Cardiac-specific VLCAD deficiency induces dilated cardiomyopathy and cold intolerance

Abstract

The very long-chain acyl-CoA dehydrogenase (VLCAD) enzyme catalyzes the first step of mitochondrial ␤-oxidation. Patients with VLCAD deficiency present with hypoketotic hypoglycemia and cardiomyopathy, which can be exacerbated by fasting and/or cold stress. Global VLCAD knockout mice recapitulate these phenotypes: mice develop cardiomyopathy, and cold exposure leads to rapid hypothermia and death. However, the contribution of different tissues to development of these phenotypes has not been studied. We generated cardiac-specific VLCAD-deficient (cVLCAD Ϫ/Ϫ ) mice by Cre-mediated ablation of the VLCAD in cardiomyocytes. By 6 mo of age, cVLCAD Ϫ/Ϫ mice demonstrated increased end-diastolic and endsystolic left ventricular dimensions and decreased fractional shortening. Surprisingly, selective VLCAD gene ablation in cardiomyocytes was sufficient to evoke severe cold intolerance in mice who rapidly developed severe hypothermia, bradycardia, and markedly depressed cardiac function in response to fasting and cold exposure (ϩ5°C). We conclude that cardiac-specific VLCAD deficiency is sufficient to induce cold intolerance and cardiomyopathy and is associated with reduced ATP production. These results provide strong evidence that fatty acid oxidation in myocardium is essential for maintaining normal cardiac function under these stress conditions. fatty acid oxidation; mitochondria; cardiac metabolism; cardiomyopathy; mouse; VLCAD; cold intolerance FATTY ACIDS ARE THE PREFERRED substrate for ATP production in the mammalian heart. Very long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the first step of mitochondrial ␤-oxidation, the dehydrogenation of acyl-CoAs with 14 to 20 carbon-chain fatty acids. Mutations in the VLCAD gene are the most common inherited long-chain fatty acid oxidation (FAO) disorder, with an incidence currently estimated to be between 1/42,500 and 1/120,000 (3,7,27, 46). Affected individuals demonstrate a variety of clinical symptoms including nonketotic hypoglycemia, heart and liver lipidosis, encephalopathy, skeletal myopathy, cardiomyopathy, arrhythmias, and sudden death (2,5,7,22,34). Because VLCAD is highly expressed in the liver, heart, lung, brown adipose tissue (BAT), and skeletal muscles, global VLCAD deficiency causes multiple organ dysfunction and diverse clinical symptoms. Three phenotypes have been described: 1) a severe childhood form with no residual enzyme activity, typically presenting with cardiomyopathy and resulting in high mortality (2, 29, 41); 2) a milder childhood form with hypoketotic hypoglycemia as the main feature (2, 3) and 3) an adult presentation with intermittent skeletal myopathy mainly triggered by fasting or exercise (2).Global VLCAD knockout (KO) mice recapitulate some features of human VLCAD deficiency. Adult KO mice demonstrate cardiomyopathy with increased numbers of degenerative fibers, collagen deposition, and vacuolated myocytes as well as increased lipid accumulation in cardiomyocytes (16), abnormal cardiac electrophysiological changes including facilitated i...

Metabolite accumulation in VLCAD deficiency markedly disrupts mitochondrial bioenergetics and Ca2+ homeostasis in the heart

“…Therefore, it could be also considered that LCFA accumulating in this disorder may be cardiotoxic and important with respect to explaining the cardiomyopathy that affects patients, particularly during crises of metabolic decompensation in which the concentrations of these fatty acids increase dramatically. Similarly, there is evidence of bioenergetics disruption in the hearts of VLCAD-deficient mice, including a decrease in the phosphoreatine/ATP ratio [25], as well as the ATP pool [26], both associated with cardiac dysfunction in mice. Similarly, there is evidence of bioenergetics disruption in the hearts of VLCAD-deficient mice, including a decrease in the phosphoreatine/ATP ratio [25], as well as the ATP pool [26], both associated with cardiac dysfunction in mice.…”

The Modulating Effects of Cardiac Resynchronization Therapy on Myocardial Metabolism in Heart Failure

“…Furthermore, Tucci et al. and Xiong et al found that primary cardiomyopathy and HF were associated with mutations in the human very‐long‐chain acyl‐CoA dehydrogenase gene, which catalyzes the first step in the FFA β‐oxidation. Tuunanen et al .…”

“…Uriel et al 15 found that plasma norepinephrine correlated with FFA levels in HF patients and contributed to insulin resistance. Furthermore, Tucci et al and Xiong et al 16,17 found that primary cardiomyopathy and HF were associated with mutations in the human very-long-chain acyl-CoA dehydrogenase gene, which catalyzes the first step in the FFA β-oxidation. Tuunanen et al 18 suggested that inhibition of FFA metabolism with trimetazidine, the selective inhibitor of mitochondrial long-chain 3-ketoacyl CoA thiolase, has beneficial effects on cardiac performance, exercise capacity, and clinical symptoms in patients with chronic HF.…”

AAV9 gene replacement therapy for respiratory insufficiency in very‐long chain acyl‐CoA dehydrogenase deficiency

“…To better understand the mechanisms behind VLCADD respiratory cycle deficits, we characterized the myopathy and pathophysiology of respiratory insufficiency in exercised and fasted VLCADD mice (VLCAD −/− ). VLCAD −/− mice are an established model for the study of VLCADD because they exhibit cardiomyopathy and have metabolic derangements after stress with fasting and cold . However, no study has described the respiratory phenotype in a clinically relevant fast/exercise stress model.…”

“…VLCAD −/− mice are an established model for the study of VLCADD because they exhibit cardiomyopathy and have metabolic derangements after stress with fasting and cold. [9][10][11][12] However, no study has described the respiratory phenotype in a clinically relevant fast/exercise stress model. This characterization is necessary for the development of therapies that adequately targets respiratory insufficiency in VLCADD.…”