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Dietary medium-chain triglycerides can prevent changes in myosin and SR due to CPT-1 inhibition by etomoxir
Abstract:
To define determinants of subcellular structures of heart, Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were treated for 5 wk with 15 mg.kg-1.day-1 etomoxir [reduces mitochondrial carnitine palmitoyltransferase-1 (CPT-1) activity and fatty acid synthesis]. To bypass CPT-1 inhibition, etomoxir-treated rats were fed a medium-chain fatty acid (MCFA) diet. Etomoxir induced a proportionate growth of heart, which could partially (WKY, P < 0.05) or completely (SHR, P < 0.05) be prevented by the MCFA diet. Also the etomoxir-induced increase in myosin V1 was partially prevented (P < 0.05). Etomoxir increased (P < 0.05) rate of sarcoplasmic reticulum (SR) Ca2+ uptake of WKY and SHR ventricular homogenates in the presence or absence of the SR Ca2+ release inhibitor ruthenium red. The MCFA diet resulted in SR Ca2+ uptake rates that were in between those of etomoxir-treated and untreated rats. The in vitro 32P incorporation into phospholamban and troponin I did not differ significantly in WKY. Etomoxir induced, however, an increase (P < 0.05) in the phosphorylated intermediate of the Ca2+ adenosinetriphosphatase in WKY that was prevented by the MCFA diet. In SHR, etomoxir increased the in vitro phospholamban phosphorylation, which was reduced compared with WKY. The data show that myosin and SR are affected by a chronically altered substrate utilization of heart.
Insights
Etomoxir treatment alters heart structure and function by affecting fatty acid metabolism. A medium-chain fatty acid diet partially or fully reversed these cardiac changes in rats.
Area of Science:
- Cardiovascular Physiology
- Mitochondrial Metabolism
- Cardiac Substrate Utilization
Background:
- Altered cardiac substrate utilization impacts heart structure and function.
- Carnitine palmitoyltransferase-1 (CPT-1) plays a key role in fatty acid metabolism within the heart.
- Understanding these pathways is crucial for addressing cardiac pathologies.
Purpose of the Study:
- To investigate the effects of inhibiting mitochondrial carnitine palmitoyltransferase-1 (CPT-1) on cardiac subcellular structures.
- To determine if a medium-chain fatty acid (MCFA) diet can mitigate CPT-1 inhibition-induced cardiac changes.
- To elucidate the role of altered substrate utilization in myosin and sarcoplasmic reticulum (SR) function.
Main Methods:
- Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were treated with etomoxir to inhibit CPT-1.
- A subset of etomoxir-treated rats received a medium-chain fatty acid (MCFA) diet to bypass CPT-1 inhibition.
- Cardiac growth, myosin V1 expression, SR Ca2+ uptake, and protein phosphorylation (phospholamban, troponin I, Ca2+ ATPase) were assessed.
Main Results:
- Etomoxir induced cardiac growth, which was partially or completely prevented by the MCFA diet.
- Etomoxir increased SR Ca2+ uptake rates, an effect modulated by the MCFA diet.
- Etomoxir altered myosin V1 levels and Ca2+ ATPase phosphorylation, with some effects mitigated by the MCFA diet.
Conclusions:
- Chronic inhibition of cardiac fatty acid metabolism via CPT-1 affects cardiac structure and sarcoplasmic reticulum function.
- A medium-chain fatty acid diet can partially or completely reverse etomoxir-induced cardiac alterations.
- Altered substrate utilization significantly impacts myosin and SR Ca2+ handling in the heart.