{Reference Type}: Journal Article
{Title}: Physiological stress improves stem cell modeling of dystrophic cardiomyopathy.
{Author}: Fullenkamp DE;Willis AB;Curtin JL;Amaral AP;Dittloff KT;Harris SI;Chychula IA;Holgren CW;Burridge PW;Russell B;Demonbreun AR;McNally EM;
{Journal}: Dis Model Mech
{Volume}: 17
{Issue}: 6
{Year}: 2024 Jun 1
{Factor}: 5.732
{DOI}: 10.1242/dmm.050487
{Abstract}: Heart failure contributes to Duchenne muscular dystrophy (DMD), which arises from mutations that ablate dystrophin, rendering the plasma membrane prone to disruption. Cardiomyocyte membrane breakdown in patients with DMD yields a serum injury profile similar to other types of myocardial injury with the release of creatine kinase and troponin isoforms. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are highly useful but can be improved. We generated hiPSC-CMs from a patient with DMD and subjected these cells to equibiaxial mechanical strain to mimic in vivo stress. Compared to healthy cells, DMD hiPSC-CMs demonstrated greater susceptibility to equibiaxial strain after 2 h at 10% strain. We generated an aptamer-based profile of proteins released from hiPSC-CMs both at rest and subjected to strain and identified a strong correlation in the mechanical stress-induced proteome from hiPSC-CMs and serum from patients with DMD. We exposed hiPSC-CMs to recombinant annexin A6, a protein resealing agent, and found reduced biomarker release in DMD and control hiPSC-CMs subjected to strain. Thus, the application of mechanical strain to hiPSC-CMs produces a model that reflects an in vivo injury profile, providing a platform to assess pharmacologic intervention.