Pharmacological Evidence Suggests Acetate And Pyruvate Modulate Myocyte Systolic And Diastolic Function By Effects On Mitochondrial Ca2+ Handling
BIOPHYSICAL JOURNAL(2012)
摘要
We have recently demonstrated that there may be a direct link between energy substrate utilization and contractile function. Mice that have increased cardiac lipid storage and oxidation as a result of fatty acid transport protein 1 overexpression in the heart exhibit cellular diastolic dysfunction and acute exposure of myocytes to the long chain fatty acid palmitate attenuates contractility by disrupting E-C coupling. Glucose and long chain fatty acids are typical energy substrates that support cardiac function; however, cardiac myocytes can oxidize a variety of substrates for energy generation. For example, the short chain fatty acid, acetate, can be oxidized in preference to glucose in some circumstances. In the present study, we explore the effects of acute exposure to acetate or pyruvate on contractile function of isolated mouse ventricular myocytes. Acute exposure of myocytes to Tyrode solution supplemented with 10 mM sodium acetate causes a marked, but transient, decrease in sarcomere shortening (1.49±0.20% vs. 5.58±0.49% in control) and a significant increase in diastolic sarcomere length (1.77±0.01 μm vs. 1.81±0.01 μm in control) that persists in the continued presence of acetate for up to 60 minutes. Pyruvate (the major mitochondrial substrate), and dichloroacetate (indirectly stimulates mitochondrial pyruvate oxidation) cause similar effects. Interestingly, pretreatment of cells with the mitochondrial Ca2+ uptake blocker, Ru-360 (10 μM), markedly suppressed the effect of acetate on both myocyte contractile amplitude and diastolic sarcomere length. Taken together, the data suggest that 1) acute exposure to acetate or pyruvate can modulate both systolic and diastolic cardiac function and that 2) mitochondrial Ca2+ uptake seems to be a key mediator of this effect.
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关键词
pyruvate modulate myocyte systolic,mitochondrial ca2+,diastolic function,pharmacological evidence
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