Expression of slow skeletal TnI in adult mouse hearts confers metabolic protection to ischemia

Pound, Kayla M; Arteaga, Grace M.; Fasano, Mathew; Wilder, Tanganyika; Fischer, Susan K.; Warren, Chad M.; Wende, Adam R.; Farjah, Mariam; Solaro, R. John; Lewandowski, E. Douglas

doi:10.1016/j.yjmcc.2011.05.014

Cited by 18 publications

(22 citation statements)

References 40 publications

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“…It is unlikely though that an energy deprivation is responsible for the arrhythmias in the ssTnI model, which undergoes metabolic remodeling resulting in increased glycolysis compared to controls. We have previously demonstrated that TG-ssTnI hearts are highly resistant to global ischemia with preservation of ATP concentration as a result of increased glycolysis [22]. We think in the case of TG-ssTnI hearts it is highly unlikely that there are localized energy deficits, and that remodeling of Ca 2+ fluxes is more likely to be responsible.…”

Section: Discussionmentioning

confidence: 98%

“…Moreover, we have previously reported that compared to controls, TG-ssTnI cardiac myofilaments demonstrate a substantial increase in Ca 2+ -sensitivity [19], a resistance to desensitization by acidic pH [20], and a blunted response to changes in sarcomere length [21]. Hearts of TG-ssTnI mice are also significantly resistant to ATP loss in global ischemia associated with remodeling to a relatively high glycolytic phenotype compared to controls [22]. We studied isolated cardiac myocytes from relatively young mice (5~7 months old) and relatively old mice (11~13 months old).…”

Section: Introductionmentioning

confidence: 99%

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Influence of a constitutive increase in myofilament Ca2+-sensitivity on Ca2+-fluxes and contraction of mouse heart ventricular myocytes

Puglisi

Goldspink

Gomes

et al. 2014

Archives of Biochemistry and Biophysics

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Chronic increases in myofilament Ca2+-sensitivity in the heart are known to alter gene expression potentially modifying Ca2+-homeostasis and inducing arrhythmias. We tested age-dependent effects of a chronic increase in myofilament Ca2+-sensitivity on induction of altered alter gene expression and activity of Ca2+ transport systems in cardiac myocytes. Our approach was to determine the relative contributions of the major mechanisms responsible for restoring Ca2+ to basal levels in field stimulated ventricular myocytes. Comparisons were made from ventricular myocytes isolated from non-transgenic (NTG) controls and transgenic mice expressing the fetal, slow skeletal troponin I (TG-ssTnI) in place of cardiac TnI (cTnI). Replacement of cTnI by ssTnI induces an increase in myofilament Ca2+-sensitivity. Comparisons included myocytes from relatively young (5–7 months) and older mice (11–13 months). Employing application of caffeine in normal Tyrode and in 0Na+ 0Ca2+ solution, we were able to dissect the contribution of the sarcoplasmic reticulum Ca2+ pump (SR Ca2+-ATPase), the Na+/Ca2+ exchanger (NCX), and “slow mechanisms” representing the activity of the sarcolemmal Ca2+ pump and the mitochondrial Ca2+ uniporter. The relative contribution of the SR Ca2+-ATPase to restoration of basal Ca2+levels in younger TG-ssTnI myocytes was lower than in NTG (81.12 ± 2.8% vs 92.70 ± 1.02%), but the same in the older myocytes. Younger and older NTG myocytes demonstrated similar contributions from the SR Ca2+-ATPase and NCX to restoration of basal Ca2+. However, the slow mechanisms for Ca2+ removal were increased in the older NTG (3.4 ± 0.3%) vs the younger NTG myocytes (1.4 ± 0.1%). Compared to NTG, younger TG-ssTnI myocytes demonstrated a significantly bigger contribution of the NCX (16 ± 2.7% in TG vs 6.9 ± 0.9% in NTG) and slow mechanisms (3.3 ± 0.4% in TG vs 1.4 ± 0.1% in NTG). In older TG-ssTnI myocytes the contributions were not significantly different from NTG (NCX: 4.9 ± 0.6% in TG vs 5.5±0.7% in NTG; slow mechanisms: 2.5 ± 0.3% in TG vs 3.4 ± 0.3% in NTG). Our data indicate that constitutive increases in myofilament Ca2+-sensitivity alter the relative significance of the NCX transport system involved in Ca2+-homeostasis only in a younger group of mice. This modification may be of significance in early changes in altered gene expression and electrical stability hearts with increased myofilament Ca-sensitivity.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Influence of a constitutive increase in myofilament Ca2+-sensitivity on Ca2+-fluxes and contraction of mouse heart ventricular myocytes

Puglisi

Goldspink

Gomes

et al. 2014

Archives of Biochemistry and Biophysics

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“…This protein is usually expressed highly in the prenatal mammalian heart, but is rapidly downregulated after birth when hearts begin to express predominantly cTnI [19]. Transgenic mice overexpressing ssTnI in their hearts maintain ATP production during ischemia by upregulating glycolytic activity [39]. Expression of ssTnI in the adult mouse heart during heart failure can also help maintain systolic function during respiratory hypercapnia.…”

