4.5 Article

Abnormal cardiac development in the absence of heart glycogen

Journal

MOLECULAR AND CELLULAR BIOLOGY
Volume 24, Issue 16, Pages 7179-7187

Publisher

AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.24.16.7179-7187.2004

Keywords

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Funding

  1. NHLBI NIH HHS [R01 HL070259-03, R01 HL070259] Funding Source: Medline
  2. NIDDK NIH HHS [R56 DK027221, DK27221, R37 DK027221, U24 DK56937, U24 DK059637, R01 DK027221] Funding Source: Medline

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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 similar to90% 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.

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