Duchenne: 'Crosstalk' between muscle and spleen
Researchers discover a new connection in muscular dystrophy

Date:
August 27, 2020
Source:
University of Bonn
Summary:
Duchenne muscular dystrophy (DMD) is the most common muscle disease
in children and is passed on by X-linked recessive inheritance.

Characteristic is a progressive muscular atrophy. Researchers have
found a connection between dystrophic muscles and the lymphatic
system in mice with Duchenne disease.



FULL STORY ========================================================================== Duchenne muscular dystrophy (DMD) is the most common muscle
disease in children and is passed on by X-linked recessive
inheritance. Characteristic is a progressive muscular atrophy. The disease often results in death before the third decade of life. Researchers of
the Universities of Maynooth (Ireland) and Bonn have found a connection
between dystrophic muscles and the lymphatic system in mice with Duchenne disease. The results have now been published in the journal iScience.


==========================================================================
The muscular atrophy in Duchenne disease is caused by a lack of
dystrophin, a protein of the cytoskeleton. In vertebrates, dystrophin
is found in the muscle fiber membrane and is important for muscle
contraction. Although the disease is principally caused by a defective
single gene (DMD gene), as a primarily neuromuscular disease it also
has far-reaching and complex health-relevant effects on non-muscular
tissues and organ systems.

In recent years, the research groups associated with Prof. Dr. Dieter Swandulla, Physiological Institute of the University of Bonn, and
Prof. Dr. Kay Ohlendieck, National University of Ireland, Maynooth,
have used mass spectrometric protein analysis (proteomics) to show
that Duchenne muscular dystrophy causes changes in the respective set
of proteins (proteome) in a number of organs including heart, brain,
kidney and liver as well as in 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," says senior author Prof. Swandulla.

In the current study, the researchers used proteomics in mice suffering
from Duchenne muscular dystrophy to model how the skeletal muscles and
the spleen influence each other in view of the dystrophin deficiency. The spleen plays a key role in the immune response and is located in the
abdominal cavity near the stomach. It ensures the proliferation of
lymphocytes, which are white blood cells, and also stores monocyte-type
immune cells and disposes of worn-out red blood cells.

The researchers used the Duchenne mice to decode for the first time
the set of proteins (proteome) of the spleen in comparison to healthy
control animals and created a comprehensive protein archive for this
organ. "The mice with Duchenne disease showed numerous changes in
the proteomic signature of the spleen compared to the controls," says
Prof. Kay Ohlendieck of the National University of Ireland, Maynooth.

Furthermore, the researchers found for the first time a shorter form of dystrophin (DP71), which is synthesized as a protein in the spleen. "This dystrophin variant is apparently not affected by the disease because
it occurs unchanged in Duchenne mice," says Swandulla. The "crosstalk"
is expressed especially by the fact that a large number of proteins in
the spleen are drastically reduced due to the loss of the long form of dystrophin. "This includes proteins that are involved in lipid transport
and metabolism and in the immune response and inflammatory processes." Secondary effects in the lymphatic system Furthermore, the study provides evidence that the loss of the long form of dystrophin, as observed
in Duchenne muscular dystrophy in skeletal muscle, apparently causes
secondary effects in the lymphatic system. "It's a real 'crosstalk'
between skeletal muscles and the lymphatic system," says lead author
Dr. Paul Dowling of Maynooth University.

The term "crosstalk" is used, for example, when there is a disruptive
overlay of another conversation on the phone that can be heard in the background. In the specific case of Duchenne muscular dystrophy, the "crosstalk" was particularly expressed by the fact that the short form
of the dystrophin was still produced as normal in the spleen, but there
were disruptive changes of the proteomic signature in the other protein species.

The researchers point out that the results of the study suggest that
the mechanisms of the inflammatory processes which occur in the course
of Duchenne muscular dystrophy merit special attention. This is because
these inflammatory mechanisms are an important feature of muscle fiber degeneration and contribute significantly to the progression of the
disease. "The specific interactions of the dystrophin deficiency with
the immune system might therefore open up new therapeutic approaches,"
says Prof. Swandulla.


========================================================================== Story Source: Materials provided by University_of_Bonn. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Paul Dowling, Stephen Gargan, Margit Zweyer, Michael Henry, Paula
Meleady, Dieter Swandulla, Kay Ohlendieck. Proteome-wide
changes in the spleen due to pathophysiological crosstalk with
dystrophin-deficient skeletal muscle. iScience, 2020; 101500 DOI:
10.1016/j.isci.2020.101500 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200827105948.htm

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