HomeLarge Type Edition
HOME ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Services
Right arrow Download to citation manager
PubMed
Right arrow PubMed Citation
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 63:1027-1033 (2008)
© 2008 The Gerontological Society of America

L-Carnitine Supplementation and Physical Exercise Restore Age-Associated Decline in Some Mitochondrial Functions in the Rat

Arnaud Bernard, Caroline Rigault, Frédéric Mazue, Françoise Le Borgne and Jean Demarquoy

INSERM, U866, Université de Bourgogne, Dijon, France.

Address correspondence to Jean Demarquoy, PhD, INSERM, U866, Université de Bourgogne, 6 boulevard Gabriel, 21000 Dijon, France. E-mail: jean.demarquoy{at}u-bourgogne.fr


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
In mammals, during the aging process, an atrophy of the muscle fibers, an increase in body fat mass, and a decrease in skeletal muscle oxidative capacities occur. Compounds and activities that interact with lipid oxidative metabolism may be useful in limiting damages that occur in aging muscle. In this study, we evaluated the effect of L-carnitine and physical exercise on several parameters related to muscle physiology. We described that supplementing old rats with L-carnitine at 30 mg/kg body weight for 12 weeks (a) allowed the restoration of L-carnitine level in muscle cells, (b) restored muscle oxidative activity in the soleus, and (c) induced positive changes in body composition: a decrease in abdominal fat mass and an increase in muscle capabilities without any change in food intake. Moderate physical exercise was also effective in (a) limiting fat mass gain and (b) inducing an increase in the capacities of the soleus to oxidize fatty acids.

Key Words: L-carnitine • Muscle • Rat • Aging

AGING is a highly complex phenomenon involving both genetic and environmental factors. Aging causes a multitude of detrimental changes in the organism; it decreases many maximum functional capacities and increases the probability of suffering degenerative diseases (1). Several hypotheses have been enunciated to explain aging, most of them linked to the mitochondria and the dysregulation of the mitochondrial metabolism (2).

Aging is associated with a decrease in muscle mass and muscle oxidative capacities associated with an atrophy of the muscle fibers, an increase in fat gain, and a decrease in lean mass. These changes are probably influenced by hormonal status and also by alterations in the structure and the metabolism of muscle cells which could lead to a progressive degeneration and a mitochondrial release of cytochrome c (3) and eventually apoptosis (4).

Although aging is not reversible, several compounds seem to be able to slow down the negative aspects of aging. Among those are antioxidants and agents such as L-carnitine known to regulate energy production (5). One can also include moderate physical exercise, an activity that can regulate the production of oxidants, as a factor favorably influencing aging.

L-carnitine is a cofactor in the channeling of fatty acids inside the cell. It plays two major functions in the cell: It is involved in fatty acid oxidation as it acts as a cofactor in the transport of acyl groups across the inner mitochondrial membrane, through the carnitine palmitoyl transferase/carnitine acyl-carnitine transferase (CPT/CACT) system (6). It also removes acyl groups from the mitochondria and the cell as acylcarnitines (7). L-carnitine found in the body is either provided by food stuffs (especially meat products) (8) or comes from an endogenous biosynthetic pathway. The final step in L-carnitine biosynthesis is made by the cytosolic {gamma} butyrobetaine hydroxylase (BBH). In rats, this enzyme is mainly found in the liver (9).

There is a lack of consistency in results regarding whether physical exercise increases or decreases oxidative stress (10). The production of reactive oxygen species may considerably increase when mitochondria increase their oxygen input (11) such as during physical exercise. In contrast, moderate physical exercise ameliorates mitochondrial function in the liver (12).

Thus, one can hypothesize that nutritional supplementation with L-carnitine and moderate physical exercise may improve the mitochondrial oxidative metabolism and subsequently limit the side effects of aging. This was the aim of this study.


   MATERIALS AND METHODS
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Chemicals
L-carnitine (Carnipure) was provided by Lonza (Basel, Switzerland). All other chemicals were of reagent grade and were obtained from Sigma (St. Louis, MO).

Animals
Male Wistar rats, approximately 4 months old (young) and 24 month old (old), were used in this study. Animals were housed in individual cages at a temperature of 22 ± 2°C with a 12-hour day/night cycle. The rats were adapted to the housing conditions for at least 2 weeks before the experimentation. Animals had free access to food (AO 4; U.A.R., Charlette sur Loing, France) and water.

