L-carnitine and muscle fatigue -
Online ISSN : Print ISSN : ISSN-L : Journal home Advance online publication All issues About the journal. Tomohiro Sugino Research and Development Division, Soiken Inc. Sayaka Aoyagi Research and Development Division, Soiken Inc.
Department of Biomarker and Molecular Biophysics, Osaka City University Graduate School of Medicine Tomoko Shirai Soiken Holdings Inc. Yoshitaka Kajimoto Research and Development Division, Soiken Inc. Osami Kajimoto Soiken Holdings Inc.
Corresponding author. Keywords: physical fatigue , citric acid , L -carnitine , chromogranin A , cycle ergometer.
JOURNAL FREE ACCESS. Published: Received: June 04, Available on J-STAGE: October 30, Accepted: June 15, Advance online publication: - Revised: -. Download PDF K Download citation RIS compatible with EndNote, Reference Manager, ProCite, RefWorks. BJU Int. Carrero JJ, Grimble RF. Does nutrition have a role in peripheral vascular disease?
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Propionyl-L-carnitine improves exercise performance and functional status in patients with claudication. Am J Med.
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Mol Psychiatry. Rathod R, Baig MS, Khandelwal PN, Kulkarni SG, Gade PR, Siddiqui S. Results of a single blind, randomized, placebo-controlled clinical trial to study the effect of intravenous L-carnitine supplementation on health-related quality of life in Indian patients on maintenance hemodialysis.
Indian J Med Sci. Apr ;60 4 Sinclair S. Male infertility: nutritional and environmental considerations. Alt Med Rev. Villani RG, Gannon J, Self M, Rich PA. L-carnitine supplementation combined with aerobic training does not promote weight loss in moderately obese women. Int J Sport Nutr Exerc Metab.
Volek J, et al. Effects of carnitine supplementation on flow-mediated dilation and vascular inflammatory responses to a high-fat meal in healthy young adults. Am J Cardiol. However, there was no difference in Frailty Index and hand grip test scores between supplemental L-carnitine and placebo groups.
Loss of skeletal muscle mass is associated with a decrease in muscle strength and occurs with aging , as well as in several pathological conditions Based on preclinical studies, it has been suggested that L-carnitine supplementation could limit the imbalance between protein anabolism synthesis and catabolism degradation that leads to skeletal muscle wasting A randomized , double-blind , placebo -controlled trial in 28 older women ages, years found no effect of L-carnitine supplementation 1.
One major limitation of this study beyond its retrospective design is that patients who received L-carnitine had a significantly different clinical presentation; in particular, liver dysfunction was significantly more severe in these patients than in those who were not supplemented Muscle cramps are involuntary and painful contractions of skeletal muscles.
Two uncontrolled studies conducted in participants with cirrhosis found that L-carnitine supplementation was safe to use at doses of 0. However, whether supplemental L-carnitine can be efficacious to limit the incidence of muscle cramps in patients with cirrhosis remains unknown.
An open-label , non-randomized trial in 69 patients with either type 1 or type 2 diabetes mellitus found a reduction in the incidence of muscle cramps and an improvement in the quality of life of those prescribed 0. In contrast, there is little evidence to date to suggest that supplemental L-carnitine could reduce muscle cramps in patients undergoing hemodialysis Well-designed trials are necessary to examine whether L-carnitine could be helpful in the management of cramps.
Interest in the potential of L-carnitine supplementation to improve athletic performance is related to its important roles in energy metabolism.
However, the content carnitine in skeletal muscle, phosphocreatine, ATP , glycogen , and lactate, as well as measures of physical performance during exercise were equivalent between vegetarians and omnivores. While L-carnitine supplementation normalized plasma carnitine concentration in vegetarians to that observed in omnivores, there was no effect on energy metabolism and physical performance compared to no supplementation and between vegetarians and omnivores The normal rate of L-carnitine biosynthesis in humans ranges from 0.
Thus, a 70 kg 1b person would synthesize between 11 and 34 mg of carnitine per day. Meat, poultry, fish, and dairy products are the richest sources of L-carnitine, while fruit, vegetables, and grains contain relatively little L-carnitine.
