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Developmental biology - Evolutionary Genetics|
An Essential Mechanism Generates Healthy Muscle
Edgar Gomes explains: "We had previously shown a molecular mechanism in muscle cells moves their own nucleus to the correct position at the periphery of the cell wall. But we still knew very little about how that movement was activated. Now we've discovered another type of cell, the myofibroblast, activates movement of the nucleus."
João Martins, co-first author of the study continues: "We saw local accumulation of fibronectin in the vicinity where myofibroblasts were in contact with muscle. It was exciting to identify this was accompanied by movement of the nucleus to the periphery of the muscle cell."
"It is known that myofibroblasts produce fibronectin during muscle regeneration. We now demonstrate that fibronectin produced by myofibroblast cells can activate the movement of the nucleus to the correct peripheral position."
"We propose a mechanism by which cells can sense tissue architecture and regulate nuclear positioning in accordance with a local cue. This is of major importance to understand muscle differentiation, functionality and regeneration and might contribute to future therapeutic strategies to treat muscular diseases where the position of the nucleus is impaired," adds Edgar Gomes.
• Myofibroblasts deposit extracellular fibronectin at the periphery of muscle cells
• Fibronectin hotspots are sufficient to trigger local peripheral nuclear positioning
• ?5ß1 integrin via FAK, Src, and Cdc42 organize desmin for nuclear movement
Skeletal muscle cells (myofibers) are rod-shaped multinucleated cells surrounded by an extracellular matrix (ECM) basal lamina. In contrast to other cell types, nuclei in myofibers are positioned just below the plasma membrane at the cell periphery. Peripheral nuclear positioning occurs during myogenesis and is driven by myofibril crosslinking and contraction. Here we show that peripheral nuclear positioning is triggered by local accumulation of fibronectin secreted by myofibroblasts. We demonstrate that fibronectin via ?5-integrin mediates peripheral nuclear positioning dependent on FAK and Src activation. Finally, we show that Cdc42, downstream of restricted fibronectin activation, is required for myofibril crosslinking but not myofibril contraction. Thus we identify that local activation of integrin by fibronectin secreted by myofibroblasts activates peripheral nuclear positioning in skeletal myofibers.
Authors: William Roman, João P. Martins and Edgar R. Gomes.
This study was performed at iMM and funded by the European Research Council, EMBO, AIM France, POR Lisboa 2020 - Programa Operacional Regional de Lisboa, PORTUGAL 2020, and Fundação para a Ciência e a Tecnologia.
We thank the Gomes Laboratory for discussions, Isabelle Marty for the triadin antibody and the histology facility, and the bio-imaging team at the Instituto de Medicina Molecular (iMM). This work was supported by the European Research Council (E.R.G.), EMBO installation (E.R.G.), AIM France (W.R., E.R.G.), LISBOA-01-0145-FEDER-007391, project co-funded by FEDER, through POR Lisboa 2020 – Programa Operacional Regional de Lisboa, PORTUGAL 2020, and Fundação para a Ciência e a Tecnologia.
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Confocal microscopy image showing the interaction of a myofibroblast (right side)
with a muscle fiber (left side). Image: João Martins.