Cardiomyocyte-specific ATGL overexpression decreased reliance on fatty acid oxidation, improved baseline systolic function, and protected mice from pressure overload-induced systolic dysfunction.
Does cardiomyocyte-specific ATGL overexpression improve cardiac function and protect against pressure overload-induced dysfunction in mice?
Cardiomyocyte-specific ATGL overexpression shifts myocardial metabolism from fatty acid to glucose oxidation, protecting against pressure overload-induced cardiac dysfunction in mice.
Alterations in myocardial triacylglycerol content have been associated with poor left ventricular function, suggesting that enzymes involved in myocardial triacylglycerol metabolism play an important role in regulating contractile function. Myocardial triacylglycerol catabolism is mediated by adipose triglyceride lipase (ATGL), which is rate limiting for triacylglycerol hydrolysis. To address the influence of triacylglycerol hydrolysis on myocardial energy metabolism and function, we utilized mice with cardiomyocyte-specific ATGL overexpression (MHC-ATGL). Biochemical examination of MHC-ATGL hearts revealed chronically reduced myocardial triacylglycerol content but unchanged levels of long-chain acyl coenzyme A esters, ceramides, and diacylglycerols. Surprisingly, fatty acid oxidation rates were decreased in ex vivo perfused working hearts from MHC-ATGL mice, which was compensated by increased rates of glucose oxidation. Interestingly, reduced myocardial triacylglycerol content was associated with moderately enhanced in vivo systolic function in MHC-ATGL mice and increased isoproterenol-induced cell shortening of isolated primary cardiomyocytes. Most importantly, MHC-ATGL mice were protected from pressure overload-induced systolic dysfunction and detrimental structural remodeling following transverse aortic constriction. Overall, this study shows that ATGL overexpression is sufficient to alter myocardial energy metabolism and improve cardiac function.
Kienesberger et al. (Tue,) conducted a other in Pressure overload-induced cardiac dysfunction. Cardiomyocyte-specific ATGL overexpression vs. Wild-type littermates was evaluated on Systolic function and structural remodeling following transverse aortic constriction. Cardiomyocyte-specific ATGL overexpression decreased reliance on fatty acid oxidation, improved baseline systolic function, and protected mice from pressure overload-induced systolic dysfunction.
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