Myocardial ATGL Overexpression Decreases the Reliance on Fatty Acid Oxidation and Protects against Pressure Overload-Induced Cardiac Dysfunction

   1. Petra C. Kienesbergera,b,
   2. Thomas Pulinilkunnila,b,
   3. Miranda M. Y. Sunga,b,c,
   4. Jeevan Nagendrana,d,
   5. Guenter Haemmerlee,
   6. Erin E. Kershawf,
   7. Martin E. Youngg,
   8. Peter E. Lighth,
   9. Gavin Y. Ouditi,
  10. Rudolf Zechnere and
  11. Jason R. B. Dycka,b,c

   1.
      aCardiovascular Research Centre, Mazankowski Alberta Heart Institute
   2.
      bDepartments of Pediatrics
   3.
      cPharmacology
   4.
      dMedicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
   5.
      eInstitute of Molecular Biosciences, University of Graz, Graz, Austria
   6.
      fDivision of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
   7.
      gDepartment of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
   8.
      hDepartment of Pharmacology, Alberta Diabetes Institute and Cardiovascular Research Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
   9.
      iDivision of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada

ABSTRACT

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.
FOOTNOTES

          o Received 24 October 2011.
          o Returned for modification 14 November 2011.
          o Accepted 30 November 2011.
    * Address correspondence to Jason R. B. Dyck, jason.dyck{at}ualberta.ca.
    *

      Published ahead of print 12 December 2011

    * Copyright © 2012, American Society for Microbiology. All Rights Reserved.

