Thin filament regulation of cardiac muscle power output: Implications for targets to improve human failing hearts

Phosphorylation of the N-terminal region of cardiac troponin I was found to regulate myofilament power output, and this posttranslational modification can be leveraged to increase power output in myofilaments from human failing hearts. The heart's pumping capacity is determined by myofilament power generation. Power is work done per unit time and measured as the product of force and velocity. At a sarcomere level, these contractile properties are linked to the number of attached cross-bridges and their cycling rate, and many signaling pathways modulate one or both factors. We previously showed that power is increased in rodent permeabilized cardiac myocytes following PKA-mediated phosphorylation of myofibrillar proteins. The current study found that that PKA increased power by similar to 30% in permeabilized cardiac myocyte preparations (n = 8) from human failing hearts. To address myofilament molecular specificity of PKA effects, mechanical properties were measured in rat permeabilized slow-twitch skeletal muscle fibers before and after exchange of endogenous slow skeletal troponin with recombinant human Tn complex that contains cardiac (c)TnT, cTnC and either wildtype (WT) cTnI or pseudo-phosphorylated cTnI at sites Ser23/24Asp, Tyr26Glu, or the combinatorial Ser23/24Asp and Tyr26Glu. We found that cTnI Ser23/24Asp, Tyr26Glu, and combinatorial Ser23/24Asp and Tyr26Glu were sufficient to increase power by similar to 20%. Next, we determined whether pseudo-phosphorylated cTnI at Ser23/24 was sufficient to increase power in cardiac myocytes from human failing hearts. Following cTn exchange that included cTnI Ser23/24Asp, power output increased similar to 20% in permeabilized cardiac myocyte preparations (n = 6) from the left ventricle of human failing hearts. These results implicate cTnI N-terminal phosphorylation as a molecular regulator of myocyte power and could serve as a regional target for small molecule therapy to unmask myocyte power reserve capacity in human failing hearts.

Automated summary

Phosphorylation of cardiac troponin I regulates myofilament power output and can increase power output in failing human hearts. PKA-mediated phosphorylation of myofibrillar proteins increases power in rodent cardiac myocytes. The study also found that specific phospho-residues of cardiac troponin I can increase power in skeletal muscle fibers and cardiac myocytes. These findings suggest that phosphorylation of cardiac troponin I is a molecular regulator of myocyte power and could be targeted for therapy in failing hearts.