Lymphatic Structure and Function Are Associated with Duchenne Muscular Dystrophy Pathogenesis

Duchenne Muscular Dystrophy (DMD) leads to progressive disability in 1 of every 5000 males due to an X-linked mutation of the DMD gene. DMD is the absence of functional dystrophin protein characterized by persistent inflammation, muscle degeneration and fibrosis. The early onset of inflammation not only exacerbates tissue damage but also plays a pivotal role in the progression of the disease. The lymphatic system plays a critical role in regulating inflammation and fibrosis during pathogenesis of diseases; therefore, we hypothesized that impaired structure and function of the lymphatic vasculature in skeletal muscle is one of the key factors contributing to the progression of DMD. We employed two animal models, golden retriever muscular dystrophy (GRMD) and D2. mdx mice. The micro-lymphangiography study showed a decrease in lymph transport in the lower limb of D2. mdx mice. Lymphatic functional study using isolated flank lymphatic vessels inferred that the diastolic diameter, phasic contractile frequency and ejection fraction were reduced in the D2. mdx mice. Results from the gadolinium-enhanced magnetic resonance lymphangiography showed a significant decrease in lymph transport in GRMD dogs. Additionally, proinflammatory markers and the lymphatic marker podoplan in are significantly increased in hindlimb skeletal muscles of D2. mdx mice and GRMD dogs. The adeno-associated virus (AAV)-microdystrophin-5 (µDys5) treatment that showed improved muscle function in the GRMD dogs, significantly decreased inflammation, specifically IL-6 and decreased podoplanin expression. Our findings provide initial evidence indicating: 1) a reduction in lymph transport function in DMD mouse and canine models and 2) a link between an elevated inflammatory state in skeletal muscle, both contributing to increased inflammatory lymphangiogenesis in dystrophic muscle. Additionally, treatment with µDys mitigates inflammatory lymphangiogenesis. NIH R01AR080129, NIH T32HL170975, NIH T32GM135748 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.