Lymphatic dysfunction is linked to disease pathogenesis in Duchenne muscular dystrophy animal models
Abstract
Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disorder characterized by progressive muscle weakness and inflammation caused by mutations in the DMD gene. Chronic inflammation in DMD exacerbates the complications associated with disease progression. Since the lymphatic system plays a crucial role in regulating and resolving inflammation, our primary goal was to investigate whether lymphatics were dysregulated in skeletal muscle of DMD animals. We used the D2.mdx murine and golden retriever muscular dystrophy (GRMD) canine models, as well as mouse and rat lymphatic muscle cells (LMCs) to determine the role of dystrophin in lymphatic structure and function in skeletal muscles. Single-cell RNA sequencing data from control LMCs showed dystrophin expression, and protein results demonstrated that the 427-, 140-, and 71-kDa dystrophin isoforms were detectable in the LMCs from control mice, whereas the 427 kDa isoform was undetectable in LMCs derived from D2.mdx mice. Microlymphangiography and magnetic resonance lymphangiogram results showed a significant decrease in lymph transport in D2. mdx mice and GRMD dogs, respectively. Isolated flank lymphatic vessels from D2. mdx mice exhibited an increase in tonic contraction and a significant decrease in the phasic contractile frequency and amplitude, supporting lymphatic vessel dysfunction. The gene expression profile and immunofluorescence analyses of dystrophic muscle revealed inflammatory lymphangiogenesis in dystrophic muscle. Skeletal muscle tissues that showed improvement in function after adeno-associated virus-microdystrophin treatment also showed significant improvement in inflammatory lymphangiogenesis in GRMD dogs. Thus, these results show a linkage between lymphatic function and DMD pathogenesis that merits further investigation in DMD patients.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Bhuvaneshwaran Subramanian
Department of Medical Physiology, Naresh K. Vashisht College of Medicine, Texas A&M University
Shedreanna Johnson
Department of Medical Physiology, Naresh K. Vashisht College of Medicine, Texas A&M University
Akshaya Narayanan
Department of Medical Physiology, Naresh K. Vashisht College of Medicine, Texas A&M University
Wei Wang
Bonnie L. Seaberg
Department of Neuroscience and Experimental Therapeutics, Naresh K. Vashisht College of Medicine, Texas A&M University
Jillian Ball
Department of Medical Physiology, Naresh K. Vashisht College of Medicine, Texas A&M University
Ilse M. Paredes Mares
Department of Medical Physiology, Naresh K. Vashisht College of Medicine, Texas A&M University
Ahana Majumder
Department of Medical Physiology, Naresh K. Vashisht College of Medicine, Texas A&M University
Alexandria Aceves
Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University
Sarah E. Frazier
Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University
Alexis Rutledge
Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University
John F. Griffin
Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University
Soumiya Pal
Department of Medical Pharmacology and Physiology, University of Missouri
Scott Zawieja
Department of Medical Pharmacology and Physiology, University of Missouri
Michael J. Davis
Joseph M. Rutkowski
Department of Medical Physiology, Naresh K. Vashisht College of Medicine, Texas A&M University
Peter P. Nghiem
Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University
Mendell Rimer
Department of Neuroscience and Experimental Therapeutics, Naresh K. Vashisht College of Medicine, Texas A&M University
Mariappan Muthuchamy
Department of Medical Physiology, Naresh K. Vashisht College of Medicine, Texas A&M University