Fast skeletal myosin binding protein-C expression exacerbates dysfunction in heart failure.

During heart failure (HF), gene and protein expression profiles undergo extensive compensatory and pathological remodeling. We previously observed that fast skeletal myosin binding protein-C (fMyBP-C) is upregulated in diseased mouse hearts. While fMyBP-C shares significant homology with its cardiac paralog, cardiac myosin binding protein-C (cMyBP-C), there are key differences that may affect cardiac function. However, the consequence of cardiac expression of fMyBP-C is unknown. Here, we aim to elucidate the impact of fMyBP-C expression on cardiac function and pathology. To determine the sufficiency of fMyBP-C to cause cardiac dysfunction, we generated cardiac-specific fMyBP-C over-expression mice. These mice were crossed into cMyBP-C null mice to assess the effect of fMyBP-C in the complete absence of cMyBP-C. Finally, fMyBP-C null mice underwent transverse aortic constriction (TAC) to define the requirement of fMyBP-C in HF. We confirmed the upregulation of fMyBP-C in several models of cardiac disease, including lineage tracing models. Low levels of fMyBP-C caused mild cardiac remodeling and sarcomere dysfunction. Exclusive expression of fMyBP-C in a HF model exacerbated cardiac pathology. Furthermore, reduction of fMyBP-C expression by shRNA in HF improved cardiac function. Following pressure overload, fMyBP-C null mice demonstrated greater resistance to cardiac decompensation. Mechanistically, our data suggest the differential regulation of the myosin super-relaxed state by cMyBP-C and fMyBP-C plays a contributing role. These findings suggest the elevated expression of fMyBP-C in diseased hearts is a pathological response. Targeted therapies to prevent upregulation of fMyBP-C may prove beneficial in the treatment of HF.