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Abstract: Rat hearts perfused for up to 60min in the working mode with palmitate, but not with glucose, resulted in substantial formation of palmitoylcarnitine and stearoylcarnitine. To test whether lipolysis of endogenous lipids was responsible for the increased stearoylcarnitine content or whether some of the perfused palmitate underwent chain elongation, hearts were perfused with hexadecanoic-16,16,16-d 3 acid (M+3). The pentafluorophenacyl ester of deuterium labeled stearoylcarnitine had an M+3 (639.4 m/z) compared to the unlabeled M+0 (636.3 m/z) consistent with a direct chain elongation of the perfused palmitate. Furthermore, the near equal isotope enrichment of palmitoyl- (90.2±5.8%) and stearoylcarnitine (78.0±7.1%) suggest that both palmitoyl- and stearoyl-CoA have ready access to mitochondrial carnitine palmitoyltransferase and that most of the stearoylcarnitine is derived from the perfused palmitate. [Copyright &y& Elsevier]

Alterations in oxidation of substrates and the phosphorylation process in cardiac and skeletal muscle mitochondria may be a key mechanism in the pathogenesis of both myocardium and skeletal muscle dysfunction in heart failure (HF). Subsarcolemmal (SSM) and intefibrillar (IFM) mitochondria were isolated from gastrocnemius muscle of control dogs and dogs with pacing-induced HF. HF was evident by an increase in end diastolic volume from 58±6 to 112±25 ml and a decrease in fractional shortening from 32±2% to 16±2% (Mean±SE, control vs HF, respectively). The significant decrease in oxidative phosphorylation in IFM was relieved in IFM upon raising the ADP concentration or uncoupling oxidation from the phosphorylation process. The activities of the individual ETC enzymes were in normal range in mitochondria isolated from HF dogs. These data demonstrate that the phosphorylation process rather than substrate oxidation is damaged with HF. A significant decrease in the activity of the ATP synthase was found specifically in skeletal muscle SSM. IFM have a significant decrease in the amount of the adenine nucleotide translocase 2 isoform. In conclusion, during moderate severity HF the different populations of skeletal muscle mitochondria develop specific defects localized in the phosphorylation apparatus. [ABSTRACT FROM AUTHOR]

Reperfusion of ischemic hearts results in increased fatty acid oxidation and decreased functional recovery. Here we tested whether the greater susceptibility of hearts from elderly rats to ischemia/reperfusion injury as compared to adult ones is due to excessive accumulation of arrythmogenic long-chain acylcarnitines. 24 and 6 month Fischer 344 rats were anesthetized (Nembutal) and the hearts perfused in the working mode with 5mM glucose, 0.1mU insulin, and 1.2mM palmitate/3% fatty acid free BSA for 15min, followed by 15min ischemia, or 15min ischemia and 30min reperfusion. Hearts were, freeze-clamped and the total, free, acylcarnitine and individual acylcarnitines determined by LC/MS. There is a significant decrease in total, free and acylcarnitine with age without a change in the acylcarnitine/free carnitine ratio. Anesthesia significantly decreases the acylcarnitine/free carnitine ratio in both adult and elderly hearts due to increases in free carnitine and decreases the acylcarnitine fraction. Perfusion of adult and elderly rat hearts results in loss of tissue carnitine. While ischemia and ischemia/reperfusion of adult and elderly hearts have no significant effect on short-chain acylcarnitines, there is a significant accumulation of the long-chain acylcarnitines, particularly palmitoyl- and stearoylcarnitine. [ABSTRACT FROM AUTHOR]