Impaired insulin signaling accelerates cardiac mitochondrial dysfunction after
myocardial infarction.
Authors Sena S, Hu P, Zhang D, Wang X, Wayment B, Olsen C, Avelar E, Abel ED, Litwin SE.
Submitted By E. Dale Abel on 3/19/2009
Status Published
Journal Journal of molecular and cellular cardiology
Year 2009
Date Published 6/1/2009
Volume : Pages 46(6) : 910 - 918
PubMed Reference 19249310
Abstract Diabetes increases mortality and accelerates left ventricular (LV) dysfunction
following myocardial infarction (MI). This study sought to determine the impact
of impaired myocardial insulin signaling, in the absence of diabetes, on the
development of LV dysfunction following MI. Mice with cardiomyocyte-restricted
knock out of the insulin receptor (CIRKO) and wildtype (WT) mice were subjected
to proximal left coronary artery ligation (MI) and followed for 14 days. Despite
equivalent infarct size, mortality was increased in CIRKO-MI vs. WT-MI mice (68%
vs. 40%, respectively). In surviving mice, LV ejection fraction and dP/dt were
reduced by >40% in CIRKO-MI vs. WT-MI. Relative to shams, isometric developed
tension in LV papillary muscles increased in WT-MI but not in CIRKO-MI. Time to
peak tension and relaxation times were prolonged in CIRKO-MI vs. WT-MI
suggesting impaired, load-independent myocardial contractile function. To
elucidate mechanisms for impaired LV contractility, mitochondrial function was
examined in permeabilized cardiac fibers. Whereas maximal ADP-stimulated
mitochondrial O(2) consumption rates (V(ADP)) with palmitoyl carnitine were
unchanged in WT-MI mice relative to sham-operated animals, V(ADP) was
significantly reduced in CIRKO-MI (13.17+/-0.94 vs. 9.14+/-0.88 nmol
O(2)/min/mgdw, p<0.05). Relative to WT-MI, expression levels of GLUT4,
PPAR-alpha, SERCA2, and the FA-Oxidation genes MCAD, LCAD, CPT2 and the electron
transfer flavoprotein ETFDH were repressed in CIRKO-MI. Thus reduced insulin
action in cardiac myocytes accelerates post-MI LV dysfunction, due in part to a
rapid decline in mitochondrial FA oxidative capacity, which combined with
limited glucose transport capacity that may reduce substrate utilization and
availability.


Investigators with authorship
NameInstitution
E. Dale AbelUniversity of Iowa

Complications









Genes
SymbolDescription
Acadlacetyl-Coenzyme A dehydrogenase, long-chain
Atp2a2ATPase, Ca++ transporting, cardiac muscle, slow twitch 2
Cpt2carnitine palmitoyltransferase 2
Insrinsulin receptor
Pparaperoxisome proliferator activated receptor alpha
Slc2a4solute carrier family 2 (facilitated glucose transporter), member 4