Research ArticleMuscular Dystrophy

Rebalancing expression of HMGB1 redox isoforms to counteract muscular dystrophy

See allHide authors and affiliations

Science Translational Medicine  02 Jun 2021:
Vol. 13, Issue 596, eaay8416
DOI: 10.1126/scitranslmed.aay8416

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

Restoring redox regularity

Oxidative stress causes cell damage and has been linked to muscular dystrophies, but the mechanisms remain unclear. Here, Careccia et al. studied the role of the redox-sensitive alarmin HMGB1 in muscular dystrophy. Muscle biopsies and serum from patients and mouse models showed that HMGB1 was increased and oxidized, and that the oxidized HMGB1 isoform contributed to the dystrophic phenotype by exacerbating inflammation and muscle degeneration. Treating a mouse model of muscular dystrophy with a nonoxidizable form of HMGB1 reduced inflammation and fibrosis, promoted muscle regeneration, and improved muscle function. Results help illustrate how the different redox isoforms of HMGB1 are associated with disease versus tissue regeneration.

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.

View Full Text

Stay Connected to Science Translational Medicine