Link Beween Metalloproteases and Duchenne Muscular Dystrophy Discovered

Link Beween Metalloproteases and Duchenne Muscular Dystrophy Discovered

A study recently published in the journal Biochimica et Biophysica Acta (BBA) revealed new insights into the roles played by a specific metalloprotease in a mouse model of Duchenne muscular dystrophy (DMD). The study was led by researchers at Shinshu University School of Medicine and Shinshu University Hospital in Japan, and is entitled “Differential roles of MMP-9 in early and late stages of dystrophic muscles in a mouse model of Duchenne muscular dystrophy”.

Muscular dystrophies correspond to inherited disorders that lead to muscle weakness and wasting. A common and severe condition is DMD, a disorder characterized by a rapid progressive skeletal muscle weakness caused by chronic inflammation and the degeneration of muscle cells and tissue, which can compromise locomotion and the respiratory function, leading to breathing complications and cardio-respiratory failure. The disorder has a rapid progression and affects mainly boys, being estimated that up to 1 in every 3,500 – 5,000 live male births develops the disease. The majority of all DMD patients require a wheelchair by the age of 12 and patients often succumb to the disease in their 20s due to respiratory and cardiac failure.

A protein called matrix metalloprotease (MMP)-9 has been suggested to be involved with DMD pathogenesis. MMP-9 is known to play a role in the degradation of the extracellular matrix, namely through the degradation of collagen and other extracellular matrix proteins. The exact function of MMP-9 in DMD is, however, not clear.

The goal of the study was to determine the impact of genetically depleting MMP-9 in a DMD mouse model called mdx.

Researchers found that in early disease stage, the muscles of mice lacking mdx and MMP-9 had a decline in necrosis (tissue death) and neutrophil (a type of white blood cell) invasion, a mechanism important in the inflammatory process that is also a major cause of tissue damage. These mutant mice were also found to have a decreased expression of the macrophage inflammatory protein 2 (MIP-2), an inflammatory chemokine known to attract neutrophils. Interestingly, DMD mice lacking MMP-9 exhibited enhanced muscle regeneration and strength, along with an increase in macrophage infiltration and expression of monocyte chemoattractant protein 1 (MCP-1), a chemokine that regulates migration and infiltration of monocytes/macrophages (a type of white blood cells). However, at later disease stages, DMD mice lacking MMP-9 had muscle growth impairment due to the altered expression of muscle factors and increased fibro-adipose tissue.

The research team concluded that MMP-9 seems to play several roles during DMD disease progression in mice models. Depletion of MMP-9 was found to lead to a decrease in necrosis and an increase in muscle regeneration in mice at early stages of the disease; while at later stages, MMP-9 depletion promoted fibrosis. The team believes that therapies targeting MMP-9 might be a useful strategy to improve muscle pathology in DMD at an early disease stage only, as continuous inhibition of the protein may lead to exacerbated fibrosis and reduced muscle strength.

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