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

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L-Carnitine Supplementation and Physical Exercise Restore Age-Associated Decline in Some Mitochondrial Functions in the Rat Journal of Gerontology: BIOLOGICAL SCIENCES Copyright 2008 by The Gerontological Society of America 2008, Vol. 63A, No. 10, 1027–1033 L-Carnitine Supplementation and Physical Exercise Restore Age-Associated Decline in Some Mitochondrial Functions in the Rat Arnaud Bernard, Caroline Rigault, Fre´de´ric Mazue, Franc¸oise Le Borgne, and Jean Demarquoy Downloaded from https://academic.oup.com/biomedgerontology/article/63/10/1027/559196 by guest on 30 September 2021 INSERM, U866, Universite´ de Bourgogne, Dijon, France. 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. GING is a highly complex phenomenon involving pathway. The final step in L-carnitine biosynthesis is made Aboth genetic and environmental factors. Aging causes by the cytosolic c butyrobetaine hydroxylase (BBH). In rats, a multitude of detrimental changes in the organism; it this enzyme is mainly found in the liver (9). decreases many maximum functional capacities and in- There is a lack of consistency in results regarding whether creases the probability of suffering degenerative diseases physical exercise increases or decreases oxidative stress (1). Several hypotheses have been enunciated to explain (10). The production of reactive oxygen species may con- aging, most of them linked to the mitochondria and the siderably increase when mitochondria increase their oxygen dysregulation of the mitochondrial metabolism (2). input (11) such as during physical exercise. In contrast, Aging is associated with a decrease in muscle mass and moderate physical exercise ameliorates mitochondrial func- muscle oxidative capacities associated with an atrophy of tion in the liver (12). the muscle fibers, an increase in fat gain, and a decrease in Thus, one can hypothesize that nutritional supplementa- lean mass. These changes are probably influenced by tion with L-carnitine and moderate physical exercise may hormonal status and also by alterations in the structure improve the mitochondrial oxidative metabolism and sub- and the metabolism of muscle cells which could lead to sequently limit the side effects of aging. This was the aim of a progressive degeneration and a mitochondrial release of this study. cytochrome c (3) and eventually apoptosis (4). Although aging is not reversible, several compounds MATERIALS AND METHODS seem to be able to slow down the negative aspects of aging. Among those are antioxidants and agents such as L-carnitine Chemicals known to regulate energy production (5). One can also L-carnitine (Carnipure) was provided by Lonza (Basel, include moderate physical exercise, an activity that can Switzerland). All other chemicals were of reagent grade and regulate the production of oxidants, as a factor favorably were obtained from Sigma (St. Louis, MO). influencing aging. L-carnitine is a cofactor in the channeling of fatty acids Animals inside the cell. It plays two major functions in the cell: It is Male Wistar rats, approximately 4 months old (young) involved in fatty acid oxidation as it acts as a cofactor in and 24 month old (old), were used in this study. Animals the transport of acyl groups across the inner mitochondrial were housed in individual cages at a temperature of 22 6 membrane, through the carnitine palmitoyl transferase/ 28C with a 12-hour day/night cycle. The rats were adapted to carnitine acyl-carnitine transferase (CPT/CACT) system the housing conditions for at least 2 weeks before the (6). It also removes acyl groups from the mitochondria experimentation. Animals had free access to food (AO 4; and the cell as acylcarnitines (7). L-carnitine found in the U.A.R., Charlette sur Loing, France) and water. body is either provided by food stuffs (especially meat The young animals were randomly assigned to two products) (8) or comes from an endogenous biosynthetic different groups: a control group receiving tap water and 1027 1028 BERNARD ET AL. a group receiving L-carnitine at 30 mg/kg body weight of the cytosolic fraction was routinely estimated with through the drinking water (based on a 17.5 mL water intake specific markers as in (13). per day). The old animals were divided into four groups (control, L-carnitine-supplemented rats, rats doing physical L-Carnitine Determination exercise, rats doing physical exercise and supplemented L-carnitine concentration was determined in the cytosolic with L-carnitine). Each group consisted of six animals. fraction using a radioisotopic method (8). Physical exercise was done under a moderate protocol. Three times a week animals were put on a treadmill for 20 Determination of Biochemical Parameters minutes at a speed of 13 m/min. Control animals were Downloaded from https://academic.oup.com/biomedgerontology/article/63/10/1027/559196 by guest on 30 September 2021 mock-treated and were placed on the treadmill once a week. b-oxidation determination.