Rebalancing expression of HMGB1 redox isoforms to counteract muscular dystrophy

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.

The Immune System in Duchenne Muscular Dystrophy Pathogenesis

“…In physiological conditions, these events are strictly and timely orchestrated to preserve the immune privilege that protects muscles from harmful inflammation (Figure 1A). In DMD, the abnormal regulation of regenerative processes leads to the rising of inflammation, the activation of the immune system and the consequent invasion of cytotoxic T-lymphocytes, neutrophils and macrophages that promote muscle damage [2,11] and cardiac dysfunctions [12][13][14] (Figure 1B).…”

CFTR corrector C17 is effective in muscular dystrophy, in vivo proof of concept in LGMDR3

“…Furthermore, we are acting on the primary cause of the disease, even though it is well known that secondary events such as inflammation, oxidative stress, etc., are responsible for exacerbating symptoms and accelerating the disease progression ( 8 , 39 , 43 ). Therefore, to improve the outcome, it is possible to propose combo treatments with drugs aiming at mitigating the secondary events of the muscular dystrophy ( 44 ).…”

Inflammation in Duchenne Muscular Dystrophy–Exploring the Role of Neutrophils in Muscle Damage and Regeneration

“…Remarkably, preventing this interaction in mdx mice by deleting TLR2 or providing a TLR7/9 antagonist, significantly reduced muscle inflammation and improved skeletal muscle function, demonstrating a role of TLR-DAMP interactions in promoting muscle degeneration in DMD [20,21]. Furthermore, increased levels of HMGB1 in mdx mice are reported to promote inflammation and muscle degeneration, indicating the importance of identifying additional DAMPs which have the potential to act as biomarkers for DMD [22].…”