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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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Related in: MedlinePlus

Acetate stimulates mitochondrial Ca2+uptake. Summary of rhod-2-AM fluorescence recorded during exposure to 10 mM sodium acetate in the presence (n = 8) or absence (n = 10) of Ru-360 (10 μM). Background-subtracted fluorescence was normalized to mean fluorescence during the period prior to addition of 10 mM acetate (n =10) or control (no acetate, n = 9). Acetate solution was added at the arrow.
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Fig4: Acetate stimulates mitochondrial Ca2+uptake. Summary of rhod-2-AM fluorescence recorded during exposure to 10 mM sodium acetate in the presence (n = 8) or absence (n = 10) of Ru-360 (10 μM). Background-subtracted fluorescence was normalized to mean fluorescence during the period prior to addition of 10 mM acetate (n =10) or control (no acetate, n = 9). Acetate solution was added at the arrow.

Mentions: It has been shown previously that acetate increases Ca2+ uptake in isolated liver and heart mitochondria [13-15]. In this light, we hypothesized that the acute application of acetate might lead to an increase in mitochondrial Ca2+ uptake, leaving less Ca2+ available to activate the myofilaments. To test this hypothesis, we first monitored mitochondrial Ca2+ during exposure to acetate using the fluorescent Ca2+ indicator, Rhod-2 AM (5 μM) in the presence of 200 μM MnCl2 to quench cytosolic fluorescence [17,18]. Figure 4 shows normalized cell fluorescence during exposure to 10 mM acetate in the presence or absence of the mitochondrial Ca2+ uptake inhibitor, Ru-360 (n = 9 and 8 respectively). This concentration of Ru-360 was chosen as it has previously been shown to have no effect on transmembrane Ca2+ fluxes other than mitochondrial uptake [19,20]. The results indicate that acetate causes a specific increase in Rhod-2 fluorescence consistent with the conclusion that acetate increases mitochondrial Ca2+ uptake.Figure 4


Acetate transiently inhibits myocardial contraction by increasing mitochondrial calcium uptake.

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

Acetate stimulates mitochondrial Ca2+uptake. Summary of rhod-2-AM fluorescence recorded during exposure to 10 mM sodium acetate in the presence (n = 8) or absence (n = 10) of Ru-360 (10 μM). Background-subtracted fluorescence was normalized to mean fluorescence during the period prior to addition of 10 mM acetate (n =10) or control (no acetate, n = 9). Acetate solution was added at the arrow.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4274725&req=5

Fig4: Acetate stimulates mitochondrial Ca2+uptake. Summary of rhod-2-AM fluorescence recorded during exposure to 10 mM sodium acetate in the presence (n = 8) or absence (n = 10) of Ru-360 (10 μM). Background-subtracted fluorescence was normalized to mean fluorescence during the period prior to addition of 10 mM acetate (n =10) or control (no acetate, n = 9). Acetate solution was added at the arrow.
Mentions: It has been shown previously that acetate increases Ca2+ uptake in isolated liver and heart mitochondria [13-15]. In this light, we hypothesized that the acute application of acetate might lead to an increase in mitochondrial Ca2+ uptake, leaving less Ca2+ available to activate the myofilaments. To test this hypothesis, we first monitored mitochondrial Ca2+ during exposure to acetate using the fluorescent Ca2+ indicator, Rhod-2 AM (5 μM) in the presence of 200 μM MnCl2 to quench cytosolic fluorescence [17,18]. Figure 4 shows normalized cell fluorescence during exposure to 10 mM acetate in the presence or absence of the mitochondrial Ca2+ uptake inhibitor, Ru-360 (n = 9 and 8 respectively). This concentration of Ru-360 was chosen as it has previously been shown to have no effect on transmembrane Ca2+ fluxes other than mitochondrial uptake [19,20]. The results indicate that acetate causes a specific increase in Rhod-2 fluorescence consistent with the conclusion that acetate increases mitochondrial Ca2+ uptake.Figure 4

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