Section: Discussionmentioning

confidence: 99%

“…This harsh, energetically constrained habitat of highly variable oxygen availability and high levels of carbon dioxide relative to that experienced above ground is, thus likely to have shaped both their metabolic physiology and their cardiovascular system. In many cardiovascular disease states, adult mammalian hearts, like those of healthy naked mole-rats, also have to contend with the stressful conditions of hypoxia and hypercapnia [23, 39, 45]. Such diseased states are also responsible for disrupting cardiac homeostasis and causing dysregulation of the contractile protein signature [39, 42, 43].…”

Section: Introductionmentioning

confidence: 99%

The naked mole-rat exhibits an unusual cardiac myofilament protein profile providing new insights into heart function of this naturally subterranean rodent

Grimes

Barefield

Kumar

et al. 2017

Pflugers Arch - Eur J Physiol

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The long-lived, hypoxic-tolerant naked mole-rat well-maintains cardiac function over its three-decade-long lifespan and exhibits many cardiac features atypical of similar-sized laboratory rodents. For example, they exhibit low heart rates and resting cardiac contractility, yet have a large cardiac reserve. These traits are considered ecophysiological adaptations to their dank subterranean atmosphere of low oxygen and high carbon dioxide levels and may also contribute to negligible declines in cardiac function during aging. We asked if naked mole-rats had a different myofilament protein signature to that of similar-sized mice that commonly show both high heart rates and high basal cardiac contractility. Adult mouse ventricles predominantly expressed α-myosin heavy chain (97.9 ± 0.4%). In contrast, and more in keeping with humans, β myosin heavy chain was the dominant isoform (79.0 ± 2.0%) in naked mole-rat ventricles. Naked mole-rat ventricles diverged from those of both humans and mice, as they expressed both cardiac and slow skeletal isoforms of troponin I. This myofilament protein profile is more commonly observed in mice in utero and during cardiomyopathies. There were no species differences in phosphorylation of cardiac myosin binding protein-C or troponin I. Phosphorylation of both ventricular myosin light chain 2 and cardiac troponin T in naked mole-rats was approximately half that observed in mice. Myofilament function was also compared between the two species using permeabilized cardiomyocytes. Together, these data suggest a cardiac myofilament protein signature that may contribute to the naked mole-rat’s suite of adaptations to its natural subterranean habitat.

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“…It was previously demonstrated that replacement of the adult isoform of cardiac troponin I (cTnI) with the isoform expressed in the fetal heart, slow skeletal troponin I (ssTnI), confers ischemic protection by delaying the decline in myocardial ATP levels 15 . ATP stores were maintained through an upregulation of the glycolytic rate during ischemia while no phenotype was evident at baseline.…”

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confidence: 99%

Metabolic Efficiency Promotes Protection From Pressure Overload in Hearts Expressing Slow Skeletal Troponin I

Carley

Taglieri

et al. 2015

Circ: Heart Failure

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Background The failing heart displays increased glycolytic flux that is not matched by a commensurate increase in glucose oxidation. This mismatch induces increased anaplerotic flux and inefficient glucose metabolism. We previously found adult transgenic mouse hearts expressing the fetal troponin I isoform, (ssTnI) to be protected from ischemia by increased glycolysis. In the present study we investigated the metabolic response of adult mouse hearts expressing ssTnI to chronic pressure overload. Methods and Results At 2–3 months of age ssTnI mice or their nontransgenic (NTG) littermates underwent aortic constriction (TAC). TAC induced a 25% increase in NTG heart size but only a 7% increase in ssTnI hearts (P<0.05). NTG TAC developed diastolic dysfunction (65% increased E/A ratio), while the E/A ratio actually decreased in ssTnI TAC. Isolated perfused hearts from NTG TAC mice showed reduced cardiac function and reduced PCr:ATP (16% reduction), but ssTnI TAC hearts maintained cardiac function and energy charge. Contrasting NTG TAC, ssTnI TAC significantly increased glucose oxidation at the expense of palmitate oxidation, preventing the increase in anaplerosis observed in NTG TAC hearts. Elevated glucose oxidation was mediated by a reduction in PDK4 expression, enabling PDH to compete against anaplerotic enzymes for pyruvate carboxylation. Conclusions Expression of a single fetal myofilament protein into adulthood in the ssTnI-TG mouse heart induced downregulation of the gene expression response for PDK to pressure overload. The consequence of elevated pyruvate oxidation in ssTnI during TAC reduced anaplerotic flux, ameliorating inefficiencies in glucose oxidation, with energetic and functional protection against cardiac decompensation.

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Expression of slow skeletal TnI in adult mouse hearts confers metabolic protection to ischemia

Cited by 18 publications

References 40 publications

Influence of a constitutive increase in myofilament Ca2+-sensitivity on Ca2+-fluxes and contraction of mouse heart ventricular myocytes

Influence of a constitutive increase in myofilament Ca2+-sensitivity on Ca2+-fluxes and contraction of mouse heart ventricular myocytes

The naked mole-rat exhibits an unusual cardiac myofilament protein profile providing new insights into heart function of this naturally subterranean rodent

Metabolic Efficiency Promotes Protection From Pressure Overload in Hearts Expressing Slow Skeletal Troponin I

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