Early targets and progressive deterioration in cardiac performance in response to chronically modified cardiac
Vani S Ravichandran1,2, Tabea M Schatz1, Emily Lavey1
1Department of Cardiac Surgery, University of Michigan Medical School, Ann Arbor, Michigan, United States.
Abstract:
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.NEW & NOTEWORTHY 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.
Insights
Chronic cardiac troponin I phosphorylation causes heart failure by impairing cardiac contractility and initiating mitochondrial dysfunction. A novel peptide therapy improved survival and slowed disease progression in mouse models.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Cardiac Physiology
Background:
- Cardiac troponin I (cTnI) phosphorylation at Ser43/45 increases in heart failure (HF).
- Chronic cTnI phosphorylation impairs cardiac myocyte contractility, but in vivo effects remain unclear.
Purpose of the Study:
- To investigate the in vivo impact of chronic cTnI Ser43/45 phosphorylation on cardiac function and remodeling.
- To explore early mitochondrial alterations driven by cTnI phosphorylation in heart failure progression.
Main Methods:
- Generated transgenic mouse lines expressing phospho-mimetic cTnIS43/45D (SD) at varying levels.
- Assessed in vivo and cellular contractile function, cardiac structure, and mitochondrial parameters.
- Evaluated the therapeutic potential of a novel peptide derived from elamipretide.
Main Results:
- Transgenic mice developed progressive cardiac dysfunction, structural remodeling, and accelerated deterioration to end-stage HF.
- cTnISD induced early mitochondrial dysfunction, including reduced DNA, altered gene expression, and increased oxidative stress, preceding major cardiac remodeling.
- Mitochondrial ultrastructure changes favoring fusion were observed, and the elamipretide-derived peptide improved survival and slowed disease progression.
Conclusions:
- Chronic cTnI S43/45 phosphorylation drives cardiac dysfunction and initiates early mitochondrial responses.
- Mitochondrial dysfunction is a key early driver of progressive cardiac deterioration to end-stage heart failure.
- Targeting mitochondrial pathways offers a potential therapeutic strategy for heart failure.
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