Early targets and progressive deterioration in cardiac performance in response to chronically modified cardiac troponin I.

Protein kinase C (PKC) targeted thin filament cardiac troponin I (cTnI) Ser43/45 phosphorylation (p-S43/45) increases during heart failure (HF). Chronic cTnI p-S43/45 causes contractile dysfunction in cardiac myocytes, but the in vivo impact is less clear. To investigate the in vivo impact of this cluster, three lines of transgenic mice were generated with high (HE-), moderate (ME-), and low (LE-) phosphomimetic cTnIS43/45D (SD) replacement of endogenous cTnI within sarcomere thin filament. Each mouse line developed chronic in vivo and/or cellular contractile dysfunction, which initiated structural remodeling and a progressive deterioration in cardiac function. Higher cTnISD replacement levels accelerated the rate of deterioration and progression to end-stage heart failure. In further work, cTnISD initiated sarcomere communication to produce early alterations in mitochondria before the progressive deterioration in cardiac performance. Specifically, early reductions developed in mitochondrial/nuclear DNA, mitochondrial master regulator gene expression, electron transport proteins, and antioxidants along with increased mitochondria-related oxidative stress before extensive remodeling in cTnISD mice. In addition, cTnISD mice developed early differences in mitochondrial ultrastructure and evidence favoring fusion over fission compared with nontransgenic (Ntg) littermates. A second-generation peptide derived from elamipretide improved survival and slowed the progression of remodeling and contractile dysfunction. Overall, the results demonstrate that chronic cTnISD causes cardiac dysfunction and initiates early mitochondrial responses that serve as important drivers of progressive deterioration in cardiac performance to end-stage HF.Elevated cardiac troponin I (cTnI) Ser43/45 phosphorylation accompanies human heart failure. A mouse model with phosphomimetic substitutions shows that chronic sarcomere replacement with cTnI Ser43/45Asp causes cardiac dysfunction and initiates early downstream changes in mitochondria before the onset of progressive remodeling and progressive deterioration in cardiac performance. These early alterations include differences in mitochondrial architecture and function and oxidative stress. Early mitochondrial targeting improves survival and cardiac function.