Catherine H. Le

Dietary linoleate preserves cardiolipin and attenuates mitochondrial dysfunction in the failing rat heart

AIMS Cardiolipin (CL) is a tetra-acyl phospholipid that provides structural and functional support to several proteins in the inner mitochondrial membrane. The majority of CL in the healthy mammalian heart contains four linoleic acid acyl chains (L(4)CL). A selective loss of L(4)CL is associated with mitochondrial dysfunction and heart failure in humans and animal models. We examined whether supplementing the diet with linoleic acid would preserve cardiac L(4)CL and attenuate mitochondrial dysfunction and contractile failure in rats with hypertensive heart failure. METHODS AND RESULTS Male spontaneously hypertensive heart failure rats (21 months of age) were administered diets supplemented with high-linoleate safflower oil (HLSO) or lard (10% w/w; 28% kilocalorie fat) or without supplemental fat (control) for 4 weeks. HLSO preserved L(4)CL and total CL to 90% of non-failing levels (vs. 61-75% in control and lard groups), and attenuated 17-22% decreases in state 3 mitochondrial respiration observed in the control and lard groups (P < 0.05). Left ventricular fractional shortening was significantly higher in HLSO vs. control (33 ± 2 vs. 29 ± 2%, P < 0.05), while plasma insulin levels were lower (5.4 ± 1.1 vs. 9.1 ± 2.3 ng/mL; P < 0.05), with no significant effect of lard supplementation. HLSO also increased serum concentrations of several eicosanoid species compared with control and lard diets, but had no effect on plasma glucose or blood pressure. CONCLUSION Moderate consumption of HLSO preserves CL and mitochondrial function in the failing heart and may be a useful adjuvant therapy for this condition.

Delta-6-desaturase Links Polyunsaturated Fatty Acid Metabolism With Phospholipid Remodeling and Disease Progression in Heart Failure

Background— Remodeling of myocardial phospholipids has been reported in various forms of heart failure for decades, but the mechanism and pathophysiological relevance of this phenomenon have remained unclear. We examined the hypothesis that &dgr;-6 desaturase (D6D), the rate-limiting enzyme in long-chain polyunsaturated fatty acid biosynthesis, mediates the signature pattern of fatty acid redistribution observed in myocardial phospholipids after chronic pressure overload and explored plausible links between this process and disease pathogenesis. Methods and Results— Compositional analysis of phospholipids from hearts explanted from patients with dilated cardiomyopathy revealed elevated polyunsaturated fatty acid product/precursor ratios reflective of D6D hyperactivity, manifesting primarily as lower levels of linoleic acid with reciprocally higher levels of arachidonic and docosahexaenoic acids. This pattern of remodeling was attenuated in failing hearts chronically unloaded with a left ventricular assist device. Chronic inhibition of D6D in vivo reversed similar patterns of myocardial polyunsaturated fatty acid redistribution in rat models of pressure overload and hypertensive heart disease and significantly attenuated cardiac hypertrophy, fibrosis, and contractile dysfunction in both models. D6D inhibition also attenuated myocardial elevations in pathogenic eicosanoid species, lipid peroxidation, and extracellular receptor kinase 1/2 activation; normalized cardiolipin composition in mitochondria; reduced circulating levels of inflammatory cytokines; and elicited model-specific effects on cardiac mitochondrial respiratory efficiency, nuclear factor &kgr; B activation, and caspase activities. Conclusions— These studies demonstrate a pivotal role of essential fatty acid metabolism in myocardial phospholipid remodeling induced by hemodynamic stress and reveal novel links between this phenomenon and the propagation of multiple pathogenic systems involved in maladaptive cardiac remodeling and contractile dysfunction.

Inhibition of Delta-6 Desaturase Reverses Cardiolipin Remodeling and Prevents Contractile Dysfunction in the Aged Mouse Heart Without Altering Mitochondrial Respiratory Function

Aging results in a redistribution of polyunsaturated fatty acids (PUFAs) in myocardial phospholipids. In particular, a selective loss of linoleic acid (18:2n6) with reciprocal increases of long-chain PUFAs (eg, arachidonic and docosahexaenoic acids) in the mitochondrial phospholipid cardiolipin correlates with cardiac mitochondrial dysfunction and contractile impairment in aging and related pathologies. In this study, we demonstrate a reversal of this aged-related PUFA redistribution pattern in cardiac mitochondria from aged (25 months) C57Bl/6 mice by inhibition of delta-6 desaturase, the rate limiting enzyme in long-chain PUFA biosynthesis. Interestingly, delta-6 desaturase inhibition had no effect on age-related mitochondrial respiratory dysfunction, H2O2 release, or lipid peroxidation but markedly attenuated cardiac dilatation, hypertrophy, and contractile dysfunction in aged mice. Taken together, our studies indicate that PUFA metabolism strongly influences phospholipid remodeling and cardiac function but dissociates these processes from mitochondrial respiratory dysfunction and oxidant production in the aged mouse heart.

