The sarcomere is the central force-generating unit of muscle. Its constituents maintain cardiac function through intricately regulated cross-bridge cycling over several billion beats during lifetime. Constant turnover of myofilament proteins is necessary to accomplish this and failing protein quality control is a hallmark of heart failure.
In the current paper Martin and co-workers study the role of Bcl2-associated athanogene 3 (BAG3) in sarcomere function and heart failure. BAG3 is a heat shock protein (HSP) co-chaperone that mediates protein degradation through autophagy. BAG3 mutations cause genetic cardiomyopathy in humans and BAG3 knockout mice have impaired protein turnover and develop heart failure.
First, the authors show that besides reduced calcium sensitivity, myofilaments from DCM hearts also exhibit reduced maximum force (Fmax) generation. Myofilament protein ubiquitination is increased, which is consistent with marking of dysfunctional proteins for degradation. Interestingly, ubiquitinated proteins remain imbedded in the sarcomere and do not co-localize with protein aggregates, potentially blocking incorporation of newly synthesized proteins into the myofilament and thereby affecting myofilament function. Myofilament BAG3 expression was reduced in failing human hearts and while this did not correlate with calcium sensitivity, it did correlate with maximum developed force. This was mirrored in mice haploinsufficient for BAG3. Next, the authors identified that heat shock proteins HSP70 and HSPB8 interact with BAG3 and localize to the sarcomere Z-disc. In skeletal muscle, the BAG3/HSP70/HSPB8 complex is known to engage in chaperone-assisted selective autophagy (CASA). Proteotoxic stress increased expression of this complex at the sarcomere in cultured neonatal rat ventricular myocytes (NRVMs). Finally, AAV9 mediated BAG3 overexpression rescued myofilament function (Fmax generation) in post-ischemic heart failure in mice and this was linked to increased CASA member expression and reduced myofilament ubiquitination. Candidates for BAG3-mediated protein turnover in the myofilament identified in this paper include filamin-C, desmin, alpha-actinin, and myosin binding protein C.
This study highlights the importance of proper protein quality control (or proteostasis) to maintain myofilament function in heart muscle. In constantly working heart muscle, timely exchange of dysfunctional proteins is key, much like exchanging worn parts in an engine. In stressed or failing hearts protein quality control fails and this impairs function. Apparently, BAG3 is not only involved in rather rare forms of hereditary cardiomyopathies - the mechanism laid out by the authors is likely important in much more frequent acquired (here: ischemic) heart failure. Improving proteostasis holds promise as future therapeutic approach in heart failure and this exciting study provides new potential targets.