Markus Spaniol

Universitätsspital Basel, Bâle, Basel-City, Switzerland

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Publications (6)47.82 Total impact

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    ABSTRACT: Carnitine is essential for mitochondrial metabolism of long-chain fatty acids and thus for myocardial energy production. Accordingly, carnitine deficiency can be associated with cardiomyopathy. To better understand this disease, we determined myocardial function and energy metabolism in a rat model of carnitine deficiency. Carnitine deficiency was induced by a 3- or 6-week diet containing N-trimethyl-hydrazine-3-propionate, reducing cardiac and plasma carnitine by 70-85%. Myocardial function was investigated in isolated isovolumic heart preparations. Carnitine-deficient hearts showed left ventricular systolic dysfunction, reduced contractile reserve, and a blunted frequency-force relationship independently of the substrate used (glucose or palmitate). After glycogen depletion, palmitate could not sustain myocardial function. Histology and activities of carnitine palmitoyl transferase, citrate synthase, and cytochrome c oxidase were unaltered. Thus, as little as 3-6 weeks of systemic carnitine deficiency can lead to abnormalities in myocardial function. These abnormalities are masked by endogenous glycogen and are not accompanied by structural alterations of the myocardium or by altered activities of important mitochondrial enzymes.
    Cellular and Molecular Life Sciences CMLS 05/2003; 60(4):767-75. DOI:10.1007/s00018-003-3011-1 · 5.81 Impact Factor
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    ABSTRACT: Rats with systemic carnitine deficiency induced by treatment with trimethylhydraziniumpropionate (THP) develop liver steatosis. This study aims to investigate the mechanisms leading to steatosis in THP-induced carnitine deficiency. Rats were treated with THP (20 mg/100 g) for 3 or 6 weeks and were studied after starvation for 24 h. Rats treated with THP had reduced in vivo palmitate metabolism and developed mixed liver steatosis at both time points. The hepatic carnitine pool was reduced in THP-treated rats by 65% to 75% at both time points. Liver mitochondria from THP-treated rats had increased oxidative metabolism of various substrates and of beta-oxidation at 3 weeks, but reduced activities at 6 weeks of THP treatment. Ketogenesis was not affected. The hepatic content of CoA was increased by 23% at 3 weeks and by 40% at 6 weeks in THP treated rats. The cytosolic content of long-chain acyl-CoAs was increased and the mitochondrial content decreased in hepatocytes of THP treated rats, compatible with decreased activity of carnitine palmitoyltransferase I in vivo. THP-treated rats showed hepatic peroxisomal proliferation and increased plasma VLDL triglyceride and phospholipid concentrations at both time points. A reduction in the hepatic carnitine pool is the principle mechanism leading to impaired hepatic fatty acid metabolism and liver steatosis in THP-treated rats. Cytosolic accumulation of long-chain acyl-CoAs is associated with increased plasma VLDL triglyceride, phospholipid concentrations, and peroxisomal proliferation.
    The Journal of Lipid Research 02/2003; 44(1):144-53. DOI:10.1016/S0168-8278(02)80065-4 · 4.42 Impact Factor
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    ABSTRACT: Amiodarone is a well-known mitochondrial toxin consisting of a benzofuran ring (ring A) coupled to a p-OH-benzene structure substituted with 2 iodines and a diethyl-ethanolamine side chain (ring B). To find out which part of amiodarone is responsible for mitochondrial toxicity. Amiodarone, ring A and B without the ethanolamine side-chain and iodines (B0), ring A and B with iodines but no ethanolamine (B2), ring B with 1 iodine and no ethanolamine (C1) and ring B with ethanolamine and 2 iodines (D2) were studied. In freshly isolated rat liver mitochondria, amiodarone inhibited state 3 glutamate and palmitoyl-CoA oxidation and decreased the respiratory control ratios. B0 and B2 were more potent inhibitors than amiodarone and B2 more potent than B0. C1 and D2 showed no significant mitochondrial toxicity. After disruption, mitochondrial oxidases and complexes of the electron transport chain were inhibited by amiodarone, B0 and B2, whereas C1 and D2 revealed no inhibition. Beta-oxidation showed a strong inhibition by amiodarone, B0 and B2 but not by C1 or D2. Ketogenesis was almost unaffected. Amiodarone, B0 and B2 are uncouplers of oxidative phosphorylation, and inhibit complexes I, II and III, and beta-oxidation. The benzofuran structure is responsible for mitochondrial toxicity of amiodarone and the presence of iodine is not essential.
    Journal of Hepatology 12/2001; 35(5):628-36. DOI:10.1016/S0168-8278(01)00189-1 · 11.34 Impact Factor
  • Markus M. Spaniol · Roswitha Bracher · Ha Riem · Stephan Kraehenbuehl ·

    Journal of Hepatology 04/2001; 34:192-192. DOI:10.1016/S0168-8278(01)81583-X · 11.34 Impact Factor

  • Journal of Hepatology 04/2001; 34:192-193. DOI:10.1016/S0168-8278(01)81584-1 · 11.34 Impact Factor
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    ABSTRACT: Mammals cover their carnitine needs by diet and biosynthesis. The last step of carnitine biosynthesis is the conversion of butyrobetaine to carnitine by butyrobetaine hydroxylase. We investigated the effect of N-trimethyl-hydrazine-3-propionate (THP), a butyrobetaine analogue, on butyrobetaine hydroxylase kinetics, and carnitine biosynthesis and body homeostasis in rats fed a casein-based or a vegetarian diet. The Km of butyrobetaine hydroxylase purified from rat liver was 41 ± 9 μmol·L-1 for butyrobetaine and 37 ± 5 μmol·L-1 for THP, and THP was a competitive inhibitor of butyrobetaine hydroxylase (Ki 16 ± 2 μmol·L-1). In rats fed a vegetarian diet, renal excretion of total carnitine was increased by THP (20 mg·100 g-1·day-1 for three weeks), averaging 96 ± 36 and 5.3 ± 1.2 μol·day-1 in THP-treated and control rats, respectively. After three weeks of treatment, the total carnitine plasma concentration (8.8 ± 2.1 versus 52.8 ± 11.4 μmol·L-1) and tissue levels were decreased in THP-treated rats (liver 0.19 ± 0.03 versus 0.59 ± 0.08 and muscle 0.24 ± 0.04 versus 1.07 ± 0.13 μmol·g-1). Carnitine biosynthesis was blocked in THP-treated rats (-20.22 ± 0.13 versus 0.57 ± 0.21 μmol·100 g-1·day-1). Similar results were obtained in rats treated with the casein-based diet. THP inhibited carnitine transport by rat renal brush-border membrane vesicles competitively (Ki 41 ± 3 μmol·L-1). Palmitate metabolism in vivo was impaired in THP-treated rats and the livers showed mixed steatosis. Steady-state mRNA levels of the carnitine transporter rat OCTN2 were increased in THP-treated rats in skeletal muscle and small intestine. In conclusion, THP inhibits butyrobetaine hydroxylase competitively, blocks carnitine biosynthesis in vivo and interacts competitively with renal carnitine reabsorption. THP-treated rats develop systemic carnitine deficiency over three weeks and can therefore serve as an animal model for human carnitine deficiency.
    European Journal of Biochemistry 04/2001; 268(6):1876-87. DOI:10.1046/j.1432-1327.2001.02065.x · 3.58 Impact Factor