Delta-6-desaturase Links PUFA Metabolism with Phospholipid Remodeling and Disease Progression in Heart Failure

Background— Remodeling of myocardial phospholipids has been reported in various forms of heart failure for decades, but the mechanism and pathophysiological relevance of this phenomenon have remained unclear. We examined the hypothesis that &dgr;-6 desaturase (D6D), the rate-limiting enzyme in long-chain polyunsaturated fatty acid biosynthesis, mediates the signature pattern of fatty acid redistribution observed in myocardial phospholipids after chronic pressure overload and explored plausible links between this process and disease pathogenesis. Methods and Results— Compositional analysis of phospholipids from hearts explanted from patients with dilated cardiomyopathy revealed elevated polyunsaturated fatty acid product/precursor ratios reflective of D6D hyperactivity, manifesting primarily as lower levels of linoleic acid with reciprocally higher levels of arachidonic and docosahexaenoic acids. This pattern of remodeling was attenuated in failing hearts chronically unloaded with a left ventricular assist device. Chronic inhibition of D6D in vivo reversed similar patterns of myocardial polyunsaturated fatty acid redistribution in rat models of pressure overload and hypertensive heart disease and significantly attenuated cardiac hypertrophy, fibrosis, and contractile dysfunction in both models. D6D inhibition also attenuated myocardial elevations in pathogenic eicosanoid species, lipid peroxidation, and extracellular receptor kinase 1/2 activation; normalized cardiolipin composition in mitochondria; reduced circulating levels of inflammatory cytokines; and elicited model-specific effects on cardiac mitochondrial respiratory efficiency, nuclear factor &kgr; B activation, and caspase activities. Conclusions— These studies demonstrate a pivotal role of essential fatty acid metabolism in myocardial phospholipid remodeling induced by hemodynamic stress and reveal novel links between this phenomenon and the propagation of multiple pathogenic systems involved in maladaptive cardiac remodeling and contractile dysfunction.

High fatty acid oxidation capacity and phosphorylation control despite elevated leak and reduced respiratory capacity in northern elephant seal muscle mitochondria

Northern elephant seals (Mirounga angustirostris) are extreme, hypoxia-adapted endotherms that rely largely on aerobic metabolism during extended breath-hold dives in near-freezing water temperatures. While many aspects of their physiology have been characterized to account for these remarkable feats, the contribution of adaptations in the aerobic powerhouses of muscle cells, the mitochondria, are unknown. In the present study, the ontogeny and comparative physiology of elephant seal muscle mitochondrial respiratory function was investigated under a variety of substrate conditions and respiratory states. Intact mitochondrial networks were studied by high-resolution respirometry in saponin-permeabilized fiber bundles obtained from primary swimming muscles of pup, juvenile and adult seals, and compared with fibers from adult human vastus lateralis. Results indicate that seal muscle maintains a high capacity for fatty acid oxidation despite a progressive decrease in total respiratory capacity as animals mature from pups to adults. This is explained by a progressive increase in phosphorylation control and fatty acid utilization over pyruvate in adult seals compared with humans and seal pups. Interestingly, despite higher indices of oxidative phosphorylation efficiency, juvenile and adult seals also exhibit a ~50% greater capacity for respiratory ‘leak’ compared with humans and seal pups. The ontogeny of this phenotype suggests it is an adaptation of muscle to the prolonged breath-hold exercise and highly variable ambient temperatures experienced by mature elephant seals. These studies highlight the remarkable plasticity of mammalian mitochondria to meet the demands for both efficient ATP production and endothermy in a cold, oxygen-limited environment.

Adaptive remodeling of skeletal muscle energy metabolism in high-altitude hypoxia: Lessons from AltitudeOmics

Metabolic responses to hypoxia play important roles in cell survival strategies and disease pathogenesis in humans. However, the homeostatic adjustments that balance changes in energy supply and demand to maintain organismal function under chronic low oxygen conditions remain incompletely understood, making it difficult to distinguish adaptive from maladaptive responses in hypoxia-related pathologies. We integrated metabolomic and proteomic profiling with mitochondrial respirometry and blood gas analyses to comprehensively define the physiological responses of skeletal muscle energy metabolism to 16 days of high-altitude hypoxia (5260 m) in healthy volunteers from the AltitudeOmics project. In contrast to the view that hypoxia down-regulates aerobic metabolism, results show that mitochondria play a central role in muscle hypoxia adaptation by supporting higher resting phosphorylation potential and enhancing the efficiency of long-chain acylcarnitine oxidation. This directs increases in muscle glucose toward pentose phosphate and one-carbon metabolism pathways that support cytosolic redox balance and help mitigate the effects of increased protein and purine nucleotide catabolism in hypoxia. Muscle accumulation of free amino acids favor these adjustments by coordinating cytosolic and mitochondrial pathways to rid the cell of excess nitrogen, but might ultimately limit muscle oxidative capacity in vivo. Collectively, these studies illustrate how an integration of aerobic and anaerobic metabolism is required for physiological hypoxia adaptation in skeletal muscle, and highlight protein catabolism and allosteric regulation as unexpected orchestrators of metabolic remodeling in this context. These findings have important implications for the management of hypoxia-related diseases and other conditions associated with chronic catabolic stress.