A group of researchers at IRCCS San Raffaele Hospital in Milan identified a protein as a link between oxidative stress and inflammation, deleterious processes contributing to the pathology of skeletal muscular dystrophies, genetic disorders that progressively lead to the degeneration and wasting of skeletal muscle. The protein is High Mobility Group Box 1 (HMGB1), a key player in inflammatory and regenerative processes, both fundamental for tissue healing.

The research team, headed by Emilie Venereau, Group Leader of the Tissue Regeneration & Homeostasis laboratory at San Raffaele, tested in two models of muscular dystrophies a modified form of the protein of interest (called 3S-HMGB1). Results of the study, published in Science Translational Medicine, demonstrated – in mouse models of muscular dystrophies – that 3S-HMGB1 administration stimulates the regeneration and ameliorate the muscle function, aside from reducing degeneration, inflammation and fibrosis. The engineered protein could be a new therapeutic strategy, in the future, to delay the progression of the dystrophic phenotype.

The research was conducted with the collaboration of other research groups, including the one led by Dr. Stefano Previtali, also from San Raffaele, and the one directed by Prof. Graziella Messina from the University of Milan.

 

The double face of HMGB1 in muscular dystrophies

HMGB1 (High Mobility Group Box 1) protein normally resides in the nucleus of the cells but after stress or tissue damage, HMGB1 is released outside the cells where it acts as a danger signal to attract immune cells at the site of damage. The inflammatory phase is fundamental for the clearance of the damaged tissue. However, a second phase of regeneration must quickly follow this first phase, in which the stem cells reconstitute the tissue. In 2018, the researchers at San Raffaele previously demonstrated that depending on its oxidation state, HMGB1 can influence the transition between the two phases: when oxidated, HMGB1 promotes inflammation; whereas when it is reduced (not oxidized), HMGB1 attracts and stimulates cells for tissue healing.

“Analyses of animal models and muscular biopsies from patients affected by muscular dystrophies revealed a high expression of oxidized HMGB1 in dystrophic muscles that exacerbates the inflammation and muscle degeneration” explains Giorgia Careccia, first author of the study. “We identified, in the excessive presence of the oxidized protein, a possible target to slow down the disease”.

 

A new therapeutic approach

“Nowadays most of the approaches to target HMGB1 aims at the complete neutralization of the protein, blocking both the proinflammatory and regenerating activities. Instead, we decided to use the dual nature of HMGB1 to our advantage: to develop a new possible therapeutic approach aimed at promoting muscle regeneration and, at the same time, limiting inflammation of the muscular microenvironment” specifies Emilie Venereau.”

To achieve this purpose, the researchers administered an engineered version of the protein (called 3S-HMGB1), previously created in the laboratory at San Raffaele, to the experimental models of the study. The modified version cannot be oxidized and promotes muscle regeneration in experimental models of muscular dystrophies by acting on muscle stem cells and by limiting the inflammatory response and fibrosis.

“3S-HMGB1 is potentially a promising drug candidate for the treatment of muscular dystrophies, although this engineered protein has only been used in the laboratory until now. Further preclinical studies will therefore be needed to evaluate safety and efficacy even in the long term before we can hope to pass to humans” closes Emilie Venereau.