scholarly journals Increased myofilament calcium sensitivity is associated with decreased cardiac troponin I phosphorylation in the diabetic rat heart

2021 ◽  
Author(s):  
Angela C. Greenman ◽  
Gary M. Diffee ◽  
Amelia S. Power ◽  
Gerard T. Wilkins ◽  
Olivia M. S. Gold ◽  
...  
Keyword(s):  
Cardiac Troponin ◽  
Rat Heart ◽  
Troponin I ◽  
Calcium Sensitivity ◽  
Cardiac Troponin I ◽  
Diabetic Rat ◽  
Myofilament Calcium Sensitivity

scholarly journals Increased myofilament calcium sensitivity is associated with decreased cardiac troponin I phosphorylation in the diabetic rat heart

2021 ◽  
Author(s):  
Angela Greenman ◽  
Gary M. Diffee ◽  
Amelia Power ◽  
Gerard T. Wilkins ◽  
Olivia M. S. Gold ◽  
...  
Keyword(s):  
Cardiac Troponin ◽  
Troponin I ◽  
Calcium Sensitivity ◽  
Cardiac Troponin I ◽  
Diabetic Heart ◽  
Diabetic Rat ◽  
Zdf Rat ◽  
Regulation Of Contraction ◽  
Systolic And Diastolic Function ◽  
Myofilament Calcium Sensitivity

Abstract Background The diabetic heart has impaired systolic and diastolic function independent of other comorbidities. The availability of calcium is altered, but does not fully explain the cardiac dysfunction seen in the diabetic heart. Thus, we explored if myofilament protein regulation of contraction is altered. Methods Calcium sensitivity (pCa50) was measured in Zucker Diabetic Fatty (ZDF) rat hearts at the initial stage of diabetes (12-week-old) and after 8 weeks of uncontrolled hyperglycaemia (20-week-old) and in non-diabetic (nDM) littermates. Skinned cardiomyocytes were connected to a capacitance-gauge transducer and a torque motor to measure force as a function of pCa (-log[Ca2+]). Fluorescent gel stain (ProQ Diamond) was used to measure total protein phosphorylation. Specific phospho-sites on cardiac troponin I (cTnI) and total cTnI O-GlcNAcylation were quantified using immunoblot. Results pCa50 was greater in both 12- and 20-week-old diabetic (DM) rats compared to nDM littermates (p = 0.0005). Total cTnI and cTnI serine 23/24 phosphorylation were lower in DM rats (p = 0.003 & p = 0.01, respectively), but cTnI O-GlcNAc protein expression was not different. pCa50 is greater in DM rats and corresponds with an overall reduction in cTnI phosphorylation. Conclusions These findings indicate that myofilament calcium sensitivity is increased and cTnI phosphorylation is reduced in ZDF DM rats, which suggests an important role for cTnI phosphorylation in the DM heart.

Abstract 219: Histidine Substituted Cardiac Troponin I (a164h) Improves Survival And Protects Cardiac Contractility During Acute Hypoxia In The Aged Murine Heart.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Nathan Palpant ◽  
Sharlene Day ◽  
Kimber Converso ◽  
Joseph Metzger
Keyword(s):  
Cardiac Troponin ◽  
Troponin I ◽  
Acute Hypoxia ◽  
Cardiac Contractility ◽  
Systolic Pressure ◽  
Calcium Sensitivity ◽  
The Elderly ◽  
Cardiac Troponin I ◽  
Pump Failure ◽  
Myofilament Calcium Sensitivity