The young animals were randomly assigned to two different groups: a control group receiving tap water and a group receiving L-carnitine at 30 mg/kg body weight through the drinking water (based on a 17.5 mL water intake per day). The old animals were divided into four groups (control, L-carnitine-supplemented rats, rats doing physical exercise, rats doing physical exercise and supplemented with L-carnitine). Each group consisted of six animals.

Physical exercise was done under a moderate protocol. Three times a week animals were put on a treadmill for 20 minutes at a speed of 13 m/min. Control animals were mock-treated and were placed on the treadmill once a week.

Thus, six groups of animals were used: Group I = control young rats; Group II = L-carnitine-supplemented young rats; Group III = control old rats; Group IV = old rats receiving L-carnitine; Group V = old rats doing physical exercise; and Group VI = old rats administered L-carnitine and doing physical exercise. The experimental procedure was conducted for 12 weeks.

On completion of the experimental period, animals were anesthetized using isoflurane and were quickly killed by cervical dislocation. Organs were immediately excised and kept on ice for immediate use or were frozen in liquid nitrogen and kept at –82°C.

Physiological Parameters
All animals had their body weight recorded once a week during the experiment. Food intake was estimated regularly (on a weekly basis) by differential weighing of food offered and food remaining the next day. Water intake per day was also estimated on a weekly basis. At the end of the training, the mass of the liver, the brain, the soleus and the tibialis anterioris muscles, the periepididymal fat, the kidney, and the brain was measured. After all the organs were removed, the abdominal fat was removed and weighed.

Subcellular Fractionation
Mitochondrial isolation.-- The liver and the muscles were washed in homogenizing medium (0.25 M sucrose, 5 mM HEPES buffer, and 1 mM EDTA, pH 7.2), minced into small pieces (around 100 mg), and homogenized using a Teflon-on-glass (Potter–Elvehjem) homogenizer. The homogenate was centrifuged at 500 x g for 10 minutes and the pellet discarded. The supernatant (S1) was centrifuged at 10,000 x g for 10 minutes. The resulting supernatant (S2) was used for cytosol preparation as described in the following paragraph. The pellet was resuspended into the homogenizing buffer and centrifuged again at 10,000 x g for 10 minutes. The final pellet was resuspended in a small volume of the homogenizing buffer and represents the mitochondrial fraction. The content of the fractions was estimated by determining the activity of markers in the fractions as in (13). Only fractionations with relevant results were used in this article.

Cytosol isolation.-- The S2 supernatant was centrifuged at 18,000 x g for 20 minutes at 4°C to remove the mitochondria, the peroxisomes, and the lysosomes. The supernatant was centrifuged again at 100,000 x g for 60 minutes to remove remaining microsomes. The final supernatant was used as the cytosolic fraction. The nature of the cytosolic fraction was routinely estimated with specific markers as in (13).

L-Carnitine Determination
L-carnitine concentration was determined in the cytosolic fraction using a radioisotopic method (8).

Determination of Biochemical Parameters
β-oxidation determination.-- The β-oxidation of [1-14C]oleic acid by liver and skeletal muscle mitochondria was assessed according to (14). The incubation vials contained 500 µg of mitochondrial protein in 900 µL of incubation solution. They were closed with a rubber stopper and incubated for 15 minutes at 37°C.

Enzymatic activities.-- CPT activity was determined on mitochondrial fractions obtained from liver and muscles. CPT activity was measured by the formation of palmitoyl-[3H]carnitine from palmitoyl-coenzyme A (CoA) and L-[3H]carnitine (15). The activity of {gamma} BBH, the enzyme responsible for L-carnitine biosynthesis, was measured by the formation of L-carnitine as in (9).

Protein content.-- Protein concentration was estimated using the Pierce BCA (bicinchoninic acid) procedure with bovine serum albumin as a standard (16).

Statistical Analysis
Data shown in the table and the figures are the means ± standard error of the mean. Comparison between the different groups was done with a Kruskal–Wallis test. Pairwise comparison between each group of animals was done with a Mann–Whitney U test. Significance was assumed at p <.05.