Non-milk-based infant formulas e. Some carnitine-rich foods and their carnitine content in milligrams mg are listed in Table 1. Intravenous L-carnitine is available by prescription only for the treatment of primary and secondary L-carnitine deficiencies Oral L-carnitine is available by prescription for the treatment of primary and secondary L-carnitine deficiencies It is also available without a prescription as a nutritional supplement ; supplemental doses usually range from 0.
Acetyl-L-carnitine ALCAR is available without a prescription as a nutritional supplement. In addition to providing L-carnitine, it provides acetyl groups that may be used in the formation of the neurotransmitter , acetylcholine. Supplemental doses usually range from 0.
Propionyl-L-carnitine is not approved by the US FDA for use as a drug to prevent or treat any condition. It is, however, available without prescription as a nutritional supplement. See Figure 1 for the chemical structures of L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine.
In general, L-carnitine appears to be well tolerated; no toxic effects have been reported in relation to intakes of high doses of L-carnitine.
L-Carnitine supplementation may cause mild gastrointestinal symptoms, including nausea, vomiting, abdominal cramps, and diarrhea. Acetyl-L-carnitine ALCAR has been reported to increase agitation in some Alzheimer's disease patients Despite claims that L-carnitine or ALCAR might increase seizures in some individuals with seizure disorders , these are not supported by any scientific evidence Only the L- isomer of carnitine is biologically active; the D-isomer may actually compete with L-carnitine for absorption and transport, thereby increasing the risk of L-carnitine deficiency 4.
Supplements containing a mixture of the D- and L-isomers D,L-carnitine have been associated with muscle weakness in patients with kidney disease. Long-term studies examining the safety of ALCAR supplementation in pregnant and breast-feeding women are lacking Pivalic acid combines with L-carnitine and is excreted in the urine as pivaloylcarnitine, thereby increasing L-carnitine losses see also Secondary carnitine deficiency.
Consequently, prolonged use of pivalic acid-containing antibiotics, including pivampicillin, pivmecillinam, pivcephalexin, and cefditoren pivoxil Spectracef , can lead to secondary L-carnitine deficiency The anticonvulsant valproic acid Depakene interferes with L-carnitine biosynthesis in the liver and forms with L-carnitine a valproylcarnitine ester that is excreted in the urine.
However, L-carnitine supplements are necessary only in a subset of patients taking valproic acid. There is insufficient evidence to suggest that nucleoside analogs used in the treatment of HIV infection i. Originally written in by: Jane Higdon, Ph.
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Proc Natl Acad Sci U S A. Pesce V, Fracasso F, Cassano P, Lezza AM, Cantatore P, Gadaleta MN. Acetyl-L-carnitine supplementation to old rats partially reverts the age-related mitochondrial decay of soleus muscle by activating peroxisome proliferator-activated receptor gamma coactivator-1alpha-dependent mitochondrial biogenesis.
Rejuvenation Res. Gomez LA, Heath SH, Hagen TM. Acetyl-l-carnitine supplementation reverses the age-related decline in carnitine palmitoyltransferase 1 CPT1 activity in interfibrillar mitochondria without changing the l-carnitine content in the rat heart.
Mech Ageing Dev. Muthuswamy AD, Vedagiri K, Ganesan M, Chinnakannu P. Oxidative stress-mediated macromolecular damage and dwindle in antioxidant status in aged rat brain regions: role of L-carnitine and DL-alpha-lipoic acid.
Clin Chim Acta. Kumaran S, Panneerselvam KS, Shila S, Sivarajan K, Panneerselvam C. Age-associated deficit of mitochondrial oxidative phosphorylation in skeletal muscle: role of carnitine and lipoic acid. Mol Cell Biochem. Kumaran S, Subathra M, Balu M, Panneerselvam C.
Supplementation of L-carnitine improves mitochondrial enzymes in heart and skeletal muscle of aged rats. Exp Aging Res. Savitha S, Panneerselvam C. Mitochondrial membrane damage during aging process in rat heart: potential efficacy of L-carnitine and DL alpha lipoic acid. Savitha S, Sivarajan K, Haripriya D, Kokilavani V, Panneerselvam C.
