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Metallothionein Prevents High Fat Diet-Induced Cardiac Contractile Dysfunction: Role of Peroxisome Proliferator-Activated Receptor Coactivator-1 and Mitochondrial Biogenesis

¹Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071

Correspondence: jren{at}uwyo.edu

Key Words: antioxidant • high fat • myocardial function • mitochondrial biogenesis • PGC-1

Obesity is associated with oxidative stress, mitochondrial and myocardial dysfunction although interaction among which remains elusive. This study was designed to evaluate the impact of the free radical scavenger metallothionein on high fat diet-induced myocardial, intracellular Ca²⁺ and mitochondrial dysfunction. FVB and metallothionein transgenic mice were fed a high or low fat diet for 5 months to induce obesity. Echocardiography revealed decreased fractional shortening, increased end systolic diameter and cardiac hypertrophy in high fat-fed FVB mice. Cardiomyocytes from high fat-fed FVB mice displayed enhanced ROS production, contractile and intracellular Ca²⁺ defects including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, reduced intracellular Ca²⁺ rise and Ca²⁺ clearance. Transmission microscopy noted overt mitochondrial damage with reduced mitochondrial density. Western blot analysis revealed enhanced phosphorylation of nuclear factor Foxo3a without changes in Foxo3a, Foxo1a, pFoxo1a, silent information regulator (Sirt), Akt and pAkt in high fat diet-fed FVB hearts. The PPAR coactivator 1 (PGC-1), a key regulator of mitochondrial biogenesis, was significantly depressed by high fat diet feeding and in vitro palmitic acid treatment. RT-PCR further depicted reduced levels of the PGC-1 downstream nuclear respiratory factors 1,2, mitochondrial transcription factor A and mitochondrial DNA copy number in high fat-fed FVB hearts. Intriguingly, the high fat diet-induced alterations in ROS, myocardial contractile, mitochondrial and cell signaling were negated by metallothionein with the exception of pFoxo3a. These data suggest that metallothionein may protect against high fat diet-induced cardiac dysfunction possibly associated with upregulation of PGC-1 and preservation of mitochondrial biogenesis.

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