   RESULTS
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
L-Carnitine Content in Plasma, Liver, and Muscles
L-carnitine content was determined in the plasma, the liver, the soleus (a lipolytic muscle), and the tibialis anterioris (a mixed-glycolytic muscle; Table 1).


View this table:
[in this window]
[in a new window]

  		Table 1. Evolution of Several Physiological and Biochemical Parameters During the 12-Week Period: Effect of L-Carnitine Supplementation and Physical Exercise.

 
In young animals, L-carnitine supplementation induced an increase in the L-carnitine plasma level (21%, p <.05). In old animals receiving L-carnitine (groups IV and VI), supplementation induced a statistically significant increase in L-carnitine plasma levels whereas physical exercise alone did not alter L-carnitine content in the plasma.

In the liver, L-carnitine content remained the same along the experiments in all groups of animals. No significant difference was found between young and old rats, and L-carnitine supplementation or physical exercise remained ineffective in modifying liver L-carnitine level.

In the soleus muscle of old rats, L-carnitine concentration was found to be significantly decreased (–34%, p <.05) as compared to young animals. L-carnitine supplementation allowed an increase in L-carnitine content reaching levels observed in the young rats. Physical activity alone did not alter L-carnitine content in the soleus of old animals, whereas the combination of physical activity and L-carnitine supplementation increased L-carnitine content in this muscle. In young rats, L-carnitine supplementation did not alter the soleus muscle L-carnitine content.

In the tibialis anterioris, L-carnitine level was found to be slightly lower than in the soleus (–52%) in all animals. In this muscle, whatever the age or the treatment, no significant differences were found between young and old rats. In old rats, neither L-carnitine treatment nor physical exercise (alone or with an L-carnitine supplementation) induced any change in L-carnitine content or the tibialis anterioris (Table 1).

Evolution of Various Physiological Parameters
Evolution of body weight.-- The data concerning the evolution of body weight are presented in Table 1. For all rats, body weight increased during the 12-week period. For the control young rats, the increase was found to be 118 ± 19 g. This increase was the same in young animals receiving L-carnitine.

In control old rats, the weight increase was 63 ± 12 g. Old rats receiving L-carnitine showed no weight increase during the 12-week period. Animals doing physical exercise exhibited a weight increase of 44 ± 6 g (which was significantly different from the control and the L-carnitine-treated animals), and old animals receiving L-carnitine and exercising had a weight increase of 6 ± 3 g. This value was found to be the same as in L-carnitine–treated animals. The increase in body weight did not appear to be associated with an increase in either food intake or water consumption. Food and water intakes were recorded all during the experiment, and no change was found.

Organ weights.-- The weight of various organs and tissues were recorded at the end of the experiment. These values are summarized in Table 1. No differences were observed in the liver, the heart, the kidney, the brain, the testis, the periepididymal fat, or the soleus and the tibialis anterioris muscles between the animals of the different groups. In contrast, in old control animals, the amount of abdominal fat was higher than in old animals of any other group. However, only between old control animals and old animals receiving L-carnitine supplementation and exercise was this difference statistically significant.

Food and water intakes.-- Food and water intakes were determined, and no alteration was observed during the experiment in young or old rats.

Mitochondrial β-Oxidation
β-oxidation rates were determined in the liver and in the soleus and the tibialis anterioris muscles. In the liver, the β-oxidation was not altered by age, L-carnitine treatment, or physical exercise (Figure 1). Even if β-oxidation of old rats was always lower than in young rats, no significant difference was found.


Figure 01
View larger version (23K):
[in this window]
[in a new window]

  		Figure 1. Fatty acid oxidation in the liver. Fatty acid oxidation was determined using oleic acid as a substrate. It is expressed in nanomoles of oleate oxidized per hour and per gram of liver. Each value represents the average of six rats ± standard error. Group I = young control rats; II = young rats supplemented with L-carnitine; III = old control rats; IV = old rats supplemented with L-carnitine; V = old rats doing physical exercise; and VI = old rats receiving L-carnitine and doing physical exercise

 
In the soleus muscle of young animals, the β-oxidation of oleic acid was not modified by L-carnitine supplementation (Figure 2). In old rats, the β-oxidation rate was generally reduced (–24%) compared to the young rats. In old animals, physical exercise alone allowed an increase in the mitochondrial ability to oxidize fatty acids (from 39.8 to 54.7 nmol/h/g tissue). Also adding L-carnitine to the drinking water of old rats induced a marked increase of the mitochondrial oxidation of oleic acid (55%). When L-carnitine was given to animals doing physical exercise, no further increase in β-oxidation was observed.


