With an increase in the body’s metabolic demand (e.g., exercise), the heart must increase its pumping performance. To achieve this increased performance, the heart relies on its cardiac reserve, which is the ability to increase its systolic and diastolic function. The mechanism responsible for cardiac reserve is poorly understood. The myofilaments are essential for contraction/relaxation, with troponin I (the inhibitory subunit of troponin, TnI) being a key regulatory protein. Studies have shown that TnI serine 23/24 (S23/S24) phosphorylation is a key mechanism for accelerating relaxation by decreasing Ca2+ sensitivity. However, the role of TnI in cardiac reserve is unknown. For this study, we characterized the systolic and diastolic reserve in TnI S23/S24 phosphorylation-null transgenic mice (S23/S24 mutated to alanine [AA] mice). Even with increased Ca2+ sensitivity, the AA mice exhibited normal function at resting heart rate with no difference in cardiac structure compared with wild type. To examine the role TnI S23/S24 phosphorylation in systolic and diastolic reserve, we assessed hemodynamics via left ventricular catheterization on the Bowditch effect (i.e., an increase in contractile function with increasing heart rate) by increasing heart rate (from 240 to 420 beats per minute) and sympathetic stimulation (dobutamine). Our data exhibited a clear loss of diastolic and systolic reserve in the AA mice with increasing heart rate and dobutamine. Since we observed a clear inability to increase systolic and diastolic function in AA mice, we performed speckle tracking echocardiography to quantitatively characterize function at resting heart rate. We observed that AA mice demonstrated normal systolic function (radial strain rate) and impaired directional diastolic function (reverse radial strain rate) at resting heart rate. We conclude that TnI S23/S24 phosphorylation is essential for cardiac reserve by enhancing systolic and diastolic function. A blunted cardiac reserve leads to heart disease making TnI S23/S24 phosphorylation a potential therapeutic strategy.
Troponin I phosphorylation is essential for cardiac reserve: Calcium Signaling and Excitation–Contraction in Cardiac, Skeletal and Smooth Muscle
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Sarah L. Sturgill, Lorien G. Salyer, Vikram Shettigar, Elizabeth A. Brundage, Brandon J. Biesiadecki, Mark T. Ziolo; Troponin I phosphorylation is essential for cardiac reserve: Calcium Signaling and Excitation–Contraction in Cardiac, Skeletal and Smooth Muscle. J Gen Physiol 5 September 2022; 154 (9): e2021ecc31. doi: https://doi.org/10.1085/2021ecc31
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