TY - JOUR
T1 - Defective dystrophic thymus determines degenerative changes in skeletal muscle
AU - Farini, Andrea
AU - Sitzia, Clementina
AU - Villa, Chiara
AU - Cassani, Barbara
AU - Tripodi, Luana
AU - Legato, Mariella
AU - Belicchi, Marzia
AU - Bella, Pamela
AU - Lonati, Caterina
AU - Gatti, Stefano
AU - Cerletti, Massimiliano
AU - Torrente, Yvan
N1 - Funding Information:
This study was supported by the Associazione Centro Dino Ferrari, a French Telethon AFM grant (No. 21104), Ricerca corrente FR230 Policlinico Hospital. This paper presents independent research funded by Roby and OPSIS Foundations. Work in Torrente lab also received support from Italian Regenerative Medicine Infrastructure (IRMI)—Italian Ministry of Education, Universities and Research (MIUR), Ricerca Finalizzata 2016 (Linea di ricerca: “Theory-enhancing”). Funders of the study had no role in study design, data analysis, data interpretation, or writing of the report. We thank Ann-Christin Niehoff from Shimadzu for the outstanding assistance in the acquisition and interpretation of Imaging mass spectrometry data. We thank Silvia Erratico from Novystem for technical and scientific assistance.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - In Duchenne muscular dystrophy (DMD), sarcolemma fragility and myofiber necrosis produce cellular debris that attract inflammatory cells. Macrophages and T-lymphocytes infiltrate muscles in response to damage-associated molecular pattern signalling and the release of TNF-α, TGF-β and interleukins prevent skeletal muscle improvement from the inflammation. This immunological scenario was extended by the discovery of a specific response to muscle antigens and a role for regulatory T cells (Tregs) in muscle regeneration. Normally, autoimmunity is avoided by autoreactive T-lymphocyte deletion within thymus, while in the periphery Tregs monitor effector T-cells escaping from central regulatory control. Here, we report impairment of thymus architecture of mdx mice together with decreased expression of ghrelin, autophagy dysfunction and AIRE down-regulation. Transplantation of dystrophic thymus in recipient nude mice determine the up-regulation of inflammatory/fibrotic markers, marked metabolic breakdown that leads to muscle atrophy and loss of force. These results indicate that involution of dystrophic thymus exacerbates muscular dystrophy by altering central immune tolerance.
AB - In Duchenne muscular dystrophy (DMD), sarcolemma fragility and myofiber necrosis produce cellular debris that attract inflammatory cells. Macrophages and T-lymphocytes infiltrate muscles in response to damage-associated molecular pattern signalling and the release of TNF-α, TGF-β and interleukins prevent skeletal muscle improvement from the inflammation. This immunological scenario was extended by the discovery of a specific response to muscle antigens and a role for regulatory T cells (Tregs) in muscle regeneration. Normally, autoimmunity is avoided by autoreactive T-lymphocyte deletion within thymus, while in the periphery Tregs monitor effector T-cells escaping from central regulatory control. Here, we report impairment of thymus architecture of mdx mice together with decreased expression of ghrelin, autophagy dysfunction and AIRE down-regulation. Transplantation of dystrophic thymus in recipient nude mice determine the up-regulation of inflammatory/fibrotic markers, marked metabolic breakdown that leads to muscle atrophy and loss of force. These results indicate that involution of dystrophic thymus exacerbates muscular dystrophy by altering central immune tolerance.
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U2 - 10.1038/s41467-021-22305-x
DO - 10.1038/s41467-021-22305-x
M3 - Article
C2 - 33833239
AN - SCOPUS:85104062501
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2099
ER -