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Impaired Skeletal Muscle Development and Regeneration in Transglutaminase 2 Knockout Mice

Skeletal muscle regeneration is triggered by local inflammation and is accompanied by phagocytosis of dead cells at the injury site. Efferocytosis regulates the inflammatory program in macrophages by initiating the conversion of their inflammatory phenotype into the healing one. While pro-inflammato...

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Autores principales: Budai, Zsófia, Al-Zaeed, Nour, Szentesi, Péter, Halász, Hajnalka, Csernoch, László, Szondy, Zsuzsa, Sarang, Zsolt
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8623654/
https://www.ncbi.nlm.nih.gov/pubmed/34831312
http://dx.doi.org/10.3390/cells10113089
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author Budai, Zsófia
Al-Zaeed, Nour
Szentesi, Péter
Halász, Hajnalka
Csernoch, László
Szondy, Zsuzsa
Sarang, Zsolt
author_facet Budai, Zsófia
Al-Zaeed, Nour
Szentesi, Péter
Halász, Hajnalka
Csernoch, László
Szondy, Zsuzsa
Sarang, Zsolt
author_sort Budai, Zsófia
collection PubMed
description Skeletal muscle regeneration is triggered by local inflammation and is accompanied by phagocytosis of dead cells at the injury site. Efferocytosis regulates the inflammatory program in macrophages by initiating the conversion of their inflammatory phenotype into the healing one. While pro-inflammatory cytokines induce satellite cell proliferation and differentiation into myoblasts, growth factors, such as GDF3, released by healing macrophages drive myoblast fusion and myotube growth. Therefore, improper efferocytosis may lead to impaired muscle regeneration. Transglutaminase 2 (TG2) is a versatile enzyme participating in efferocytosis. Here, we show that TG2 ablation did not alter the skeletal muscle weights or sizes but led to the generation of small size myofibers and to decreased grip force in TG2 null mice. Following cardiotoxin-induced injury, the size of regenerating fibers was smaller, and the myoblast fusion was delayed in the tibialis anterior muscle of TG2 null mice. Loss of TG2 did not affect the efferocytic capacity of muscle macrophages but delayed their conversion to Ly6C(−)CD206(+), GDF3 expressing cells. Finally, TG2 promoted myoblast fusion in differentiating C2C12 myoblasts. These results indicate that TG2 expressed by both macrophages and myoblasts contributes to proper myoblast fusion, and its ablation leads to impaired muscle development and regeneration in mice.
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spelling pubmed-86236542021-11-27 Impaired Skeletal Muscle Development and Regeneration in Transglutaminase 2 Knockout Mice Budai, Zsófia Al-Zaeed, Nour Szentesi, Péter Halász, Hajnalka Csernoch, László Szondy, Zsuzsa Sarang, Zsolt Cells Article Skeletal muscle regeneration is triggered by local inflammation and is accompanied by phagocytosis of dead cells at the injury site. Efferocytosis regulates the inflammatory program in macrophages by initiating the conversion of their inflammatory phenotype into the healing one. While pro-inflammatory cytokines induce satellite cell proliferation and differentiation into myoblasts, growth factors, such as GDF3, released by healing macrophages drive myoblast fusion and myotube growth. Therefore, improper efferocytosis may lead to impaired muscle regeneration. Transglutaminase 2 (TG2) is a versatile enzyme participating in efferocytosis. Here, we show that TG2 ablation did not alter the skeletal muscle weights or sizes but led to the generation of small size myofibers and to decreased grip force in TG2 null mice. Following cardiotoxin-induced injury, the size of regenerating fibers was smaller, and the myoblast fusion was delayed in the tibialis anterior muscle of TG2 null mice. Loss of TG2 did not affect the efferocytic capacity of muscle macrophages but delayed their conversion to Ly6C(−)CD206(+), GDF3 expressing cells. Finally, TG2 promoted myoblast fusion in differentiating C2C12 myoblasts. These results indicate that TG2 expressed by both macrophages and myoblasts contributes to proper myoblast fusion, and its ablation leads to impaired muscle development and regeneration in mice. MDPI 2021-11-09 /pmc/articles/PMC8623654/ /pubmed/34831312 http://dx.doi.org/10.3390/cells10113089 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Budai, Zsófia
Al-Zaeed, Nour
Szentesi, Péter
Halász, Hajnalka
Csernoch, László
Szondy, Zsuzsa
Sarang, Zsolt
Impaired Skeletal Muscle Development and Regeneration in Transglutaminase 2 Knockout Mice
title Impaired Skeletal Muscle Development and Regeneration in Transglutaminase 2 Knockout Mice
title_full Impaired Skeletal Muscle Development and Regeneration in Transglutaminase 2 Knockout Mice
title_fullStr Impaired Skeletal Muscle Development and Regeneration in Transglutaminase 2 Knockout Mice
title_full_unstemmed Impaired Skeletal Muscle Development and Regeneration in Transglutaminase 2 Knockout Mice
title_short Impaired Skeletal Muscle Development and Regeneration in Transglutaminase 2 Knockout Mice
title_sort impaired skeletal muscle development and regeneration in transglutaminase 2 knockout mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8623654/
https://www.ncbi.nlm.nih.gov/pubmed/34831312
http://dx.doi.org/10.3390/cells10113089
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