Contractile dysfunction associated with ischemia is a significant cause of morbidity and mortality particularly in the elderly. Strategies designed to protect the aged heart from ischemia-mediated pump failure are needed. We have generated transgenic (Tg) mice expressing a modified form of adult cardiac troponin I, the Ca ++ -activated molecular switch of the myofilament. Consonant with the fetal isoform, this transgene encodes a histidine substitution (A164H) in the critical switch domain of TnI thus increasing myofilament calcium sensitivity in a pH-dependent manner. We hypothesized that aged mice (24 months), intrinsically susceptible to myocardial dysfunction, would retain improved cardiac contractility at baseline and during an acute hypoxic challenge by means of myofilament-mediated calcium sensitization. Methods/Results: At baseline, by echocardiography, Tg hearts had increased systolic function, with a 26% higher mean ejection fraction compared to nontransgenic (Ntg) mice: 75 ± 3% [Tg: n = 13] vs. 63 ± 4% [Ntg: n = 12], P < 0.05, with no differences in diastolic function between the groups. To study the effects of acute hypoxia on cardiac hemodynamics mice underwent microconductance Millar catheterization while ventilated with 12% oxygen. Aged Tg mice had improved survival compared to Ntg mice: time to pump failure (65% of baseline peak systolic pressure) 11.59 ± 1.25 min. [Tg: n = 3] vs. 4.11 ± 1.90 min. [Ntg: n = 3], P < 0.05. After four minutes of hypoxia, Tg mice had markedly improved cardiac contractility compared to Ntg mice with increased stroke volume (30.05 ± 4.49 uL [Tg] vs. 13.23 ± 3.21 uL [Ntg], P < 0.05), end systolic pressure (106.09 ± 11.81 mmHg [Tg] vs. 64.49 ± 4.05 mmHg [Ntg], P < 0.05) and rate of positive left ventricular pressure development (12958.66 ± 2544.68 mmHg/sec [Tg] vs. 5717.00 ± 745.67 mmHg/sec [Ntg], P = 0.05). Conclusion: An alteration in myofilament calcium sensitivity via a pH-responsive histidine button in cardiac troponin I augments baseline heart function in Tg mice over their lifetime. During acute hypoxia, cTnI A164H improves survival in aged mice by maintaining cardiac contractility, and thus holds promise for the design of gene therapeutics to treat pump failure associated with acute ischemic events in the elderly.

scholarly journals Calcium Sensitivity, Force Frequency Relation and Cardiac Troponin I: Critical Role of PKA and PKC Phosphorylation Sites

2010 ◽  
Vol 98 (3) ◽  
pp. 356a
Author(s):  
Genaro A. Ramirez-Correa ◽  
Sonia Cortassa ◽  
Brian Stanley ◽  
Wei Dong Gao ◽  
Anne M. Murphy
Keyword(s):  
Cardiac Troponin ◽  
Troponin I ◽  
Critical Role ◽  
Calcium Sensitivity ◽  
Cardiac Troponin I ◽  
Phosphorylation Sites ◽  
Force Frequency ◽  
Frequency Relation

Cardiac Troponin I and Tension Generation of Skinned Fibres in the Developing Rat Heart

1994 ◽  
Vol 26 (9) ◽  
pp. 1123-1131 ◽  
Author(s):  
S. Bartel ◽  
I. Morano ◽  
H.D. Hunger ◽  
H. Katus ◽  
H.T. Pask ◽  
...  
Keyword(s):  
Cardiac Troponin ◽  
Rat Heart ◽  
Troponin I ◽  
Cardiac Troponin I ◽  
Skinned Fibres ◽  
Tension Generation ◽  
Developing Rat

Developmental expression of rat cardiac troponin I mRNA

Development ◽  
1991 ◽  
Vol 112 (4) ◽  
pp. 1041-1051
Author(s):  
S. Ausoni ◽  
C. De Nardi ◽  
P. Moretti ◽  
L. Gorza ◽  
S. Schiaffino
Keyword(s):  
Cardiac Troponin ◽  
Troponin I ◽  
Mammalian Species ◽  
Calcium Sensitivity ◽  
Cardiac Troponin I ◽  
Developmental Expression ◽  
Adrenergic Stimulation ◽  
Adult Heart ◽  
Amino Terminal ◽  
The Difference

We have isolated and sequenced a full-length cDNA clone of rat cardiac troponin I (TnI). The amino acid sequence of rat cardiac TnI is highly similar to that of other mammalian species in the portion of the molecule (residues 33–210) that is also homologous to skeletal muscle TnI isoforms. In contrast, a lower degree of similarity is present in the cardiac TnI-specific amino terminal extension (residues 1–32). This region contains a conserved serine residue that has been shown to be selectively phosphorylated by cAMP-dependent protein kinase. Cardiac TnI mRNA is weakly expressed in the 18-day fetal heart and accumulates in neonatal and postnatal stages. No difference can be demonstrated between TnI mRNAs present in fetal and postnatal heart by RNAase protection assays. The fetal and neonatal, but not the adult heart, contain significant amounts of slow skeletal TnI transcripts, detected by oligonucleotide probes specific for the 5′- and 3′-untranslated regions of slow skeletal TnI mRNA. In situ hybridization studies show that cardiac and slow skeletal TnI mRNAs are coexpressed in the rat heart from embryonic day 11 throughout fetal and perinatal stages. Changes in troponin isoform expression during development may be responsible for the difference in calcium sensitivity and in the response to beta-adrenergic stimulation between fetal and adult heart.

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