouse omental milky spots induced by erythropoietin: light and electron microscopic study. Int J Exp Pathol 75:375–383Google Scholar
- Kosmac K, Peck BD, Walton RG, et al. (2018) Immunohistochemical identification of human skeletal muscle macrophages. Biotechnol Protoc 8(12). https://doi.org/10.21769/BioProtoc.2883
- Loufrani L, Dubroca C, You D et al (2004) Absence of dystrophin in mice reduces NO-dependent vascular function and vascular density: total recovery after a treatment with the aminoglycoside gentamicin. Arterioscler Thromb Vasc Biol 24:671–676. https://doi.org/10.1161/01.ATV.0000118683.99628.42 CrossRefGoogle Scholar
- Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
- Pigozzo SR, Da Re L, Romualdi C, et al (2013) Revertant fibers in the mdx murine model of Duchenne muscular dystrophy: an age- and muscle-related reappraisal. PLoS One 8. https://doi.org/10.1371/journal.pone.0072147
- Pituch-Noworolska A, Majka M, Janowska-Wieczorek A et al (2003) Circulating CXCR4-positive stem/progenitor cells compete for SDF-1-positive niches in bone marrow, muscle and neural tissues: an alternative hypothesis to stem cell plasticity. Folia Histochem Cytobiol 41:13–21Google Scholar
- Rangel-Moreno J, Moyron-Quiroz JE, Carragher DM et al (2009) Milky spots in the omentum develop in the absence of lymphoid tissue inducer cells and independently support B and T cell responses to peritoneal antigens. Immunity 30:731–743. https://doi.org/10.1016/j.immuni.2009.03.014 CrossRefGoogle Scholar
- Shaik-Dasthagirisaheb YB, Varvara G, Murmura G et al (2013) Vascular endothelial growth factor (VEGF), mast cells and inflammation. Int J Immunopathol Pharmacol 26:327–335. https://doi.org/10.1177/039463201302600206
- Singh AK, Pancholi N, Patel J et al (2009) Omentum facilitates liver regeneration. World J Gastroenterol 15:1057–1064Google Scholar
- Villalta SA, Rosenberg AS, Bluestone JA (2015) The immune system in Duchenne muscular dystrophy: friend or foe. Rare Dis 3. https://doi.org/10.1080/21675511.2015.1010966