Duchenne: “Crosstalk” between muscle and spleen

Duchenne Muscular Dystrophy (DMD) is the most common muscle disease in children and is inherited by an X-linked recessive inheritance. Characteristic is progressive muscular atrophy. The disease often leads to death 30 years before life. Researchers at the University of Maynooth (Ireland) and Bonn have discovered a relationship between the dystrophic muscle and lymphatic system of mice with Duchenne disease. Results published in journal iScience..

Duchenne’s muscular atrophy is caused by a deficiency of the cytoskeletal protein dystrophin. In vertebrates, dystrophin is found in muscle fiber membranes and is important for muscle contraction. The disease is caused primarily by a defective single gene (DMD gene), but because it is primarily a neuromuscular disease, it has a wide range of complex health-related effects on non-muscle tissues and organ systems. ..

Recently, a group of researchers associated with Dr. Dieter Swandulla at the Institute for Physiology, University of Bonn and Dr. Kay Ohlendieck at the National University of Ireland Maynooth, has used mass spectrometry protein analysis (proteomics) to analyze Duchenne muscular dystrophy in the heart, brain and kidneys. It causes changes in proteins (proteome) of many organs such as liver, saliva, serum and urine.

Search for disease-specific marker proteins

“Proteomics is a reliable and effective analytical method for identifying disease-specific marker proteins that provide information about the course of the disease, possible therapeutic targets, and the effectiveness of therapeutic interventions,” said the author. Says Swandulla.

In the current study, the researchers used proteomics in mice suffering from Duchenne muscular dystrophy to model how skeletal muscle and spleen interact with each other in terms of dystrophin deficiency. The spleen plays an important role in the immune response, located in the abdominal cavity near the stomach. It ensures the proliferation of lymphocytes, which are white blood cells, stores monocyte-type immune cells, and disposes of used red blood cells.

The researchers used Duchenne mice for the first time to decode a set of splenic proteins (the proteome) compared to normal control animals, creating a comprehensive protein archive for this organ. “Duchenne’s disease mice showed more alterations in the proteomic signature of the spleen compared to controls,” says Kay Orendik, a professor at the National University of Ireland Maynooth.

In addition, researchers have for the first time discovered a short form of dystrophin (DP71), which is synthesized as a protein in the spleen. “This dystrophin mutant develops unchanged in Duchenne mice and is clearly unaffected by the disease,” says Swandulla. “Crosstalk” is manifested, inter alia, by the fact that the loss of long forms of dystrophin results in a significant reduction of many proteins in the spleen. “This includes proteins involved in lipid transport and metabolism, and immune reactions and inflammatory processes.”

Secondary effects of the lymphatic system

In addition, this study provides evidence that loss of the long form of dystrophin apparently causes secondary effects on the lymphatic system, as observed in Duchenne muscular dystrophy of skeletal muscle. “It’s the actual “crosstalk” between the skeletal muscle and the lymphatic system,” said Dr Paul Dowling, lead author at Maynooth University.

The term “crosstalk” is used, for example, when you have a destructive overlay of another conversation on the phone that you hear in the background. In the particular case of Duchenne muscular dystrophy, “crosstalk” was due to the fact that short forms of dystrophin were still normally produced in the spleen, but that in other protein species there were disruptive changes in the proteomic signature. Represented

The researchers point out that the results of this study suggest that the mechanisms of inflammatory processes that occur during Duchenne muscular dystrophy are particularly noteworthy. This is because these inflammatory mechanisms are important features of muscle fiber degeneration and contribute significantly to disease progression. “Therefore, specific interactions between dystrophin deficiency and the immune system may open up new therapeutic approaches,” says Professor Swandulla.