Having been for a long time in the radar of Pura Muñoz Cánoves from the CEXS-UPF, she could now demonstrate that the severity in muscular dystrophy is fibrinogen dependent. This fibrin precursor, which is never located outside of the vascular compartment in healthy muscle, is deposited in the extracellular matrix in mdx mice, the animal model for Duchenne muscular dystrophy (DMD). In their paper published in Human Molecular Genetics the researchers could furthermore show that the mechanisms supporting disease progression depend on the αMß2-binding motif of fibrinogen. Once this motif was experimentally eliminated from the fibrinogen gamma chain, this was sufficient to alleviate disease severity in mdx dystrophic muscle.
DMD is still a fatal degenerative muscle disorder. With the discovery of fibrinogen being a critical factor for inflammation-mediated DMD progression, new strategies for treatment could be developed. The counterproductive inflammatory environment established through the αMß2-mediated leukocyte activation could be stopped by selectively targeting this motif leaving its pro-coagulant properties unaltered. The authors also suggest looking into neurodegenerative diseases like Alzheimer’s and multiple sclerosis, because evidence was recently found that interference with the fibrinogen/macrophage axis improves neurodegeneration and stops demyelination in mouse models.
Vidal B, Ardite E, Suelves M, Ruiz-Bonilla V, Janué A, Flick MJ, Degen JL, Serrano AL, Muñoz-Cánoves P
Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the αMß2 leukocyte integrin receptor.
Hum Mol Genet. 2012 Mar 1;
Repairing a tissue after an injury requires the infiltration of inflammatory cells and the activation of the resident stem cells, which will restore the damaged tissue. But for full tissue recovery to happen, the inflammation that is first necessary must be resolved. The Myogenesis research group at the CEXS-UPF, led by Pura Muñoz-Cánoves, has recently provided evidence of how this happens.
For the inflammation to disappear, macrophages (a type of immune cells that are involved in the healing of muscle and other tissues) must switch from a pro-inflammatory to an anti-inflammatory phenotype. While it is known that disturbing the interactions between inflammatory cells and tissue resident cells prevents successful healing, the molecular mechanisms underlying the interactions between these cell types are practically unknown.
In an Extra Views article recently published in Cell Cycle, the authors review their work about how macrophages control stem cell-dependent tissue repair. In particular, Muñoz-Cánoves and colleagues demonstrated, in a paper in Journal of Cell Biology, a new function for MAPK phosphatase MKP-1 (MKP-1) in the regulation of p38 MAPK (p38) signaling, which leads to the deactivation of macrophages during inflammation resolution after injury.
At advanced stages of regeneration, MKP-1 loss caused an unscheduled “exhaustion-like” state in muscle macrophages, in which neither pro- nor anti-inflammatory cytokines are expressed despite persistent tissue damage. This leads to reparation by the tissue stem cells.
Because this progressive attenuation of pro-inflammatory gene expression is also involved in the process of tolerance to bacterial infection, the authors discuss the potential similarities between the two mechanisms: inflammation resolution during tissue repair (studied in this work) and endotoxin tolerance.
Perdiguero E, Sousa-Victor P, Ruiz-Bonilla V, Jardí M, Caelles C, Serrano AL, Muñoz-Cánoves P
p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair.
J Cell Biol. 2011 Oct 17;195(2):307-22
Muscle or mosaic?
This image by Francesc Sànchez Corredera, from Esther Barreiro’s lab on Molecular mechanisms of lung cancer predisposition (IMIM-Hospital del Mar), is a 3m thick sample of a Guinea pig diaphragm muscle, dyed with an Anti-Myosin Type II antibody and amplified 20 times. The protein myosin II is expressed in fast muscle fibres, but not in slow ones. This is why in this image we can see the fast muscle fibres in which myosin II is present dyed in brown, while the slow muscle fibres are negative (not dyed and therefore white).
This way, researchers can count the number of fibres of each type and establish a fibrilar percentage of each muscle.