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Acetate transiently inhibits myocardial contraction by increasing mitochondrial calcium uptake.

Schooley JF, Namboodiri AM, Cox RT, Bünger R, Flagg TP - BMC Physiol. (2014)

Bottom Line: Acute exposure of myocytes to 10 mM sodium acetate caused a marked, but transient, decrease in systolic sarcomere shortening (1.49 ± 0.20% vs. 5.58 ± 0.49% in control), accompanied by a significant increase in diastolic sarcomere length (1.81 ± 0.01 μm vs. 1.77 ± 0.01 μm in control), with a near linear dose response in the 1-10 mM range.Unlike palmitate, acetate caused no change in action potential duration; however, acetate markedly increased mitochondrial Ca(2+) uptake.Lehninger and others have previously demonstrated that the anions of weak aliphatic acids such as acetate stimulate Ca(2+) uptake in isolated mitochondria.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, Physiology, and Genetics, Uniformed Services University for the Health Sciences, 4301 Jones Bridge Road, Rm. C-2114, Bethesda, 20814, MD, USA. James.Schooley@usuhs.edu.

ABSTRACT

Background: There is a close relationship between cardiovascular disease and cardiac energy metabolism, and we have previously demonstrated that palmitate inhibits myocyte contraction by increasing Kv channel activity and decreasing the action potential duration. Glucose and long chain fatty acids are the major fuel sources supporting cardiac function; however, cardiac myocytes can utilize a variety of substrates for energy generation, and previous studies demonstrate the acetate is rapidly taken up and oxidized by the heart. In this study, we tested the effects of acetate on contractile function of isolated mouse ventricular myocytes.

Results: Acute exposure of myocytes to 10 mM sodium acetate caused a marked, but transient, decrease in systolic sarcomere shortening (1.49 ± 0.20% vs. 5.58 ± 0.49% in control), accompanied by a significant increase in diastolic sarcomere length (1.81 ± 0.01 μm vs. 1.77 ± 0.01 μm in control), with a near linear dose response in the 1-10 mM range. Unlike palmitate, acetate caused no change in action potential duration; however, acetate markedly increased mitochondrial Ca(2+) uptake. Moreover, pretreatment of cells with the mitochondrial Ca(2+) uptake blocker, Ru-360 (10 μM), markedly suppressed the effect of acetate on contraction.

Conclusions: Lehninger and others have previously demonstrated that the anions of weak aliphatic acids such as acetate stimulate Ca(2+) uptake in isolated mitochondria. Here we show that this effect of acetate appears to extend to isolated cardiac myocytes where it transiently modulates cell contraction.

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Concentration-dependence of acetate effect on fractional shortening and diastolic sarcomere length. (A) Single averaged contractions acquired in experiments as described in Figure 1 at different concentrations of sodium acetate. Contractions in normal Tyrode (Control, dotted line) and at 2 minutes following exposure to acetate solution (Acetate, solid line) are shown. 10 mM NaCl, instead of sodium acetate, was added to normal Tyrode to collect the zero acetate data. (B) Acetate concentration response curve for maximum contraction inhibition. Data were fit with a modified Hill equation (solid line): FS/FS0 = 1/(1 + ([Acetate]/IC50)h), where IC50 is the half-maximal inhibitory concentration of acetate (IC50 = 5.6 mM) and h is the Hill coefficient (h = 1.3). (C) There was no apparent acetate concentration dependence on diastolic sarcomere length.
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Fig2: Concentration-dependence of acetate effect on fractional shortening and diastolic sarcomere length. (A) Single averaged contractions acquired in experiments as described in Figure 1 at different concentrations of sodium acetate. Contractions in normal Tyrode (Control, dotted line) and at 2 minutes following exposure to acetate solution (Acetate, solid line) are shown. 10 mM NaCl, instead of sodium acetate, was added to normal Tyrode to collect the zero acetate data. (B) Acetate concentration response curve for maximum contraction inhibition. Data were fit with a modified Hill equation (solid line): FS/FS0 = 1/(1 + ([Acetate]/IC50)h), where IC50 is the half-maximal inhibitory concentration of acetate (IC50 = 5.6 mM) and h is the Hill coefficient (h = 1.3). (C) There was no apparent acetate concentration dependence on diastolic sarcomere length.

Mentions: To test whether the short chain fatty acid, acetate, exerts negative inotropic effects, we continuously monitored average sarcomere length in isolated mouse cardiomyocytes acutely exposed to Tyrode solution containing 10 mM sodium acetate. Three major consequences of acetate exposure were observed. Figure 1 shows that acetate caused a transient decrease in active sarcomere shortening. At two minutes following acetate application, fractional shortening was markedly decreased from 5.6 ± 0.5 to 1.5 ± 0.2 (n = 12, p < 0.001, paired t-test). In the continued presence of acetate, contraction amplitude gradually recovered and returned to baseline after approximately 10 minutes. We also noted a marked increase in fractional sarcomere shortening when acetate was removed from the bath solution. In addition, exposure to acetate significantly increased the diastolic sarcomere length. We next examined the concentration dependence of the decrease in contraction observed at two minutes and diastolic sarcomere length following the exposure to acetate. Figure 2 shows that the negative inotropic effect of acetate is concentration dependent. Data were fit with a modified Hill equation with an IC50 = 5.6 mM and Hill coefficient of 1.4. There was no apparent concentration dependence for the effect on diastolic sarcomere length.Figure 1


Acetate transiently inhibits myocardial contraction by increasing mitochondrial calcium uptake.