Figure 02
View larger version (22K):
[in this window]
[in a new window]

  		Figure 2. Fatty acid oxidation in the soleus muscle. Fatty acid oxidation was determined using oleic acid as a substrate. It is expressed in nanomoles of oleate oxidized per hour and per gram of soleus. Each value represents the average of six rats ± standard error. Superscript letters indicate significant differences (p <.05). Group I = young control rats; II = young rats supplemented with L-carnitine; III = old control rats; IV = old rats supplemented with L-carnitine; V = old rats doing physical exercise; and VI = old rats receiving L-carnitine and doing physical exercise

 
The tibialis anterioris exhibited, as expected, reduced β-oxidation activity compared to the soleus (about half in the tibialis compared to the soleus). The oxidative ability remained the same between young and old animals, and neither L-carnitine nor exercise modified this metabolic activity (Figure 3).


Figure 03
View larger version (21K):
[in this window]
[in a new window]

  		Figure 3. Fatty acid oxidation in the tibialis anterioris muscle. Fatty acid oxidation was determined using oleic acid as a substrate. It is expressed in nanomoles of oleate oxidized per hour and per gram of muscle. Each value represents the average of six rats ± standard error. Group I = young control rats; II = young rats supplemented with L-carnitine; III = old control rats; IV = old rats supplemented with L-carnitine; V = old rats doing physical exercise; and VI = old rats receiving L-carnitine and doing physical exercise

 
CPT I and BBH Activities
CPT I activity was determined in the liver and the soleus and the tibialis anterioris of all animals (Table 1). In the liver, one can notice a slight decrease in CPT I activity when comparing young and old control rats (–22%). In old rats, L-carnitine supplementation induced an 18% increase in CPT I activity. Physical activity induced a comparable increase, and no cumulative effect of L-carnitine and physical exercise was observed (Table 1).

In the soleus, the CPT I activity was lower in old animals compared to young animals of the control groups (–18%). Old rats supplemented with L-carnitine exhibited an increase in their CPT I activity (18%). Interestingly, the same increase was found for animals doing physical exercise and those receiving L-carnitine and doing physical exercise.

In the tibialis anterioris, CPT I activities remained stable between young and old animals. Adding L-carnitine to the drinking water of young or old animals did not significantly alter CPT I activity. Basic physical exercise did not modify CPT I activity in old rats (Table 1).

The activity of BBH, the enzyme responsible for L-carnitine biosynthesis, was determined in the cytosolic fractions of the liver (Table 1). BBH activity remained stable whatever the treatment or the age of the animal. No significant differences were found between the different groups of animals.


   DISCUSSION
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Aging affects all types of muscle cells. It has been shown that postmitotic tissues such as muscle cells accumulate mitochondrial damage faster than mitotically active tissues (17). Thus, the maintenance of mitochondrial function may be important to maintain overall muscle function. Many authors have shown that oxidants are produced in the mitochondria. This production increases with altered function of the mitochondrial oxidative metabolism (12,18), and during aging the antioxidant defense mechanism is diminished (19).

β-oxidation of fatty acids is the major metabolic pathway for various organs and tissues to generate energy (20). It has been suggested that the β-oxidation capacities decrease during aging [reviewed in part in (21)]. Impaired fat oxidation may also play a role in the establishment of obesity. In humans as well as in rodents, several studies [very recently by Westerterp and colleagues (22)] have shown an inverse relationship between fat oxidation and weight gain (23–25), even if this hypothesis was not confirmed by other authors (26).

L-carnitine is known to reduce the intramitochondrial acyl-CoA/CoA ratio, to promote oxidative glucose utilization, and to improve insulin sensitivity (27). L-carnitine supplementation has been shown to alter lipid accumulation in the skeletal muscle by influencing the influx of fatty acids into the mitochondria (28) and to increase the oxidation of dietary fatty acids in healthy humans (29,30). In old rats there is a significant decrease of total L-carnitine levels in the brain, serum, heart, and skeletal muscle, accompanied by an increase in the liver level (31,32).

