Defective dystrophic thymus determines degenerative changes in skeletal muscle

Author:

Farini Andrea,Sitzia Clementina,Villa Chiara,Cassani Barbara,Tripodi Luana,Legato Mariella,Belicchi Marzia,Bella Pamela,Lonati Caterina,Gatti StefanoORCID,Cerletti Massimiliano,Torrente YvanORCID

Abstract

AbstractIn 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.

Funder

AFM-Téléthon

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Ministero dell'Istruzione, dell'Università e della Ricerca

Ricerca Finalizzata 2016

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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