Mcd-/- KO mice may be useful for studying the mechanisms of cardiac glucose oxidation and recovery from cardiac ischemic injury.
Gary Lopaschuk, University of Alberta
Mcd-/- KO mice contain a neo cassette replacing exon 1 of the malonyl-CoA decarboxylase (Mlycd) gene, abolishing gene expression. Malonyl-CoA has been implicated in the regulating of feeding behavior, hepatocyte-mediated insulin resistance, energy expenditure and subsequent storage of fat in adipose tissue, pancreatic beta cell insulin secretion, skeletal muscle–mediated insulin resistance and type 2 diabetes, and cardiac ischemia/reperfusion injury. Expression of cardiac MCD protects the heart from ischemic damage by inhibiting fatty acid oxidation and stimulating glucose oxidation. MCD acts to regulate fatty acid oxidation by inhibiting carnitine palmitoyltransferase 1 (CPT1) which is the key enzyme involved in mitochondrial long-chain fatty acid uptake. Mice homozygous for this allele are viable and fertile. No protein from the targeted gene is detected by Western blot analysis of cardiac tissue. Mcd-/- KO mice exhibit no significant differences in rates of fatty acid oxidation, glucose oxidation, glycolysis, or in vivo and ex vivo cardiac function. They show an increase in the expression of genes regulating fatty acid utilization. They do have an increase in glucose oxidation and improved functional recovery of the heart after ischemia. These mice resist diet-induced glucose intolerance. When homozygotes are challenged with diet-induced obesity they display a more robust insulin-stimulated glucose oxidation and less incomplete fatty acid oxidation. Mcd-/- KO mice do not show pulmonary vasoconstriction during exposure to acute hypoxia and do not develop pulmonary arterial hypertension during chronic hypoxia.
A targeting vector was designed to replace exon 1 of the malonyl-CoA decarboxylase (Mlycd) gene with a neomycin resistance (neo) cassette. The construct was electroporated into 129S7/SvEvBrd-Hprtb-m2-derived AB2.2 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts and the resulting chimeric males were bred to C57BL/6 females. Mcd-/- mice were backcrossed 6 generations to C57BL/6 mice. Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6J (Stock No. 000664) for at least one generation to establish the colony.
|Allele Name||targeted mutation 1, Kou-ichi Jishage|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Mlycd, malonyl-CoA decarboxylase|
|Strain of Origin||129S7/SvEvBrd-Hprtb-m2|
|Molecular Note||Exon 1 was replaced with a neo cassette. The absence of protein product was confirmed by western blot analysis on extracts from the heart.|
When maintaining a live colony, homozygous mice may be bred together.
When using the Mcd- mouse strain in a publication, please cite the originating article(s) and include JAX stock #026523 in your Materials and Methods section.