Our results showed that, in rats, plasma L-carnitine was not significantly reduced during aging; the values remaining close to 50 µM. However, L-carnitine supplementation induced, both in young and old rats, a marked increase in the L-carnitine plasma levels, of 21% and 57%, respectively. This difference between young and old animals could be explained either by a better capacity of absorbing L-carnitine in older individuals or by a less effective transport of L-carnitine into organs leading to an increase in L-carnitine in the bloodstream. This alteration may also be a consequence of a decrease in renal excretion of L-carnitine in old animals. Whatever the reasons are, in our study the supplementation was found to be much more efficient in old than in young animals.

L-carnitine content in the liver was not altered by L-carnitine supplementation or moderate physical exercise and/or aging. This stability may result from a tight control of L-carnitine uptake by hepatic cells and/or a control of L-carnitine on its biosynthesis. As determined by BBH activity, L-carnitine biosynthesis did not seem to be repressed by L-carnitine supplementation. Davis and Monroe (33) reported earlier that modifying L-carnitine intake did not alter BBH messenger RNA level. Our results confirmed their findings.

We compared L-carnitine metabolism in two metabolically and structurally different muscles, the mainly glycolytic tibialis anterioris and the lipolytic soleus. In the tibialis anterioris muscle, no changes were observed during the experimental procedure. In the soleus, the results are different; the content of L-carnitine in this muscle was reduced during aging by 34%. L-carnitine supplementation had no effect in young rats. In old rats, L-carnitine supplementation as well as physical exercise restored L-carnitine content value. Together physical activity and L-carnitine supplementation did not show any additive effects.

The relationship between L-carnitine and body weight has always been unclear (34). From this study two different conclusions can be made. In young animals, during growth phase, supplementation with L-carnitine for 12 weeks had no effect on body weight. In old rats, L-carnitine supplementation seemed to limit body weight increase by limiting fat gain and possibly by increasing fatty acid oxidation as suggested by several authors (29,30). Our data also clearly showed that food intake is not modified by L-carnitine supplementation.

In 3-month-old rats, L-carnitine supplementation did not significantly affect body weight. These rats were still in the growing process, and during the 12 weeks of the experiment these animals gained 118 g of body weight but their amount of fat remained stable.

In control old rats, one can observe an increase in total body weight during the 12-week period. This increase does not seem to be associated with an increase in muscle mass but to an increase in the amount of abdominal fat. During our 12-week protocol, these animals exhibited an increase in body weight of 63 g. This is much less than in young animals, which seems normal because the growing process of these old animals has ended. Adding L-carnitine to the diet allowed reducing the weight gain observed in these animals. In fact, in L-carnitine-supplemented animals, no increase of body weight during the 12-week period was observed. Physical exercise also reduced body weight gain, but this reduction was less than that seen with L-carnitine treatment. Physical exercise combined with L-carnitine supplementation did not induce any cumulative effect.

Our results in old rats may look contradictory to those of several authors who reported no effect of L-carnitine supplementation on body weight. However, the models were different: In humans, Elmslie and colleagues(35) reported no effect of L-carnitine in bipolar patients; in rodents, Brandsch and Eder (36) showed no positive effect of L-carnitine supplementation on weight loss and body composition of adult (10-week-old) rats fed an energy-deficient diet. However, these authors stated that, in their models, endogenous L-carnitine synthesis was obviously adequate to ensure efficient β-oxidation of fatty acids. Again Melton and colleagues (37) reported no obvious effect of L-carnitine on body weight on ovariectomized rats. Their study was done on young female rats, which may explain the difference observed between their data and ours. Saldanha Aoki and colleagues (38) reported results that may look contradictory on young rats doing intense physical exercise. They concluded that L-carnitine was unable to promote weight loss in these animals. Those were again young animals. Concerning the young animals, our results agreed with their results and conclusions, but in old animals, L-carnitine supplementation was able to decrease body weight. Our results can also be compared with those of Malaguarnera and colleagues (39), who very recently reported a decrease in fat mass and an increase in lean mass in very old people supplemented with L-carnitine.

