Defective dystrophic thymus determines degenerative changes in skeletal muscle

Andrea Farini, Clementina Sitzia, Chiara Villa, Barbara Cassani, Luana Tripodi, Mariella Legato, Marzia Belicchi, Pamela Bella, Caterina Lonati, Stefano Gatti, Massimiliano Cerletti and Yvan Torrente ()
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Andrea Farini: Centro Dino Ferrari
Clementina Sitzia: Università degli Studi di Milano
Chiara Villa: Centro Dino Ferrari
Barbara Cassani: Consiglio Nazionale delle Ricerche-Istituto di Ricerca Genetica e Biomedica (CNR-IRGB), Milan Unit
Luana Tripodi: Centro Dino Ferrari
Mariella Legato: Centro Dino Ferrari
Marzia Belicchi: Centro Dino Ferrari
Pamela Bella: Centro Dino Ferrari
Caterina Lonati: Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico
Stefano Gatti: Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico
Massimiliano Cerletti: University College London
Yvan Torrente: Centro Dino Ferrari

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-22305-x

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