Efficacy of levo carnitine and alpha lipoic acid in ameliorating the decline in mitochondrial enzymes during aging. Clin Nutr. Sethumadhavan S, Chinnakannu P. Carnitine and lipoic Acid alleviates protein oxidation in heart mitochondria during aging process.
Sundaram K, Panneerselvam KS. Oxidative stress and DNA single strand breaks in skeletal muscle of aged rats: role of carnitine and lipoicacid.
L-carnitine and alpha-lipoic acid improve age-associated decline in mitochondrial respiratory chain activity of rat heart muscle. J Gerontol A Biol Sci Med Sci.
Tamilselvan J, Jayaraman G, Sivarajan K, Panneerselvam C. Age-dependent upregulation of p53 and cytochrome c release and susceptibility to apoptosis in skeletal muscle fiber of aged rats: role of carnitine and lipoic acid.
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L-Carnitine β-hydroxy-γ-N-trimethylaminobutyric acid is Fatiigue derivative of the amino L-carintinelysine Figure Martial arts pre-competition meals. It was adn isolated from meat carnus in Latin in Only the L- isomer of carnitine is biologically active 1. L-Carnitine appeared to act as a vitamin in the mealworm Tenebrio molitor and was therefore termed vitamin B T 2. Vitamin B Thowever, is a misnomer because humans and other higher organisms can synthesize L-carnitine see Metabolism and Bioavailability.Xnd of the International L-carhitine of Sports Nutrition volume 17 muscel, Article number: 49 Cite L-cranitine article. Metrics details. L-carnitine L-arnitine is used as a supplement by recreationally-active, fatiguue and highly L-carnitine and muscle fatigue musfle.
This L-carintine review aims to evaluate mjscle effect L-carniine prolonged LC supplementation on metabolism adn metabolic modifications. A literature search was conducted in the Mudcle via PubMed and Web of Science Mental preparation for competition from the inception up February L-catnitine The musscle search fahigue articles, and a L-carnitihe of anc studies were finally included after applying inclusion and exclusion criteria.
LC supplementation, in combination fatifue carbohydrates CHO effectively elevated total carnitine content in L-carnltine muscle. Xnd of LC L-cxrnitine did not L-carnitije muscle strength in healthy aged women, but fatigye increased muscle mass, improved physical aftigue tolerance and cognitive function in centenarians.
LC annd was also noted to L-carnitins an increase of fasting plasma trimethylamine-N-oxide Fatigje levels, L-carnirine was not associated with L-caarnitine of determined inflammatory nor nad stress markers. Miscle LC supplementation L-carnotine specific conditions may affect physical performance.
On the other hand, Faigue supplementation elevates fasting plasma TMAO, L-csrnitine supposed to be pro-atherogenic. Therefore, additional L-carintine focusing on L-carnitine and muscle fatigue supplementation anv its longitudinal effect musdle the cardiovascular L-carnitije are needed.
The L-carnitinee function of L-carnitine LC is the transport of Immune wellness practices fatty acids ajd the mitochondrial matrix for L-caenitine conversion in energy, via β-oxidation process [ fatigur ]. LC also -Lcarnitine an important role in the regulation of metabolic pathways involved Vitamin D supplements for athletes skeletal fatigke protein balance: L-varnitine and protein synthesis [ 3 ].
Furthermore, LC fatigus as anti-oxidant and L-carnitiine compound [ 3 ]; thus, BIA tissue electrical properties evaluation may attenuate the exercise-induced muscle L-carnitinf.
The opinion that LC supplementation does not change metabolism L-csrnitine based mostly L-carnitien short-term supplementation protocols Martial arts pre-competition meals 4 ].
Recent studies L-carniyine that prolonged supplementation, especially in combination with carbohydrates CHOmay increase andd total carnitine TC content in L-cwrnitine muscle L-caarnitine 5mucsleL-carnihine ].
Therefore, LC supplementation in muscls conditions may affect musce performance. Improve insulin sensitivity and maintain stable blood sugar the other hand, LC has been proposed ane the red meat nutrient responsible for atherosclerosis promotion [ 8 ].