Apart from this conclusion, our results also showed that, in our model of aging Wistar rats, the amount of the periepididymal fat is not correlated with the amount of abdominal fat and possible subsequent obesity. This makes sense because abdominal fat is largely used as an energetic storage device (40) and periepididymal fat as a protective tissue.

β-oxidation was determined in the liver and the soleus and tibialis anterioris in the six groups of animals. In the liver, in control or L-carnitine–treated young or old animals, no changes were found for oleic oxidation. In the tibialis anterioris, the β-oxidation (as measured by the oxidation of oleic acid) remained unchanged whatever the treatment or the age of the rat.

In the soleus, both the age and the treatment altered β-oxidation. The β-oxidation of oleic acid decreased by 27% in old versus young rats. L-carnitine supplementation was ineffective in increasing β-oxidation in young rats whereas in old animals the supplementation with L-carnitine induced a marked increase. Physical exercise alone significantly increased β-oxidation, but when physical exercise was done by animals receiving L-carnitine no further increase in β-oxidation was observed. These results suggest that L-carnitine and physical exercise may, at least in part, restore β-oxidation in old rats.

CPT I activity is usually considered as one of the key steps in β-oxidation and an important step for the management of weight gain (41). In our model of aging rats, there is a remarkable correlation between CPT I activity and β-oxidation level. CPT I activity is altered by age and treatments. In the liver, CPT I activity decreased in old animals. Previous studies have shown that this activity is reduced during aging both in rats (42) and humans (43). This activity appeared to be restored in animals receiving L-carnitine and/or doing moderate physical exercise. The same pattern of results was found in the lipolytic soleus muscle, whereas no alteration was detected in the glycolytic tibialis anterioris muscle.

Several studies have been conducted on the potential positive effect of L-carnitine on the side effects of aging. In this study, we concentrated on the metabolic effect of L-carnitine. We used a relatively low concentration of L-carnitine of 30 mg/kg body weight and drinking water as a vehicle to administer L-carnitine. In old (and overweight) rats, L-carnitine supplementation had dramatic effects both at the physiological and biochemical levels. Besides restoring L-carnitine content in tissues, L-carnitine supplementation in old rats slowed down the body weight increase due to an increase in fat mass. It restored also some aspects of fatty acid metabolism. During this study, we also determined the effect of physical exercise on the same parameters. Physical exercise was able to limit body weight increase and to restore, at least partly, some mitochondrial functions. However, physical exercise and L-carnitine supplementation did not exhibit any cumulative effects.

Contradictory results of the effect of L-carnitine supplementation on body weight have been published. Several studies have shown that L-carnitine supplementation can induce an increase in L-carnitine content in various tissues. An increase in L-carnitine content has been shown to increase fatty acid oxidation, and increased fatty acid oxidation has been described as effective in lowering fat mass. Besides these connected results, little evidence existed on a net effect of L-carnitine on body weight. Our study showed that in old fat rats, a supplementation with L-carnitine may limit the increase in fat mass occurring during aging with no change in food intake and improve mitochondrial functions in oxidative tissues. Extrapolated to humans, this observation may be interesting, because L-carnitine supplementation may allow humans with a reduced level of L-carnitine to reduce fat mass and to maintain a balanced diet with no caloric restriction.


   Acknowledgments
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 
We thank Dr. Palmer and Dr. Held for constructive reading of the manuscript.

L-carnitine used in these experiments was provided by Lonza (Basel, Switzerland). No limitations of any kind were made by this company on our work and conclusions.


   Footnotes
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 
Decision Editor: Huber R. Warner, PhD

