Asuka Eguchi1, Alex C. Y. Chang1, Gaspard Pardon1, Foteini Mourkioti2, Beth L. Pruitt3, Daniel Bernstein4, and Helen M. Blau1
1Baxter Laboratory, Stanford University, Stanford, CA; 2Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA ; 3Dept. Mechanical Engineering, University of California, Santa Barbara, Santa Barbara, CA ; 4Dept. of Pediatrics, Stanford University, Stanford, CA
Duchenne muscular dystrophy (DMD) is caused by a lack of dystrophin, and DMD patients face muscle degeneration that culminates in loss of respiratory muscle strength and dilated cardiomyopathy. Dystrophin serves several distinct functions, including maintenance of cell membrane integrity, structural support to the extracellular matrix, and protection against oxidative stress. While the function of dystrophin is well understood, the molecular events that lead to cardiomyocyte cell death remains to be explored. A severe limitation in the field is that the mouse model lacking functional dystrophin (mdx) does not exhibit cardiac symptoms seen in humans. For unknown reasons, mice maintain much longer telomeres than humans. When our lab generated mice with “humanized” telomeres, by crossing mdx mice with mice lacking telomerase, dilated cardiomyopathy as seen in patients was recapitulated. Preliminary data suggests that contractile stress due to the lack of dystrophin leads to a pathogenic condition of oxidative stress, telomere shortening, and mitochondrial dysfunction. Using human iPS cells derived from DMD patients, we observe telomere shortening in human DMD cardiomyocytes compared to CRISPR-corrected controls. Understanding the earliest molecular events that trigger pathogenesis will enable identification of strategies for intervention to ameliorate all forms of DMD caused by a wide range of mutations in dystrophin.
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