Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression.
To investigate the role of insulin signaling on postnatal cardiac development, physiology, and cardiac metabolism, we generated mice with a cardiomyocyte-selective insulin receptor knockout (CIRKO) using cre/loxP recombination. Hearts of CIRKO mice were reduced in size by 20-30% due to reduced cardiomyocyte size and had persistent expression of the fetal beta-myosin heavy chain isoform. In CIRKO hearts, glucose transporter 1 (GLUT1) expression was reduced by about 50%, but there was a twofold increase in GLUT4 expression as well as increased rates of cardiac glucose uptake in vivo and increased glycolysis in isolated working hearts. Fatty acid oxidation rates were diminished as a result of reduced expression of enzymes that catalyze mitochondrial beta-oxidation. Although basal rates of glucose oxidation were reduced, insulin unexpectedly stimulated glucose oxidation and glycogenolysis in CIRKO hearts. Cardiac performance in vivo and in isolated hearts was mildly impaired. Thus, insulin signaling plays an important developmental role in regulating postnatal cardiac size, myosin isoform expression, and the switching of cardiac substrate utilization from glucose to fatty acids. Insulin may also modulate cardiac myocyte metabolism through paracrine mechanisms by activating insulin receptors in other cell types within the heart.
Belke
Darrell D
DD
Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada.
Betuing
Sandrine
S
Tuttle
Martin J
MJ
Graveleau
Christophe
C
Young
Martin E
ME
Pham
Mark
M
Zhang
Dongfang
D
Cooksey
Robert C
RC
McClain
Donald A
DA
Litwin
Sheldon E
SE
Taegtmeyer
Heinrich
H
Severson
David
D
Kahn
C Ronald
CR
Abel
E Dale
ED
D000818:Animals; D001693:Biological Transport, Active; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D006019:Glycolysis; D006321:Heart / Q000033:anatomy & histology; D066298:In Vitro Techniques; D007328:Insulin / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D009206:Myocardium / Q000378:metabolism*; D009929:Organ Size; D011972:Receptor, Insulin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D024723:Ventricular Myosins / Q000378:metabolism*
D005227:Fatty Acids; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D011972:Receptor, Insulin; D024723:Ventricular Myosins; D005947:Glucose