Received November 22, 2007

Accepted April 10, 2008


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

  1. Trifunovic A. Mitochondrial DNA and ageing. Biochim Biophys Acta. 2006;1757:611-617.[Medline]
  2. Birch-Machin MA. The role of mitochondria in ageing and carcinogenesis. Clin Exp Dermatol. 2006;31:548-552.[Medline]
  3. Orrenius S, Gogvadze V, Zhivotovsky B. Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol. 2007;47:143-183.[Medline]
  4. Droge W. Oxidative stress and aging. Adv Exp Med Biol. 2003;543:191-200.[Medline]
  5. Ames BN. A role for supplements in optimizing health: the metabolic tune-up. Arch Biochem Biophys. 2004;423:227-234.[Medline]
  6. Wanders RJ, Vreken P, den Boer ME, Wijburg FA, van Gennip AH, Ijlst L. Disorders of mitochondrial fatty acyl-CoA beta-oxidation. J Inherit Metab Dis. 1999;22:442-487.[Medline]
  7. Galland S, Le Borgne F, Georges B, Demarquoy J. Carnitine, cellular and molecular aspects. Recent Res Devel Lipids. 2001;5:1-14.
  8. Demarquoy J, Georges B, Rigault C, et al. Radioisotopic determination of -carnitine content in foods commonly eaten in Western countries. Food Chem. 2004;86:137-142.
  9. Galland S, Le Borgne F, Guyonnet D, Clouet P, Demarquoy J. Purification and characterization of the rat liver gamma-butyrobetaine hydroxylase. Mol Cell Biochem. 1998;178:163-168.[Medline]
  10. Urso ML, Clarkson PM. Oxidative stress, exercise, and antioxidant supplementation. Toxicology Environmental and Nutritional Interactions Antioxidant Nutrients and Environmental Health, Part C. 2003;189:41-54.
  11. McArdle A, Vasilaki A, Jackson M. Exercise and skeletal muscle ageing: cellular and molecular mechanisms. Ageing Res Rev. 2002;1:79-93.[Medline]
  12. Navarro A, Boveris A. The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol. 2007;292:C670-C686.[Abstract/Free Full Text]
  13. Demarquoy J, Fairand A, Gautier C, Vaillant R. Demonstration of argininosuccinate synthetase activity associated with mitochondrial membrane: characterization and hormonal regulation. Mol Cell Biochem. 1994;136:145-155.[Medline]
  14. Rigault C, Le Borgne F, Georges B, Demarquoy J. Ghrelin reduces hepatic mitochondrial fatty acid beta oxidation. J Endocrinol Invest. 2007;30:RC4-RC8.[Medline]
  15. Decaux JF, Ferre P, Robin D, Robin P, Girard J. Decreased hepatic fatty acid oxidation at weaning in the rat is not linked to a variation of malonyl-CoA concentration. J Biol Chem. 1988;263:3284-3289.[Abstract/Free Full Text]
  16. Smith PK, Krohn RI, Hermanson GT, et al. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985;150:76-85.[Medline]
  17. Kowald A, Kirkwood TB. Accumulation of defective mitochondria through delayed degradation of damaged organelles and its possible role in the ageing of post-mitotic and dividing cells. J Theor Biol. 2000;202:145-160.[Medline]
  18. Humphries KM, Szweda PA, Szweda LI. Aging: a shift from redox regulation to oxidative damage. Free Radic Res. 2006;40:1239-1243.[Medline]
  19. Savitha S, Tamilselvan J, Anusuyadevi M, Panneerselvam C. Oxidative stress on mitochondrial antioxidant defense system in the aging process: role of DL-alpha-lipoic acid and L-carnitine. Clin Chim Acta. 2005;355:173-180.[Medline]
  20. Demizieux L. [Control and regulation of mitochondrial oxidation of long-chained fatty acids]. J Soc Biol. 2005;199:143-155.[Medline]
  21. Slawik M, Vidal-Puig AJ. Lipotoxicity, overnutrition and energy metabolism in aging. Ageing Res Rev. 2006;5:144-164.[Medline]
  22. Westerterp KR, Smeets A, Lejeune MP, Wouters-Adriaens MP, Westerterp-Plantenga MS. Dietary fat oxidation as a function of body fat. Am J Clin Nutr. 2008;87:132-135.[Abstract/Free Full Text]
  23. Ji H, Friedman MI. Fasting plasma triglyceride levels and fat oxidation predict dietary obesity in rats. Physiol Behav. 2003;78:767-772.[Medline]
