UC Santa Barbara

Duchenne muscular dystrophy (DMD) is a devastating X-linked genetic disorder that affects 1 in 3500 males. Characterized by progressive muscle degeneration that culminates in respiratory failure and dilated cardiomyopathy, DMD is caused by a lack of dystrophin, a protein that provides structural support between the sarcomeric cytoskeleton and the extracellular matrix. Loss of dystrophin leads to a leaky plasma membrane, contractile stress, and disruption of cellular homeostasis. However, the molecular mechanism that eventually leads to cell death remains to be explored. Recently, the Blau lab discovered a pathogenic link between DMD cardiomyopathy and telomere dysfunction. While mdx mice that lack functional dystrophin do not exhibit dilated cardiomyopathy as in human patients, when crossed with mTR mice that lack the RNA component of telomerase (TERC), mdx mice with “humanized” telomere lengths fully manifested the severe muscle wasting and cardiac failure seen in patients. Notably, the longer telomeres, characteristic of mice, appear to be cardioprotective. Importantly, we observed telomere shortening in cardiomyocytes, but not other cell types, of DMD patients compared to age-matched controls. Preliminary data suggests that contractile stress due to the lack of dystrophin leads to a pathogenic feed-forward loop which ultimately culminates in cardiomyocyte cell death. Using human iPS cells derived from DMD patients, we have modeled telomere shortening and aspects of cardiomyocyte dysfunction characteristic of DMD, including aberrant calcium transients, mechanical stress, and arrhythmia. By comparing cardiomyocytes derived from DMD iPS cells with those from CRISPR-corrected isogenic controls on patterned bioengineered hydrogel platforms of varying stiffness, we can study the role of fibrotic stiffening in the myocardium in the premature demise of DMD cardiomyocytes. Pinpointing the early molecular events that trigger the pathogenic feed-forward loop will provide strategies for intervention to ameliorate DMD cardiomyopathy.