Rebalancing expression of HMGB1 redox isoforms to counteract muscular dystrophy

Giorgia Careccia, Marielle Saclier, Mario Tirone, Elena Ruggieri, Elisa Principi, Lizzia Raffaghello, Silvia Torchio, Deborah Recchia, Monica Canepari, Andrea Gorzanelli, Michele Ferrara, Patrizia Castellani, Anna Rubartelli, Patrizia Rovere-Querini, Maura Casalgrandi, Alessandro Preti, Isabella Lorenzetti, Claudio Bruno, Roberto Bottinelli, Silvia BrunelliStefano Carlo Previtali, Marco Emilio Bianchi, Graziella Messina, Emilie Vénéreau

Research output: Contribution to journalArticlepeer-review

Abstract

Muscular dystrophies (MDs) are a group of genetic diseases characterized by progressive muscle wasting associated to oxidative stress and persistent inflammation. It is essential to deepen our knowledge on the mechanism connecting these two processes because current treatments for MDs have limited efficacy and/or are associated with side effects. Here, we identified the alarmin high-mobility group box 1 (HMGB1) as a functional link between oxidative stress and inflammation in MDs. The oxidation of HMGB1 cysteines switches its extracellular activities from the orchestration of tissue regeneration to the exacerbation of inflammation. Extracellular HMGB1 is present at high amount and undergoes oxidation in patients with MDs and in mouse models of Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy 3 (LGMDR3) compared to controls. Genetic ablation of HMGB1 in muscles of DMD mice leads to an amelioration of the dystrophic phenotype as evidenced by the reduced inflammation and muscle degeneration, indicating that HMGB1 oxidation is a detrimental process in MDs. Pharmacological treatment with an engineered nonoxidizable variant of HMGB1, called 3S, improves functional performance, muscle regeneration, and satellite cell engraftment in dystrophic mice while reducing inflammation and fibrosis. Overall, our data demonstrate that the balance between HMGB1 redox isoforms dictates whether skeletal muscle is in an inflamed or regenerating state, and that the nonoxidizable form of HMGB1 is a possible therapeutic approach to counteract the progression of the dystrophic phenotype. Rebalancing the HMGB1 redox isoforms may also be a therapeutic strategy for other disorders characterized by chronic oxidative stress and inflammation.

Original languageEnglish
Article numbereaay8416
JournalScience Translational Medicine
Volume13
Issue number596
DOIs
Publication statusPublished - Jun 2 2021

ASJC Scopus subject areas

  • Medicine(all)

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