  24. Ji H, Outterbridge LV, Friedman MI. Phenotype-based treatment of dietary obesity: differential effects of fenofibrate in obesity-prone and obesity-resistant rats. Metabolism. 2005;54:421-429.[Medline]
  25. Ravussin E, Gautier JF. Metabolic predictors of weight gain. Int J Obes Relat Metab Disord. 1999;23 Suppl 1:37-41.
  26. Commerford SR, Pagliassotti MJ, Melby CL, Wei Y, Gayles EC, Hill JO. Fat oxidation, lipolysis, and free fatty acid cycling in obesity-prone and obesity-resistant rats. Am J Physiol Endocrinol Metab. 2000;279:E875-E885.[Abstract/Free Full Text]
  27. Mingrone G, Greco AV, Capristo E, et al. L-carnitine improves glucose disposal in type 2 diabetic patients. J Am Coll Nutr. 1999;18:77-82.[Abstract/Free Full Text]
  28. Rajasekar P, Anuradha CV. Effect of L-carnitine on skeletal muscle lipids and oxidative stress in rats fed high-fructose diet. Exp Diabetes Res. 2007;2007:72741.[Medline]
  29. Muller DM, Seim H, Kiess W, Loster H, Richter T. Effects of oral L-carnitine supplementation on in vivo long-chain fatty acid oxidation in healthy adults. Metabolism. 2002;51:1389-1391.[Medline]
  30. Wutzke KD, Lorenz H. The effect of l-carnitine on fat oxidation, protein turnover, and body composition in slightly overweight subjects. Metabolism. 2004;53:1002-1006.[Medline]
  31. Costell M, O'Connor JE, Grisolia S. Age-dependent decrease of carnitine content in muscle of mice and humans. Biochem Biophys Res Commun. 1989;161:1135-1143.[Medline]
  32. Maccari F, Arseni A, Chiodi P, Ramacci MT, Angelucci L. Levels of carnitines in brain and other tissues of rats of different ages: effect of acetyl-L-carnitine administration. Exp Gerontol. 1990;25:127-134.[Medline]
  33. Davis AT, Monroe TJ. Carnitine deficiency and supplementation do not affect the gene expression of carnitine biosynthetic enzymes in rats. J Nutr. 2005;135:761-764.[Abstract/Free Full Text]
  34. Hoppel C. The role of carnitine in normal and altered fatty acid metabolism. Am J Kidney Dis. 2003;41:S4-S12.[Medline]
  35. Elmslie JL, Porter RJ, Joyce PR, Hunt PJ, Mann JI. Carnitine does not improve weight loss outcomes in valproate-treated bipolar patients consuming an energy-restricted, low-fat diet. Bipolar Disord. 2006;8:503-507.[Medline]
  36. Brandsch C, Eder K. Effect of L-carnitine on weight loss and body composition of rats fed a hypocaloric diet. Ann Nutr Metab. 2002;46:205-210.[Medline]
  37. Melton SA, Keenan MJ, Stanciu CE, et al. L-carnitine supplementation does not promote weight loss in ovariectomized rats despite endurance exercise. Int J Vitam Nutr Res. 2005;75:156-160.[Medline]
  38. Saldanha Aoki M, Rodriguez Amaral Almeida AL, Navarro F, Bicudo Pereira Costa-Rosa LF, Pereira Bacurau RF. Carnitine supplementation fails to maximize fat mass loss induced by endurance training in rats. Ann Nutr Metab. 2004;48:90-94.[Medline]
  39. Malaguarnera M, Cammalleri L, Gargante MP, Vacante M, Colonna V, Motta M. L-Carnitine treatment reduces severity of physical and mental fatigue and increases cognitive functions in centenarians: a randomized and controlled clinical trial. Am J Clin Nutr. 2007;86:1738-1744.[Abstract/Free Full Text]
  40. Wong S, Janssen I, Ross R. Abdominal adipose tissue distribution and metabolic risk. Sports Med. 2003;33:709-726.[Medline]
  41. Kuhajda FP, Ronnett GV. Modulation of carnitine palmitoyltransferase-1 for the treatment of obesity. Curr Opin Investig Drugs. 2007;8:312-317.[Medline]
  42. Mori S, Morisaki N, Saito Y, Yoshida S. Age-related changes of long-chain fatty acid metabolism in rat liver. Mech Ageing Dev. 1988;44:175-183.[Medline]
  43. Rasmussen UF, Krustrup P, Kjaer M, Rasmussen HN. Experimental evidence against the mitochondrial theory of aging. A study of isolated human skeletal muscle mitochondria. Exp Gerontol. 2003;38:877-886.[Medline]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Services
Right arrow Download to citation manager
PubMed
Right arrow PubMed Citation

HOME ARCHIVE SEARCH TABLE OF CONTENTS