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Cardiac myocyte death during heart failure is particularly detrimental, given that cardiac muscle exhibits limited regenerative potential. Protein aggregation was previously observed in end-stage heart failure, suggesting protein-misfolding in cardiac myocytes as a contributor to the disease process. However, the relationship between protein-misfolding, cardiac myocyte death, and myocardial dysfunction is yet to be clearly established. Here, we showed that protein synthesis and the unfolded protein response (UPR) declined as a function of mammalian postnatal development, especially in tissues with low mitotic activity, such as the heart. A deeper examination in animals models showed that compared to neonatal cardiac myocytes, adult cardiac myocytes expressed lower levels of the adaptive UPR transcription factor, ATF6, as well as lower levels of numerous ATF6-regulated genes, which was associated with susceptibility to ER stress-induced cell death. Further reduction of the ATF6-dependent gene program in ATF6 knock-out mice led to the accumulation of misfolded proteins in the myocardium and impaired myocardial function in response to cardiac stress, indicating that ATF6 plays a critical adaptive role in the setting of cardiac disease. Thus, strategies to increase ATF6 aimed at balancing proteostasis in cardiac myocytes might be a fruitful avenue for the development of novel therapies for heart disease and other age-associated diseases.HighlightsThe unfolded protein response (UPR) declines as a function of age in adult mammalian tissues with low mitotic activity, such as the heartDecreases in the UPR in adult cardiac myocytes is associated with impaired survival during ER stressATF6 loss of function in adult hearts increases protein misfolding and cardiac disfunction during stress |
