The lack of Troponin I Ser-23/24 phosphorylation is detrimental to in vivo cardiac function and exacerbates cardiac disease. (March 2023)

• Record Type: Journal Article
• Authors: Salhi, Hussam E.; Shettigar, Vikram; Salyer, Lorien; Sturgill, Sarah; Brundage, Elizabeth A.; Robinett, Joel; Xu, Zhaobin; Abay, Eaman; Lowe, Jeovanna; Janssen, Paul M.L.; Rafael-Fortney, Jill A.; Weisleder, Noah; Ziolo, Mark T.; Biesiadecki, Brandon J.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 176(2023)
• Page Start: 84
• Page End: 96
• Publication Date: 2023-03
• Subjects: Troponin I -- Phosphorylation -- Cardiac -- In vivo -- Heart rate -- Sympathetic; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2023.01.010
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Troponin I (TnI) is a key regulator of cardiac contraction and relaxation with TnI Ser-23/24 phosphorylation serving as a myofilament mechanism to modulate cardiac function. Basal cardiac TnI Ser-23/24 phosphorylation is high such that both increased and decreased TnI phosphorylation may modulate cardiac function. While the effects of increasing TnI Ser-23/24 phosphorylation on heart function are well established, the effects of decreasing TnI Ser-23/24 phosphorylation are not clear. To understand the in vivo role of decreased TnI Ser-23/24 phosphorylation, mice expressing TnI with Ser-23/24 mutated to alanine (TnI S23/24A) that lack the ability to be phosphorylated at these residues were subjected to echocardiography and pressure-volume hemodynamic measurements in the absence or presence of physiological (pacing increasing heart rate or adrenergic stimulation) or pathological (transverse aortic constriction (TAC)) stress. In the absence of pathological stress, the lack of TnI Ser-23/24 phosphorylation impaired systolic and diastolic function. TnI S23/24A mice also had an impaired systolic and diastolic response upon stimulation increased heart rate and an impaired adrenergic response upon dobutamine infusion. Following pathological cardiac stress induced by TAC, TnI S23/24A mice had a greater increase in ventricular mass, worse diastolic function, and impaired systolic and diastolic function upon increasing heart rate. These findings demonstrate that mice lacking the ability to phosphorylate TnI at Ser-23/24 have impaired in vivo systolic and diastolic cardiac function, a blunted cardiac reserve and a worse response to pathological stress supporting decreased TnI Ser23/24 phosphorylation is a modulator of these processes in vivo . Graphical abstract: Unlabelled Image Highlights: The loss of cardiac TnI Ser-23/24 phosphorylation impairs in vivo systolic and diastolic function TnI Ser-23/24 phosphorylation loss impairs increased systolic and diastolic function upon increasing heart rate and adrenergic stimulation TnI Ser-23/24 phosphorylation loss impairs diastolic function and blunts increased function upon increased demand following TAC cardiac stress