Extracellular matrix markers as a component of fibrosis in Duchenne Muscular Dystrophy
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Date
2024-05
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The Ohio State University
Abstract
Duchenne muscular dystrophy (DMD) is an inherited, X-linked recessive muscular degenerative disorder that affects about 1 in 5000 males, and is caused by a loss of function mutations in the DMD gene that codes for the protein dystrophin. Dystrophin is responsible for stabilizing muscle cell membranes and protecting the muscle from injury by contraction. Without dystrophin, muscles become injured from contraction and become increasingly fibrotic. The pathology of DMD progresses into a complete loss of ambulation by age 12, cardiac and skeletal failure in the patient’s late teens, until patients eventually die from the disease by age 30.
The mdx mouse model is dystrophin deficient, but cannot progress fully into cardiac failure so cardiac pathology in DMD cannot be accurately studied. Thus, the “Fiona/dko” mouse model was developed, which is a mouse that contains a double knockout (dko) of dystrophin and its partially compensating homolog, utrophin, but contains the “Fiona” human utrophin transgene, which acts to rescue skeletal muscle pathology so that cardiac pathology can fully progress in the mice.
To test the hypothesis that cardiac fibrosis in DMD cardiomyopathy contains extracellular matrix markers that are present in skeletal muscle fibrosis, I conducted immunofluorescence experiments to identify the localization of potential fibrotic markers in Fiona/dko. Thrombospondin 4 (thbs4), an extracellular matrix (ECM) deposition signaling protein, was shown to be a significant component of cardiac fibrosis in Fiona/dko mice. Interestingly, Lysyl oxidase (Lox), known to cross-link collagen, localizes to intercalated discs between cardiomyocytes, and does not localize to areas of fibrosis in either cardiac and skeletal muscle tissue. These studies will allow for the development of more targeted treatments for cardiac fibrosis, and eventually cardiomyopathy for DMD patients.
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Keywords
Duchenne Muscular Dystrophy, Neuromuscular, Extracellular Matrix, Dilated Cardiomyopathy