Schooley JF, Namboodiri AM, Cox RT, Bünger R, Flagg TP - BMC Physiol. (2014)

Concentration-dependence of acetate effect on fractional shortening and diastolic sarcomere length. (A) Single averaged contractions acquired in experiments as described in Figure 1 at different concentrations of sodium acetate. Contractions in normal Tyrode (Control, dotted line) and at 2 minutes following exposure to acetate solution (Acetate, solid line) are shown. 10 mM NaCl, instead of sodium acetate, was added to normal Tyrode to collect the zero acetate data. (B) Acetate concentration response curve for maximum contraction inhibition. Data were fit with a modified Hill equation (solid line): FS/FS0 = 1/(1 + ([Acetate]/IC50)h), where IC50 is the half-maximal inhibitory concentration of acetate (IC50 = 5.6 mM) and h is the Hill coefficient (h = 1.3). (C) There was no apparent acetate concentration dependence on diastolic sarcomere length.
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Related In: Results  -  Collection

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Fig2: Concentration-dependence of acetate effect on fractional shortening and diastolic sarcomere length. (A) Single averaged contractions acquired in experiments as described in Figure 1 at different concentrations of sodium acetate. Contractions in normal Tyrode (Control, dotted line) and at 2 minutes following exposure to acetate solution (Acetate, solid line) are shown. 10 mM NaCl, instead of sodium acetate, was added to normal Tyrode to collect the zero acetate data. (B) Acetate concentration response curve for maximum contraction inhibition. Data were fit with a modified Hill equation (solid line): FS/FS0 = 1/(1 + ([Acetate]/IC50)h), where IC50 is the half-maximal inhibitory concentration of acetate (IC50 = 5.6 mM) and h is the Hill coefficient (h = 1.3). (C) There was no apparent acetate concentration dependence on diastolic sarcomere length.
Mentions: To test whether the short chain fatty acid, acetate, exerts negative inotropic effects, we continuously monitored average sarcomere length in isolated mouse cardiomyocytes acutely exposed to Tyrode solution containing 10 mM sodium acetate. Three major consequences of acetate exposure were observed. Figure 1 shows that acetate caused a transient decrease in active sarcomere shortening. At two minutes following acetate application, fractional shortening was markedly decreased from 5.6 ± 0.5 to 1.5 ± 0.2 (n = 12, p < 0.001, paired t-test). In the continued presence of acetate, contraction amplitude gradually recovered and returned to baseline after approximately 10 minutes. We also noted a marked increase in fractional sarcomere shortening when acetate was removed from the bath solution. In addition, exposure to acetate significantly increased the diastolic sarcomere length. We next examined the concentration dependence of the decrease in contraction observed at two minutes and diastolic sarcomere length following the exposure to acetate. Figure 2 shows that the negative inotropic effect of acetate is concentration dependent. Data were fit with a modified Hill equation with an IC50 = 5.6 mM and Hill coefficient of 1.4. There was no apparent concentration dependence for the effect on diastolic sarcomere length.Figure 1

Bottom Line: Acute exposure of myocytes to 10 mM sodium acetate caused a marked, but transient, decrease in systolic sarcomere shortening (1.49 ± 0.20% vs. 5.58 ± 0.49% in control), accompanied by a significant increase in diastolic sarcomere length (1.81 ± 0.01 μm vs. 1.77 ± 0.01 μm in control), with a near linear dose response in the 1-10 mM range.Unlike palmitate, acetate caused no change in action potential duration; however, acetate markedly increased mitochondrial Ca(2+) uptake.Lehninger and others have previously demonstrated that the anions of weak aliphatic acids such as acetate stimulate Ca(2+) uptake in isolated mitochondria.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, Physiology, and Genetics, Uniformed Services University for the Health Sciences, 4301 Jones Bridge Road, Rm. C-2114, Bethesda, 20814, MD, USA. James.Schooley@usuhs.edu.

ABSTRACT

Background: There is a close relationship between cardiovascular disease and cardiac energy metabolism, and we have previously demonstrated that palmitate inhibits myocyte contraction by increasing Kv channel activity and decreasing the action potential duration. Glucose and long chain fatty acids are the major fuel sources supporting cardiac function; however, cardiac myocytes can utilize a variety of substrates for energy generation, and previous studies demonstrate the acetate is rapidly taken up and oxidized by the heart. In this study, we tested the effects of acetate on contractile function of isolated mouse ventricular myocytes.

Results: Acute exposure of myocytes to 10 mM sodium acetate caused a marked, but transient, decrease in systolic sarcomere shortening (1.49 ± 0.20% vs. 5.58 ± 0.49% in control), accompanied by a significant increase in diastolic sarcomere length (1.81 ± 0.01 μm vs. 1.77 ± 0.01 μm in control), with a near linear dose response in the 1-10 mM range. Unlike palmitate, acetate caused no change in action potential duration; however, acetate markedly increased mitochondrial Ca(2+) uptake. Moreover, pretreatment of cells with the mitochondrial Ca(2+) uptake blocker, Ru-360 (10 μM), markedly suppressed the effect of acetate on contraction.

Conclusions: Lehninger and others have previously demonstrated that the anions of weak aliphatic acids such as acetate stimulate Ca(2+) uptake in isolated mitochondria. Here we show that this effect of acetate appears to extend to isolated cardiac myocytes where it transiently modulates cell contraction.

Show MeSH
Related in: MedlinePlus