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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/H3063    most recent 00163.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Bhashyam, S. Articles by Shannon, R. P. Search for Related Content PubMed PubMed Citation Articles by Bhashyam, S. Articles by Shannon, R. P.

Aging is associated with myocardial insulin resistance and mitochondrial dysfunction

¹Department of Medicine, Allegheny General Hospital and ²Department of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and ³Department of Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey

Submitted 8 February 2007 ; accepted in final form 10 September 2007

Aging is associated with insulin resistance, often attributable to obesity and inactivity. Recent evidence suggests that skeletal muscle insulin resistance in aging is associated with mitochondrial alterations. Whether this is true of the senescent myocardium is unknown. Twelve young (Y, 4 years old) and 12 old (O, 11 years old) dogs, matched for body mass, were instrumented with left-ventricular pressure gauges, aortic and coronary sinus catheters, and flow probes on left circumflex artery. Before surgery, all dogs participated in a 6-wk exercise program. Dogs underwent measurements of hemodynamics and plasma substrates before and during a 2-h hyperinsulinemic-euglycemic clamp to measure whole body and myocardial glucose and nonesterified fatty acid uptake. Following the protocol, myocardial and skeletal samples were obtained to measure components of the insulin-signaling cascade and mitochondrial structure. There was no difference in plasma glucose (Y, 90 ± 4 mg/dl; O, 87 ± 4 mg/dl), but old dogs had higher (P < 0.02) nonesterified fatty acids (Y, 384 ± 48 µmol/l; O, 952 ± 97 µmol/l) and plasma insulin (Y, 39 ± 11 pmol/l; O, 108 ± 18 pmol/l). Old dogs had impaired total body glucose disposition (Y, 11.5 ± 1 mg·kg^–1·min^–1; O, 8.0 ± 0.5 mg·kg^–1·min^–1; P < 0.05) and insulin-stimulated myocardial glucose uptake (Y, 3.5 ± 0.3mg·min^–1·g^–1; O, 1.8 ± 0.3 mg·min^–1·g^–1; P < 0.05). The impaired insulin action was associated with altered insulin signaling and glucose transporter (GLUT4) translocation. There were myocardial mitochondrial structural changes observed in association with decreased expression of uncoupling protein-3. Aging is associated with both whole body and myocardial insulin resistance, independent of obesity and inactivity, but involving altered mitochondrial structure and impaired cellular insulin action.

myocardium; mitochondria; uncoupling protein-3