Lymphatic dysfunction is linked to disease pathogenesis in Duchenne muscular dystrophy animal models

Area of Science:

• Muscle Biology and Physiology
• Lymphatic System Research
• Genetic Disease Mechanisms

Background:

• Duchenne muscular dystrophy (DMD) is a severe genetic disorder causing progressive muscle weakness and inflammation.
• Chronic inflammation in DMD worsens disease complications.
• The lymphatic system is vital for regulating and resolving inflammation.

Purpose of the Study:

• To investigate lymphatic system dysregulation in skeletal muscle of DMD animal models.
• To determine the role of dystrophin in lymphatic structure and function within skeletal muscles.

Main Methods:

• Utilized D2.mdx murine and GRMD canine models, alongside isolated lymphatic muscle cells (LMCs).
• Employed single-cell RNA sequencing, protein analysis, microlymphangiography, and magnetic resonance lymphangiography.
• Assessed lymphatic vessel contractility and analyzed gene expression and immunofluorescence in dystrophic muscle.

Main Results:

• Dystrophin isoforms were detected in control LMCs but absent in D2.mdx mice LMCs.
• Significant decreases in lymph transport were observed in D2.mdx mice and GRMD dogs.
• Dystrophic muscle exhibited inflammatory lymphangiogenesis, which improved with micro-dystrophin treatment in GRMD dogs.

Conclusions:

• Lymphatic system dysfunction is linked to Duchenne muscular dystrophy pathogenesis.
• Dystrophin plays a role in lymphatic structure and function.
• Targeting lymphatic dysfunction may offer a novel therapeutic strategy for DMD patients.