Overview of the association between JAG1 overexpression and phenotypic changes in dystrophin-deficient muscle tissue

Topic:

Pre-Clinical Research

Poster Number: 155 M

Author(s):

Felipe de Souza Leite, PhD, Boston Children's Hospital & Harvard Medical School, Matthias Lambert, PhD, Vertex, Tracy Yuanfan Zhang, PhD, Boston Children's Hospital & Harvard Medical School, James R. Conner, Boston Children's Hospital & Harvard Medical School, Joao A. Paulo, PhD, Harvard Medical School, Sheldon Furtado Oliveira, Boston Children's Hospital & Harvard Medical School, Sanjukta Guha Thakurta, PhD, Harvard Medical School, Jennifer Bowles, Boston Children's Hospital & Harvard Medical School, Emanuela Gussoni, PhD, Boston Children's Hospital & Harvard Medical School, Steven P. Gygi, PhD, Harvard Medical School, Jeffrey J. Widrick, PhD, Boston Children's Hospital & Harvard Medical School, Louis M. Kunkel, PhD, Boston Children's Hospital & Harvard Medical School

Introduction: The identification of JAG1 as a genetic modifier in golden retriever muscular dystrophy (GRMD) dogs that did not follow typical disease progression has led to different studies examining the connection between JAG1 and muscles lacking dystrophin. Research on cells, dogs, fish, and mice has shown that overexpression of JAG1 produces noticeable differences compared to controls. Here, we show our recent findings in mice overexpressing human JAG1. Methods: We generated a dystrophin-deficient mouse model overexpressing human JAG1 (mdx5cv-JAG1) and compared it with controls mdx5cv. The animals were evaluated at three distinct time intervals: one month, four months, and twelve months. TA muscles were used for histology and in situ physiology. Quadriceps muscles were used for proteomics studies. Results: (1) After four months, mdx5cv-JAG1 mice showed an increased muscle weight to body weight ratio. (2) Histological analyses showed that over time, muscles mdx5cv-JAG1 display higher numbers of myofibers and a smaller area of fibrotic tissues. In situ physiological assessments indicated enhanced force generation in mdx5cv-JAG1 muscles from animals aged four and twelve months. (3) Muscle proteomics at three time points reveals interactions with dysferlin and Nsd1. (4) A subset of animals that exhibited supra levels of JAG1 demonstrated a more severe phenotype compared to the control group. Discussion: Exploring JAG1 to enhance the clinical progression of DMD patients appears promising. Nevertheless, our findings indicate that a more comprehensive understanding of its biological mechanisms is necessary.