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Molecular and Cellular Biology, August 2004, p. 7179-7187, Vol. 24, No. 16
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.16.7179-7187.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Abnormal Cardiac Development in the Absence of Heart Glycogen

Bartholomew A. Pederson,1,2 Hanying Chen,3 Jill M. Schroeder,1,2 Weinian Shou,3 Anna A. DePaoli-Roach,1,3 and Peter J. Roach1

Department o Biochemistry and Molecular Biology,1 Herman B. Wells Center for Pediatric Research, Department of Pediatrics, School of Medicine,3 Center for Diabetes Research, Indiana University, Indianapolis, Indiana 46202-51222

Received 6 February 2004/ Accepted 15 May 2004

Glycogen serves as a repository of glucose in many mammalian tissues. Mice lacking this glucose reserve in muscle, heart, and several other tissues were generated by disruption of the GYS1 gene, which encodes an isoform of glycogen synthase. Crossing mice heterozygous for the GYS1 disruption resulted in a significant underrepresentation of GYS1-null mice in the offspring. Timed matings established that Mendelian inheritance was followed for up to 18.5 days postcoitum (dpc) and that ~90% of GYS1-null animals died soon after birth due to impaired cardiac function. Defects in cardiac development began between 11.5 and 14.5 dpc. At 18.5 dpc, the hearts were significantly smaller, with reduced ventricular chamber size and enlarged atria. Consistent with impaired cardiac function, edema, pooling of blood, and hemorrhagic liver were seen. Glycogen synthase and glycogen were undetectable in cardiac muscle and skeletal muscle from the surviving null mice, and the hearts showed normal morphology and function. Congenital heart disease is one of the most common birth defects in humans, at up to 1 in 50 live births. The results provide the first direct evidence that the ability to synthesize glycogen in cardiac muscle is critical for normal heart development and hence that its impairment could be a significant contributor to congenital heart defects.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, School of Medicine, Indiana University, Indianapolis, IN 46202-5122. Phone: (317) 274-1582. Fax: (317) 274-4686. E-mail: proach{at}iupui.edu.

Molecular and Cellular Biology, August 2004, p. 7179-7187, Vol. 24, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.16.7179-7187.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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