The current study addresses several key issues in cardiac metabolism. First, it is generally noted that enhanced FAO is not well tolerated in cardiac tissues, especially in conditions with elevated lipid delivery. However, we demonstrate that the heart is very capable of sustaining chronic increases of FAO when lipid supply is maintained. Our results show that it is unlikely that FAO per se but rather, the balance of lipid supply and oxidation is important. Second, despite strong evidence suggesting metabolic derangements that occur during the development of cardiac hypertrophy contribute to the transition to failure; prevention of metabolic reprogramming in pathological hypertrophy has not been accomplished. Here, we show that facilitating long-chain FA entry into the mitochondria via the ACC2/malonyl CoA/CPT1 mechanism will sustain the inherent cardiac metabolic profile during the development of pathological hypertrophy. Lastly, the question of whether mechanical dysfunction is a cause or consequence of metabolism has been debated. Our results suggest that altered cardiac metabolism leads to impaired function and energetics and that maintenance of cardiac metabolism preserves these measures during the early development of mild pressure-overload hypertrophy.
Conditions of chronic increased lipid delivery, as in obesity and diabetes, have been linked to dysfunction in liver, skeletal muscle, and heart.12,30,37
In the heart, increased FAO observed during reperfusion following ischemia formulated the basis that elevated FAO was the cause of poor functional recovery.38
Studies in PPARα transgenic mice13
or PPARα agonism in hypertrophied hearts8,9
suggested that enhanced FAO was harmful to the myocardium. However, PPARα has widespread effects on lipid metabolism, including fatty acid uptake, which may lead to an imbalance between FA uptake and oxidation. In skeletal muscle, increasing FAO via high fat feeding was associated with reduced TCA cycle intermediates (TCAI) combined with elevations in acylcarnitine species, suggesting that a portion of FAO is incomplete and contributes to insulin resistance.30
However, depletion of TCAI during high fat feeding was not seen in the heart,39
suggesting that chronic elevations in cardiac FAO are not detrimental. Our present data support this as increasing cardiac FAO via reductions in malonyl CoA is well tolerated without adverse effects on cardiac function in mice up to one year of age. A similar finding has been reported recently as mice with overexpression of PDK4 had increased FAO with normal cardiac function.40
Overall, these data suggest that mitochondrial capacity for FAO in heart tissue is more robust than other tissues and high FAO in the face of unchanged FA delivery is not a culprit for mechanical and mitochondrial dysfunction.
Targeted metabolic profiling revealed significant differences in glucose and amino acid metabolism with maintained TCA cycle intermediates between CON and ACC2H−/−
hearts that remained during the development of pathological hypertrophy. The overall decreased presence of metabolites related to glucose metabolism in ACC2H−/−
hearts likely represents an overall inhibition of glucose metabolism, including glucose uptake, which results from increased FAO as proposed by the Randle or “glucose-fatty acid cyle”.41
As a result of enhanced FAO, elevations in the [acetyl-CoA]/[CoA] and [NADH]/[NAD+
] ratios lead to inhibition of pyruvate dehydrogenase (PDH) activity. Concurrently, accumulation of cytosolic citrate inhibits glycolysis via phosphofructokinase (PFK) in addition to glucose uptake.42–44
One potential negative outcome of increasing FAO is the production of acetyl CoA without the additional production of TCA cycle intermediates (TCAI) such that occurs with pyruvate.45
hearts sustained TCAI was associated with increased consumption of glucogenic amino acids which can supply TCAI. The increased amino acid catabolism becomes particularly salient in light of the demonstration that disruption of branched chain amino acids (BCAA) catabolism through loss of protein phosphatase 2Cm (PP2Cm) was associated with mitochondrial dysfunction and heart failure.46–48
Therefore, increases in the contribution of amino acids to metabolism, especially from BCAAs, may play a significant role in cardiac metabolism during pathological stress and deserves attention in future research plans.
An unexpected observation in ACC2H−/−
mice exposed to pressure-overload was the attenuation of LV hypertrophy. Unfortunately, the exact mechanism by which increased FAO via ACC2 deletion leads to an attenuation of cardiac hypertrophy is not known at this time. Interestingly, high fat feeding corresponded with reduced cardiac hypertrophy although the exact mechanism was also not uncovered.49
We speculate that the maintained metabolism and energetics in ACC2H−/−
presents an adaptive phenotype which resists pathological stress, leading to attenuation of hypertrophic growth. However, it is also possible, that increases in amino acid metabolism, including the BCAAs, could divert amino acid availability, thus, retarding the normal upregulation of protein synthesis seen in pathological hypertrophy.50
Decreased FAO and increased glycolysis has been repeatedly demonstrated in models of pathological cardiac hypertrophy.1–3
Increased anaplerosis has been recently identified in hypertrophied hearts as well contributing to the metabolic phenotype.4,5
Although glucose has the advantage of being more oxygen-efficient compared to FA, it is not a carbon-efficient as only 2/3 of the carbon in glucose is oxidized compared to the complete oxidation of FA. In this regard, reliance on carbohydrate metabolism likely represents an energy-deficient state which predisposes the hypertrophied myocardium to contractile dysfunction.6,7
We have previously shown that substantial increases of glucose entry via an insulin-independent mechanism was necessary to rescue impaired FAO and prevent heart failure in mice.24
However, since achieving such increases in glucose uptake is not physiologically feasible, focusing on maintaining the inherent cardiac metabolic profile (i.e., reliance on FA over glucose) during the development of cardiac hypertrophy may be a preferred approach. In the present study, since deletion of ACC2 in pathological hypertrophy maintained cardiac FAO, normalized the expected increases in glycolysis and anaplerosis, and led to preserved cardiac function and energetics, metabolic therapies tailored toward this outcome may be more effective in preventing the transition to heart failure.
Previous work demonstrated partial reduction of cardiac malonyl CoA content as a result of global ACC2 deletion.16,20
We made similar findings suggesting that total removal of cardiac malonyl CoA is not achievable by ACC2 deletion. In our model, several possibilities exist for this: 1) ACC1 is present and likely contributes to a portion of the remaining malonyl CoA pool; 2) αMHC-Cre recombinase does not result in total deletion of protein, so there is residual malonyl CoA formed from ACC2; and 3) since αMHC-Cre is myocyte-specific, malonyl CoA from non-myocytes is still present. Nevertheless, our results clearly show that cardiac-specific deletion of ACC2 is sufficient to lower malonyl CoA levels and significantly increase mitochondrial FAO.
In summary, modulation of mitochondrial FA entry through cardiac-specific deletion of ACC2 increases FAO without adverse effects of cardiac function in mice up to 1 year of age. Furthermore, ACC2 deletion is sufficient to prevent metabolic reprogramming during pressure-overload hypertrophy with preservation of cardiac function and energetics, representing an overall state of reduced pathological stress leading to an attenuation of hypertrophic growth. These data suggest that maintenance of the inherent metabolic profile of the heart and, as a result, maintaining mitochondrial oxidative metabolism without switching to glucose reliance is beneficial for optimal function and energetics during the development of pathological cardiac hypertrophy. Although our data clearly demonstrate the benefits of preventing metabolic remodeling in the early course of pathological hypertrophy, additional studies are needed to verify that maintaining cardiac FAO is likewise beneficial in heart failure or other cardiac pathologies.