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Medium chain acylcarnitines dominate the metabolite pattern in humans under moderate intensity exercise and support lipid oxidation.

Lehmann R, Zhao X, Weigert C, Simon P, Fehrenbach E, Fritsche J, Machann J, Schick F, Wang J, Hoene M, Schleicher ED, Häring HU, Xu G, Niess AM - PLoS ONE (2010)

Bottom Line: The release of acylcarnitines as intermediates of partial beta-oxidation was verified in skeletal muscle cell culture experiments by probing (13)C-palmitate metabolism.Further investigations in primary human myotubes and mouse muscle tissue revealed that octanoyl-, decanoyl-, and dodecanoyl-carnitine were able to support the oxidation of palmitate, proving more effective than L-carnitine.This physiological production and efflux of acylcarnitines might exert beneficial biological functions in muscle tissue.

View Article: PubMed Central - PubMed

Affiliation: Central Laboratory, Division of Clinical Chemistry and Pathobiochemistry, University Hospital Tuebingen, Tuebingen, Germany. Rainer.Lehmann@med.uni-tuebingen.de

ABSTRACT

Background: Exercise is an extreme physiological challenge for skeletal muscle energy metabolism and has notable health benefits. We aimed to identify and characterize metabolites, which are components of the regulatory network mediating the beneficial metabolic adaptation to exercise.

Methodology and principal findings: First, we investigated plasma from healthy human subjects who completed two independent running studies under moderate, predominantly aerobic conditions. Samples obtained prior to and immediately after running and then 3 and 24 h into the recovery phase were analyzed by a non-targeted (NT-) metabolomics approach applying liquid chromatography-qTOF-mass spectrometry. Under these conditions medium and long chain acylcarnitines were found to be the most discriminant plasma biomarkers of moderately intense exercise. Immediately after a 60 min (at 93% V(IAT)) or a 120 min run (at 70% V(IAT)) a pronounced, transient increase dominated by octanoyl-, decanoyl-, and dodecanoyl-carnitine was observed. The release of acylcarnitines as intermediates of partial beta-oxidation was verified in skeletal muscle cell culture experiments by probing (13)C-palmitate metabolism. Further investigations in primary human myotubes and mouse muscle tissue revealed that octanoyl-, decanoyl-, and dodecanoyl-carnitine were able to support the oxidation of palmitate, proving more effective than L-carnitine.

Conclusions: Medium chain acylcarnitines were identified and characterized by a functional metabolomics approach as the dominating biomarkers during a moderately intense exercise bout possessing the power to support fat oxidation. This physiological production and efflux of acylcarnitines might exert beneficial biological functions in muscle tissue.

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Effects of acylcarnitines on fatty acid oxidation in primary human skeletal muscle cells as well as soleus, extensor digitorum longus, tibialis and quadriceps muscles from mice.Oxidation of 3H-palmitate determined after 4 h in human myotubes in the presence of L-carnitine (L-C), acetylcarnitine (ActC), an equimolar mixture of C8:0-, C10:0- and C12:0-acylcarnitine (AC), or C8:0-(C8-AC), C10:0- (C10-AC) and C12:0-acylcarnitine (C12-AC) as indicated (A,B). Values of 3H-palmitate oxidation of control cells were set as 1. (C) Palmitate oxidation in the presence of 50 µM L-carnitine and 1, 5, 10 or 100 µM AC. Values of 3H-palmitate oxidation of cells solely incubated with 50 µM L-carnitine were set as 1; shown are means ± SEM from 4 independent experiments, * p<0.05 vs. L-carnitine; # p<0.05 vs acetyl-carnitine; † p<0.05 vs. C8-AC or C10-AC, respectively. (D) Oxidation of 3H-palmitate in mouse soleus, extensor digitorum longus (EDL), tibialis (tib) or quadriceps (Q) muscle from three different mice determined after 90 min in the presence of an equimolar mixture of C8:0-, C10:0- and C12:0-acylcarnitine as indicated. Shown are means ± SEM, values of 3H-palmitate oxidation in untreated tissues were set as 1, * p<0.05 vs. untreated tissues.
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pone-0011519-g004: Effects of acylcarnitines on fatty acid oxidation in primary human skeletal muscle cells as well as soleus, extensor digitorum longus, tibialis and quadriceps muscles from mice.Oxidation of 3H-palmitate determined after 4 h in human myotubes in the presence of L-carnitine (L-C), acetylcarnitine (ActC), an equimolar mixture of C8:0-, C10:0- and C12:0-acylcarnitine (AC), or C8:0-(C8-AC), C10:0- (C10-AC) and C12:0-acylcarnitine (C12-AC) as indicated (A,B). Values of 3H-palmitate oxidation of control cells were set as 1. (C) Palmitate oxidation in the presence of 50 µM L-carnitine and 1, 5, 10 or 100 µM AC. Values of 3H-palmitate oxidation of cells solely incubated with 50 µM L-carnitine were set as 1; shown are means ± SEM from 4 independent experiments, * p<0.05 vs. L-carnitine; # p<0.05 vs acetyl-carnitine; † p<0.05 vs. C8-AC or C10-AC, respectively. (D) Oxidation of 3H-palmitate in mouse soleus, extensor digitorum longus (EDL), tibialis (tib) or quadriceps (Q) muscle from three different mice determined after 90 min in the presence of an equimolar mixture of C8:0-, C10:0- and C12:0-acylcarnitine as indicated. Shown are means ± SEM, values of 3H-palmitate oxidation in untreated tissues were set as 1, * p<0.05 vs. untreated tissues.

