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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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Inhibition of mitochondrial Ca2+uptake with Ru-360 inhibits the effects of acetate on cell contraction. (A) Representative recording of average sarcomere length assessed continuously throughout application and removal of normal Tyrode solution (NT) supplemented with 10 mM sodium acetate in cells pretreated with 10 μM Ru-360 for 30–60 minutes and maintained in Ru-360 throughout the acetate exposure. Summary data from experiments as in A (n = 11) illustrate that pretreatment with Ru-360 markedly suppresses the effect of acetate on both (B) fractional shortening and (C) diastolic sarcomere length.
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Fig5: Inhibition of mitochondrial Ca2+uptake with Ru-360 inhibits the effects of acetate on cell contraction. (A) Representative recording of average sarcomere length assessed continuously throughout application and removal of normal Tyrode solution (NT) supplemented with 10 mM sodium acetate in cells pretreated with 10 μM Ru-360 for 30–60 minutes and maintained in Ru-360 throughout the acetate exposure. Summary data from experiments as in A (n = 11) illustrate that pretreatment with Ru-360 markedly suppresses the effect of acetate on both (B) fractional shortening and (C) diastolic sarcomere length.

Mentions: If the acetate-dependent increase in mitochondrial Ca2+ is responsible for the reduction of myocyte fractional shortening, we reasoned that inhibiting mitochondrial Ca2+ uptake would reduce or abolish the effect of acetate on myocyte contraction. To test this hypothesis, we incubated cells for 30 minutes with 10 μM Ru-360, and then measured the effects of acetate on sarcomere shortening. Figure 5 shows that Ru-360 treatment significantly attenuated the effect of acetate on both diastolic sarcomere length and fractional sarcomere shortening. Interestingly, pretreatment with Ru-360 alone also had a marked effect on contractile function prior to acetate exposure. As shown in Figure 5B (inset), fractional sarcomere shortening immediately prior to acetate exposure (time zero) was 13.03 ± 1.17% in cells pretreated with Ru-360 compared with 5.83 ± 0.43% in control cells not exposed to Ru-360. Taken together, these data support the conclusion that acetate stimulates mitochondrial Ca2+ uptake, leading to reduced availability of Ca2+ for myofilament activation.Figure 5


Acetate transiently inhibits myocardial contraction by increasing mitochondrial calcium uptake.

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

Inhibition of mitochondrial Ca2+uptake with Ru-360 inhibits the effects of acetate on cell contraction. (A) Representative recording of average sarcomere length assessed continuously throughout application and removal of normal Tyrode solution (NT) supplemented with 10 mM sodium acetate in cells pretreated with 10 μM Ru-360 for 30–60 minutes and maintained in Ru-360 throughout the acetate exposure. Summary data from experiments as in A (n = 11) illustrate that pretreatment with Ru-360 markedly suppresses the effect of acetate on both (B) fractional shortening and (C) diastolic sarcomere length.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: Inhibition of mitochondrial Ca2+uptake with Ru-360 inhibits the effects of acetate on cell contraction. (A) Representative recording of average sarcomere length assessed continuously throughout application and removal of normal Tyrode solution (NT) supplemented with 10 mM sodium acetate in cells pretreated with 10 μM Ru-360 for 30–60 minutes and maintained in Ru-360 throughout the acetate exposure. Summary data from experiments as in A (n = 11) illustrate that pretreatment with Ru-360 markedly suppresses the effect of acetate on both (B) fractional shortening and (C) diastolic sarcomere length.
Mentions: If the acetate-dependent increase in mitochondrial Ca2+ is responsible for the reduction of myocyte fractional shortening, we reasoned that inhibiting mitochondrial Ca2+ uptake would reduce or abolish the effect of acetate on myocyte contraction. To test this hypothesis, we incubated cells for 30 minutes with 10 μM Ru-360, and then measured the effects of acetate on sarcomere shortening. Figure 5 shows that Ru-360 treatment significantly attenuated the effect of acetate on both diastolic sarcomere length and fractional sarcomere shortening. Interestingly, pretreatment with Ru-360 alone also had a marked effect on contractile function prior to acetate exposure. As shown in Figure 5B (inset), fractional sarcomere shortening immediately prior to acetate exposure (time zero) was 13.03 ± 1.17% in cells pretreated with Ru-360 compared with 5.83 ± 0.43% in control cells not exposed to Ru-360. Taken together, these data support the conclusion that acetate stimulates mitochondrial Ca2+ uptake, leading to reduced availability of Ca2+ for myofilament activation.Figure 5

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