Necrotic muscle fiber, a sign of Duchenne muscular dystrophy. Credit: Jose Luis Calvo Marin & Jose Enrique Garcia-Maurino Muzquiz/ iStock/ Getty Images Plus
A research team found that the oxidation state of a single protein can make the difference between inflammation or regeneration in muscle tissue. The discovery sheds light on a novel mechanism that could be targeted to treat muscular dystrophies.
HMGB1 is a protein with many different functions, depending on where in the organism it is expressed. In extracellular spaces, it signals damage to the tissue and can either promote inflammation or lead to tissue regeneration. The team, led by Emilie Vénéreau at the San Raffaele Scientific Institute in Milan, found that the switch between the dual activity is due to the oxidation state of amino acids called cysteines, that can be induced by stress in the microenvironment. When fully reduced, HMGB1 promotes regeneration, but when it is oxidized it acts as a pro-inflammatory cytokine.
Muscular dystrophies (MDs) are conditions in which muscles progressively weaken and degenerate, primarily due to the lack of a protein called dystrophin. This progressive muscle loss is associated with chronic oxidative stress and inflammation, which led the researcher to suspect a possible involvement of HMGB1. As proof of their hypotheses, the team found high levels of HMGB1 both in patients with muscular dystrophies, and in mouse models of the disease. “We realised that the chronic oxidative stress present in the dystrophic muscle was promoting the conversion of HMGB1 towards the pro-inflammatory function”, says Vénéreau.
The scientists then decided to try a new approach, says Giorgia Careccia, also from the San Raffele Institute and first author of the article in Science Translational Medicine1. “Instead of switching off the inflammation, we wanted to re-establish the natural balance,” she explains. The lab had previously produced a recombinant, non-oxidisable HMGB1 (called 3S) that only promotes tissue regeneration. Injecting mice with 3S, the scientists discovered that they could control the inflammation and promote regeneration without side effects. “This study is a starting point,” says Vénéreau. “We need more data to evaluate the toxicity before testing the molecule in humans”. If toxicity does not prove to be an issue, 3S would become a promising candidate therapy for MDs.
“This paper changes the way we think about inflammation” says Pier Lorenzo Puri at the Sanford Burnham Prebys Medical Discovery Institute in La Jolla, Usa, who was not involved in the study. “The pharmacological potential and the proof of concept provided are remarkable”.