Mentions: To study the potential effect of medium chain acylcarnitines on fatty acid metabolism, human myotubes were incubated with an equimolar mixture of C8:0-, C10:0- and C12:0-carnitines (in the following referred to as (C8-12:0) carnitines). Comparison of palmitate oxidation in the presence of 10 or 100 µM L-carnitine, acetyl-carnitine or (C8-12:0) carnitines revealed that the medium chain acylcarnitines were most efficient in supporting β-oxidation (Fig. 4A), with C12:0 carnitine being more potent than C10:0- and C8:0-carnitine (Fig. 4B). When we performed palmitate oxidation in the presence of 50 µM L-carnitine and added increasing concentrations of (C8-12:0) carnitine we found a slight, but significant increase in fatty acid oxidation even in the presence of 1 µM of medium chain acylcarnitines (Fig. 4C), which is close to the detected physiological plasma concentration of 1.34 µM of (C8-12:0) carnitine after the run. The additional effect of 10 or 100 µM (C8-12:0)-acylcarnitine (Fig. 4C), which may reflect local extracellular concentrations in skeletal muscle under exercise conditions, was comparable to the difference in palmitate oxidation between equimolar concentrations of L-carnitine and (C8-12:0)-acylcarnitine in figure 4A. To further verify the activation of palmitate oxidation in entire muscle, the effect of 100 µM (C8-12:0)-acylcarnitines was studied ex vivo in oxidative soleus muscle as well as in glycolytic extensor digitorum longus, tibialis and quadriceps muscles from mice. A comparable increase of palmitate oxidation as detected in human myotubes was found (Fig. 4D) supporting a physiological function of the (C8-12:0)-carnitines in skeletal muscle.


Medium chain acylcarnitines dominate the metabolite pattern in humans under moderate intensity exercise and support lipid oxidation.

Lehmann R, Zhao X, Weigert C, Simon P, Fehrenbach E, Fritsche J, Machann J, Schick F, Wang J, Hoene M, Schleicher ED, Häring HU, Xu G, Niess AM - PLoS ONE (2010)

