Aging is associated with myocardial insulin resistance and mitochondrial dysfunction

Abstract

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 Ϯ 4 mg/dl; O, 87 Ϯ 4 mg/dl), but old dogs had higher (P Ͻ 0.02) nonesterified fatty acids (Y, 384 Ϯ 48 mol/l; O, 952 Ϯ 97 mol/l) and plasma insulin (Y, 39 Ϯ 11 pmol/l; O, 108 Ϯ 18 pmol/l). Old dogs had impaired total body glucose disposition (Y, 11.5 Ϯ 1 mg⅐ kgThe 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 ADVANCED AGE IS ASSOCIATED with the development of whole body insulin resistance and increased incidence of type 2 diabetes in humans (4,9,14,33). Aging is also frequently accompanied by obesity and inactivity that predispose to the development of insulin resistance (6,16,17,32,39). However, it is unclear what independent role aging plays in the pathogenesis of insulin resistance in the absence of obesity and inactivity. Furthermore, it is unclear as to whether these abnormalities in insulin action extend to the senescent myocardium, where continuous contractile function makes inactivity less relevant.Recently, skeletal muscle insulin resistance in both advanced age (1, 28) and in lean offspring of patients with type 2 diabetes (10, 22, 29) was associated with altered mitochondrial protein expression (28) and density (10). These abnormalities were seen in association with increased intracellular lipid accumulation (22,28,29). However, it is unknown whether these same alterations are evident in the senescent myocardium, whether they are associated with altered insulin action, and whether they predispose to altered left ventricle (LV) hemodynamics in the absence of hyperglycemia or other conventional risk factors.Accordingly, the purpose of the present study was to determine whether aging alone was associated with bot...

Enhanced resistance to permeability transition in interfibrillar cardiac mitochondria in dogs: effects of aging and long-term aldosterone infusion

“…We did not observe any effect of age in indexes of Ca 2ϩ -induced MPT in the present study; however, 8-yr-old beagles should be considered middle aged, as the typical life span of this strain is 13.5 Ϯ 0.2 yr (24). A previous study found that healthy 11 Ϯ 2-yr-old male beagles had a decrease in succinate dehydrogenase activity in myocardial tissue homogenates and a qualitative increased vacuolization of mitochondria by visual analysis of electron micrographs compared with 4 Ϯ 1-yr-old animals; however, mitochondrial respiration and MPT were not assessed (3). Future studies should evaluate these parameters in senescent dogs, where greater mitochondrial dysfunction would be expected.…”

“…Here we show that mitochondrial yield and functional differences between SSM and IFM were qualitatively similar in the LV and RV with responses to aging and aldosterone infusion (Figs. [3][4][5][6][7][8]. The present investigation was not designed to statistically compare the RV with the LV, as this would require a three-way ANOVA (chamber ϫ mitochondrial population ϫ age/treatment group) and thus a much larger sampled size to achieve acceptable statistical power.…”

Insulin Resistance and Progression of Heart Failure in the Older Adult

“…Aging is associated with whole body and myocardial insulin resistance, independent of obesity and inactivity as shown in a wellcharacterized large-animal model of aging with senescent beagles [22]. Moreover, the senescent myocardium was associated with myocardial insulin resistance and mitochondrial dysfunction.…”

“…In fact, in a relevant large animal model of senescent beagles, Shannon et al have demonstrated the magnitude and the mechanism of whole body and myocardial insulin resistance and the cellular mechanisms involved [22]. Myocardial insulin resistance is specifically associated with mitochondrial structural and functional abnormalities that predispose to insulin resistance.…”

“…Myocardial insulin resistance is specifically associated with mitochondrial structural and functional abnormalities that predispose to insulin resistance. The cellular basis for myocardial insulin resistance in senescent myocardium involves functional alterations in mitochondrial uncoupling proteins (UCP)-3 that lead to increased mitochondrial reactive oxygen species (ROS) and impaired NEFA oxidation [22,[83][84][85][86][87]. In turn, intramyo cardial accumulation of unoxidized NEFA contributes to progressive myocardial insulin resistance that contributes to limiting glucose availability at a time when the failing heart requires glucose.…”