—The b-oxidation of Thus, six groups of animals were used: Group I ¼ control [1-14C]oleic acid by liver and skeletal muscle mitochondria young rats; Group II ¼L-carnitine-supplemented young rats; was assessed according to (14). The incubation vials con- Group III ¼ control old rats; Group IV ¼ old rats receiving tained 500 lg of mitochondrial protein in 900 lL of incu- L-carnitine; Group V ¼ old rats doing physical exercise; and bation solution. They were closed with a rubber stopper and Group VI ¼ old rats administered L-carnitine and doing incubated for 15 minutes at 378C. physical exercise. The experimental procedure was con- ducted for 12 weeks. Enzymatic activities.—CPT activity was determined on On completion of the experimental period, animals were mitochondrial fractions obtained from liver and muscles. anesthetized using isoflurane and were quickly killed by CPT activity was measured by the formation of palmitoyl- cervical dislocation. Organs were immediately excised and [3H]carnitine from palmitoyl-coenzyme A (CoA) and L- kept on ice for immediate use or were frozen in liquid [3H]carnitine (15). The activity of c BBH, the enzyme nitrogen and kept at À828C. responsible for L-carnitine biosynthesis, was measured by the formation of L-carnitine as in (9). Physiological Parameters All animals had their body weight recorded once a week Protein content.—Protein concentration was estimated during the experiment. Food intake was estimated regularly using the Pierce BCA (bicinchoninic acid) procedure with (on a weekly basis) by differential weighing of food offered bovine serum albumin as a standard (16). and food remaining the next day. Water intake per day was also estimated on a weekly basis. At the end of the training, Statistical Analysis the mass of the liver, the brain, the soleus and the tibialis Data shown in the table and the figures are the means 6 anterioris muscles, the periepididymal fat, the kidney, and standard error of the mean. Comparison between the the brain was measured. After all the organs were removed, different groups was done with a Kruskal–Wallis test. the abdominal fat was removed and weighed. Pairwise comparison between each group of animals was done with a Mann–Whitney U test. Significance was Subcellular Fractionation assumed at p , .05. Mitochondrial isolation.—The liver and the muscles were washed in homogenizing medium (0.25 M sucrose, 5 mM RESULTS HEPES buffer, and 1 mM EDTA, pH 7.2), minced into small pieces (around 100 mg), and homogenized using a L-Carnitine Content in Plasma, Liver, and Muscles Teflon-on-glass (Potter–Elvehjem) homogenizer. The homo- L-carnitine content was determined in the plasma, the genate was centrifuged at 500 3 g for 10 minutes and the liver, the soleus (a lipolytic muscle), and the tibialis pellet discarded. The supernatant (S1) was centrifuged at anterioris (a mixed-glycolytic muscle; Table 1). 10,000 3 g for 10 minutes. The resulting supernatant (S2) In young animals, L-carnitine supplementation induced was used for cytosol preparation as described in the an increase in the L-carnitine plasma level (21%, p , .05). following paragraph. The pellet was resuspended into the In old animals receiving L-carnitine (groups IV and VI), homogenizing buffer and centrifuged again at 10,000 3 g supplementation induced a statistically significant increase for 10 minutes. The final pellet was resuspended in a small in L-carnitine plasma levels whereas physical exercise alone volume of the homogenizing buffer and represents the did not alter L-carnitine content in the plasma. mitochondrial fraction. The content of the fractions was In the liver, L-carnitine content remained the same along estimated by determining the activity of markers in the the experiments in all groups of animals. No significant fractions as in (13). Only fractionations with relevant results difference was found between young and old rats, and were used in this article. L-carnitine supplementation or physical exercise remained ineffective in modifying liver L-carnitine level. Cytosol isolation.—The S2 supernatant was centrifuged In the soleus muscle of old rats, L-carnitine concentration at 18,000 3 g for 20 minutes at 48C to remove the was found to be significantly decreased (À34%, p , .05) as mitochondria, the peroxisomes, and the lysosomes.
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