MuSK Protein’s Release Into Blood Could Underlie Autoimmunity in MG

Injury drives shedding of protein by muscles and potential 'vicious cycle'

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Shedding of the muscle-specific tyrosine kinase (MuSK) protein from the surface of muscle cells into the bloodstream could be the reason why anti-MuSK antibodies drive myasthenia gravis (MG) in some cases, according to a study.

The protein was found in the blood of healthy mice and people, and was at elevated levels in some cases of MG.

Additional experiments showed that MuSK levels seem to increase after injuries that lead to denervation, or a loss of nerve input, to the muscles — a hallmark of neuromuscular diseases. While these levels normalize as healing occurs, their elevation could be a stimulus for antibody production.

“Such discoveries pave the way for new MG treatments, and MuSK may be used as a biomarker for other neuromuscular diseases in preclinical studies, clinical diagnostics, therapeutics, and drug discovery,” the researchers wrote.

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The study, “Proteolytic ectodomain shedding of muscle-specific tyrosine kinase in myasthenia gravis,” was published in Experimental Neurology.

MG is caused by the production of self-reactive antibodies, or autoantibodies, that launch an attack on proteins important for the function of the neuromuscular junction, the region where nerve cells and muscles meet to communicate.

Most often, these antibodies target acetylcholine receptors (AChRs), but less commonly they target other proteins, such as MuSK or low-density lipoprotein receptor-related protein 4 (LRP4).

People with MuSK antibodies have distinct clinical features from those with the other two antibody types, including a higher likelihood of breathing problems, and a tendency to be less responsive to conventional MG treatments, according to the researchers.

Present on the surface of skeletal muscle cells, MuSK is critical for the development and maintenance of neuromuscular junctions. Still, the mechanisms by which the body produces disease-driving antibodies against this protein aren’t fully understood.

Researchers in Japan aimed to investigate the potential mechanisms by which MuSK antibodies arise in MG.

In cell cultures of mouse muscle cells, they found evidence that cells shed MuSK protein fragments, or peptides, from their surface into the surrounding fluid. When certain proteases — a type of enzyme that breaks down proteins — were inhibited, the release of MuSK from muscle cells was reduced.

MuSK was also measurable in the blood of mice. Levels of the protein were significantly higher in a mouse model of LRP4-MG compared with healthy animals, but not in animals with MuSK-MG.

MuSK levels were similarly elevated in blood samples of some MuSK-MG patients — five out of 19 — as well as two of 122 people with AChR-MG, and two of 32 MG patients negative for both types of these antibodies.

Still, overall MuSK levels in these patient groups were not statistically higher than those observed in blood samples from healthy people.

The presence of anti-MuSK antibodies in mice and patients with MuSK-MG could have interfered with the assay used to measure the protein, causing its levels to be underestimated, the team noted. Among seven patients with MuSK protein levels below the measurable cut-off, all had very high levels of anti-MuSK antibodies.

Altogether, these data demonstrate that “a certain amount of MuSK is present in the blood of healthy mice and humans, and the amount of MuSK in the blood of [LRP4-MG mice] and some patients with MG is significantly increased,” the researchers wrote.

MuSK protein’s presence as source of autoimmunity in myasthenia gravis

Similar increases in the protein were seen in a mouse model of motor nerve cell injury marked by muscle denervation. Interestingly, MuSK levels returned to normal as nerve cells healed and reinnervated muscles.

Taken together, the findings “indicate that serum MuSK levels are reversible and accurately reflect the degree of nerve denervation and reinnervation” in neuromuscular disease, the researchers wrote.

Researchers believe this work as a whole suggests that the MuSK released from muscle cells into the blood is the source of the protein that’s made available to the immune system to drive autoimmunity in MG.

Injury itself appears to increase the protein’s release, leading to a “vicious cycle” in which MG autoimmune attacks at the neuromuscular junction could further exacerbate the production of disease-causing antibodies.

According to researchers, this could help explain why MuSK-MG tends to be associated with severe symptoms and responds poorly to standard treatments.

The team noted this study paves the way for the identification of new therapeutic strategies to suppressing anti-MuSK autoimmunity in MG.