Effects of acylcarnitines on fatty acid oxidation in primary human skeletal muscle cells as well as soleus, extensor digitorum longus, tibialis and quadriceps muscles from mice.Oxidation of 3H-palmitate determined after 4 h in human myotubes in the presence of L-carnitine (L-C), acetylcarnitine (ActC), an equimolar mixture of C8:0-, C10:0- and C12:0-acylcarnitine (AC), or C8:0-(C8-AC), C10:0- (C10-AC) and C12:0-acylcarnitine (C12-AC) as indicated (A,B). Values of 3H-palmitate oxidation of control cells were set as 1. (C) Palmitate oxidation in the presence of 50 µM L-carnitine and 1, 5, 10 or 100 µM AC. Values of 3H-palmitate oxidation of cells solely incubated with 50 µM L-carnitine were set as 1; shown are means ± SEM from 4 independent experiments, * p<0.05 vs. L-carnitine; # p<0.05 vs acetyl-carnitine; † p<0.05 vs. C8-AC or C10-AC, respectively. (D) Oxidation of 3H-palmitate in mouse soleus, extensor digitorum longus (EDL), tibialis (tib) or quadriceps (Q) muscle from three different mice determined after 90 min in the presence of an equimolar mixture of C8:0-, C10:0- and C12:0-acylcarnitine as indicated. Shown are means ± SEM, values of 3H-palmitate oxidation in untreated tissues were set as 1, * p<0.05 vs. untreated tissues.
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pone-0011519-g004: Effects of acylcarnitines on fatty acid oxidation in primary human skeletal muscle cells as well as soleus, extensor digitorum longus, tibialis and quadriceps muscles from mice.Oxidation of 3H-palmitate determined after 4 h in human myotubes in the presence of L-carnitine (L-C), acetylcarnitine (ActC), an equimolar mixture of C8:0-, C10:0- and C12:0-acylcarnitine (AC), or C8:0-(C8-AC), C10:0- (C10-AC) and C12:0-acylcarnitine (C12-AC) as indicated (A,B). Values of 3H-palmitate oxidation of control cells were set as 1. (C) Palmitate oxidation in the presence of 50 µM L-carnitine and 1, 5, 10 or 100 µM AC. Values of 3H-palmitate oxidation of cells solely incubated with 50 µM L-carnitine were set as 1; shown are means ± SEM from 4 independent experiments, * p<0.05 vs. L-carnitine; # p<0.05 vs acetyl-carnitine; † p<0.05 vs. C8-AC or C10-AC, respectively. (D) Oxidation of 3H-palmitate in mouse soleus, extensor digitorum longus (EDL), tibialis (tib) or quadriceps (Q) muscle from three different mice determined after 90 min in the presence of an equimolar mixture of C8:0-, C10:0- and C12:0-acylcarnitine as indicated. Shown are means ± SEM, values of 3H-palmitate oxidation in untreated tissues were set as 1, * p<0.05 vs. untreated tissues.
Mentions: To study the potential effect of medium chain acylcarnitines on fatty acid metabolism, human myotubes were incubated with an equimolar mixture of C8:0-, C10:0- and C12:0-carnitines (in the following referred to as (C8-12:0) carnitines). Comparison of palmitate oxidation in the presence of 10 or 100 µM L-carnitine, acetyl-carnitine or (C8-12:0) carnitines revealed that the medium chain acylcarnitines were most efficient in supporting β-oxidation (Fig. 4A), with C12:0 carnitine being more potent than C10:0- and C8:0-carnitine (Fig. 4B). When we performed palmitate oxidation in the presence of 50 µM L-carnitine and added increasing concentrations of (C8-12:0) carnitine we found a slight, but significant increase in fatty acid oxidation even in the presence of 1 µM of medium chain acylcarnitines (Fig. 4C), which is close to the detected physiological plasma concentration of 1.34 µM of (C8-12:0) carnitine after the run. The additional effect of 10 or 100 µM (C8-12:0)-acylcarnitine (Fig. 4C), which may reflect local extracellular concentrations in skeletal muscle under exercise conditions, was comparable to the difference in palmitate oxidation between equimolar concentrations of L-carnitine and (C8-12:0)-acylcarnitine in figure 4A. To further verify the activation of palmitate oxidation in entire muscle, the effect of 100 µM (C8-12:0)-acylcarnitines was studied ex vivo in oxidative soleus muscle as well as in glycolytic extensor digitorum longus, tibialis and quadriceps muscles from mice. A comparable increase of palmitate oxidation as detected in human myotubes was found (Fig. 4D) supporting a physiological function of the (C8-12:0)-carnitines in skeletal muscle.

Bottom Line: The release of acylcarnitines as intermediates of partial beta-oxidation was verified in skeletal muscle cell culture experiments by probing (13)C-palmitate metabolism.Further investigations in primary human myotubes and mouse muscle tissue revealed that octanoyl-, decanoyl-, and dodecanoyl-carnitine were able to support the oxidation of palmitate, proving more effective than L-carnitine.This physiological production and efflux of acylcarnitines might exert beneficial biological functions in muscle tissue.

View Article: PubMed Central - PubMed

Affiliation: Central Laboratory, Division of Clinical Chemistry and Pathobiochemistry, University Hospital Tuebingen, Tuebingen, Germany. Rainer.Lehmann@med.uni-tuebingen.de

ABSTRACT

Background: Exercise is an extreme physiological challenge for skeletal muscle energy metabolism and has notable health benefits. We aimed to identify and characterize metabolites, which are components of the regulatory network mediating the beneficial metabolic adaptation to exercise.

Methodology and principal findings: First, we investigated plasma from healthy human subjects who completed two independent running studies under moderate, predominantly aerobic conditions. Samples obtained prior to and immediately after running and then 3 and 24 h into the recovery phase were analyzed by a non-targeted (NT-) metabolomics approach applying liquid chromatography-qTOF-mass spectrometry. Under these conditions medium and long chain acylcarnitines were found to be the most discriminant plasma biomarkers of moderately intense exercise. Immediately after a 60 min (at 93% V(IAT)) or a 120 min run (at 70% V(IAT)) a pronounced, transient increase dominated by octanoyl-, decanoyl-, and dodecanoyl-carnitine was observed. The release of acylcarnitines as intermediates of partial beta-oxidation was verified in skeletal muscle cell culture experiments by probing (13)C-palmitate metabolism. Further investigations in primary human myotubes and mouse muscle tissue revealed that octanoyl-, decanoyl-, and dodecanoyl-carnitine were able to support the oxidation of palmitate, proving more effective than L-carnitine.

Conclusions: Medium chain acylcarnitines were identified and characterized by a functional metabolomics approach as the dominating biomarkers during a moderately intense exercise bout possessing the power to support fat oxidation. This physiological production and efflux of acylcarnitines might exert beneficial biological functions in muscle tissue.

Show MeSH
Related in: MedlinePlus