Adequate protein turnover is essential for cardiac homeostasis. Different protein quality controls are involved in the maintenance of protein homeostasis, including molecular chaperones and co-chaperones, the autophagy-lysosomal pathway, and the ubiquitin-proteasome system (UPS). In the last decade, a series of evidence has underlined a major function of the UPS in cardiac physiology and disease. Particularly, recent studies have shown that dysfunctional proteasomal function leads to cardiac disorders. Hypertrophic and dilated cardiomyopathies are the two most prevalent inherited cardiomyopathies. Both are primarily transmitted as an autosomal-dominant trait and mainly caused by mutations in genes encoding components of the cardiac sarcomere, including a relevant striated muscle-specific E3 ubiquitin ligase. A growing body of evidence indicates impairment of the UPS in inherited cardiomyopathies as determined by measurement of the level of ubiquitinated proteins, the activities of the proteasome and/or the use of fluorescent UPS reporter substrates. The present review will propose mechanisms of UPS impairment in inherited cardiomyopathies, summarize the potential consequences of UPS impairment, including activation of the unfolded protein response, and underline some therapeutic options available to restore proteasome function and therefore cardiac homeostasis and function. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy".
