Aging impairs myocardial fatty acid and ketone oxidation and modifies cardiac functional and metabolic responses to insulin in mice

Abstract

Aging presumably initiates shifts in substrate oxidation mediated in part by changes in insulin sensitivity. Similar shifts occur with cardiac hypertrophy and may contribute to contractile dysfunction. We tested the hypothesis that aging modifies substrate utilization and alters insulin sensitivity in mouse heart when provided multiple substrates. In vivo cardiac function was measured with microtipped pressure transducers in the left ventricle from control (4-6 mo) and aged (22-24 mo) mice. Cardiac function was also measured in isolated working hearts along with substrate and anaplerotic fractional contributions to the citric acid cycle (CAC) by using perfusate containing (13)C-labeled free fatty acids (FFA), acetoacetate, lactate, and unlabeled glucose. Stroke volume and cardiac output were diminished in aged mice in vivo, but pressure development was preserved. Systolic and diastolic functions were maintained in aged isolated hearts. Insulin prompted an increase in systolic function in aged hearts, resulting in an increase in cardiac efficiency. FFA and ketone flux were present but were markedly impaired in aged hearts. These changes in myocardial substrate utilization corresponded to alterations in circulating lipids, thyroid hormone, and reductions in protein expression for peroxisome proliferator-activated receptor (PPAR)alpha and pyruvate dehydrogenase kinase (PDK)4. Insulin further suppressed FFA oxidation in the aged. Insulin stimulation of anaplerosis in control hearts was absent in the aged. The aged heart shows metabolic plasticity by accessing multiple substrates to maintain function. However, fatty acid oxidation capacity is limited. Impaired insulin-stimulated anaplerosis may contribute to elevated cardiac efficiency, but may also limit response to acute stress through depletion of CAC intermediates.

The metabolic footprint of aging in mice

“…In contrast, it is well known that during fasting both free fatty acids as well as medium and long chain acylcarnitines in plasma increase, reflecting increased FAO flux41. Therefore, our data fit with reduced entry in and flux through the mitochondrial FAO pathway4243, causing an increase in FA levels and a concomitant reduced “leak” of acylcarnitines back into the plasma compartment (dashed line in Fig 6B). It is important to note that in aged humans, several fatty acids were also more abundant in plasma22, although no information is available for acylcarnitines.…”

Mitochondrial Metabolism in Aging Heart

“…Fatty acid oxidation is decreased in the aging heart. 9, 10 PDK4 content is decreased in the aged heart, 9 favoring increased glucose oxidation at the expense of fatty acid oxidation.…”

“…9 The long-chain fatty acyl-CoA is first converted to the long-chain acylcarnitine through carnitine palmitoyltransferase I (CPT-I). 11 The long-chain acylcarnitine is transported into the mitochondrial matrix across the inner mitochondrial membrane by carnitine-acylcarnitine translocase.…”

Acetyl-l-carnitine supplementation reverses the age-related decline in carnitine palmitoyltransferase 1 (CPT1) activity in interfibrillar mitochondria without changing the l-carnitine content in the rat heart

“…For example, fatty acid oxidation, which is typically the primary oxidizable substrate for myocardial bioenergetics, declines with age in rodents (Abu-Erreish et al, 1977; Hyyti et al, 2010; McMillin et al, 1993) and also in humans (Kates et al, 2003). While glucose oxidation appears to compensate this loss (Kates et al, 2003; McMillin et al, 1993), there is increasing evidence that such a shift in metabolism comes at a price, primarily in lower bioenergetic reserve capacity that limits response to heightened energy demands (Davila-Roman et al, 2002; Koonen et al, 2007; van der Meer et al, 2008).…”