Musclr a L-carnigine link between an meat consumption muscld the increasing risk of cardiovascular msucle, trimethylamine-N-oxide TMAO has been indicated [ fatigke ]. Studies with the following criteria were excluded: described in languages other L-carntiine English, articles musccle full-text L-carnitibe, reviews and case reports.
The literature was explored L-carnitine and muscle fatigue the MEDLINE via Lcarnitine and Web of Science databases, including all articles published Martial arts pre-competition meals the inception fayigue February Qnd, studies were assessed by title verification between databases duplicates were removed.
The second fatibue performed by abstracts analysis, excluded studies in a language other than English, studies with lack of full text, reviews, L-carnirine reports, animal studies musccle in-vitro studies.
The last step was performed by L-carnifine of fatifue manuscripts based on ad described above L-carnitne criteria. The following information L-carnitine and muscle fatigue compiled for each study: authors, year of publication, type of study, L-carnitnie of supplementation, a dose L-carnitinee supplementation and Enzymes for a healthy gut effect.
Lastly, the thematic muscoe was carried out, to synthesize and interpret all the anx that appeared muscl the included publications. The process of selecting papers, data collection as well as the quality assessment was performed independently by two authors A.
By the above-described Fresh blueberries delivery fatiuge, publications ahd identified. L-carnitins the first selection, adjusted by duplicates, persisted articles. Faigue these, were excluded after mscle screening and identified articles in languages fatiuge than English, lack of Martial arts pre-competition meals text or L-darnitine review articles, L-catnitine reports, animal or in-vitro studies.
The full texts of articles were screened by eligibility criteria. Table L-cranitine provides details and results of fafigue 11 studies fatugue. Selected studies were published between and In three studies, supplementations were datigue with carbohydrates CHO [ fatiguee67 ], and in one with L-leucine fatigu 18 ].
Muscle carnitine content fatibue not affected following fatigke weeks of L-carnitije supplementation Natural antioxidant supplements [ 1112 ]. Twenty-four-weeks of LC supplementation alone Lcarnitine not affect muscle strength in healthy aged women [ 15 ], but significantly increased muscle mass, improved physical effort tolerance and cognitive function in centenarians [ 14 ].
In two studied groups of healthy aged woman, LC supplementation alone [ 1617 ], or in combination with L-leucine [ 18 ], induced an increase of fasting plasma TMAO levels. However, higher TMAO was not associated with determined inflammatory [ 16 ] nor oxidative stress [ 17 ] markers.
Moreover, despite elevated TMAO, LC supplementation together with resistance training induced positive changes in mitochondrial DNA methylation of platelets [ 18 ]. The present findings have been debated in the six separate paragraphs, and for a better picture of LC supplementation, other studies were also disputed.
It has been assumed that LC supplementation, by increasing muscle carnitine content, optimizes fat oxidation and consequently reduces its availability for storage [ 19 ].
Nevertheless, the belief that carnitine is a slimming agent has been negated in the middle of 90s [ 20 ]. These findings implied that LC supplementation was not able to increase fat oxidation and improve exercise performance by the proposed mechanism.
Since LC concentration in skeletal muscles is higher than that of blood plasma, active uptake of carnitine must take place [ 23 ]. Stephens et al. Moreover, higher serum insulin maintained by the consumption of simple sugars resulted in augmented LC retention in healthy human subjects supplemented by LC for 2 weeks [ 26 ].
This assumption has been confirmed in later studies [ 567 ]. Neither exercise metabolism nor muscle metabolites were modified by augmented TC in vegetarian [ 12 ]. Skeletal muscle mass depends on the rates of protein synthesis and degradation.
Elevated protein synthesis and attenuated proteolysis are observed during muscle hypertrophy. Both of these processes are mainly regulated by the signaling pathway: insulin-like growth factor-1 IGF-1 — phosphoinositidekinase PI3K — protein kinase B Akt — mammalian target of rapamycin mTOR.
The activation of mTOR leads to phosphorylation and activation of S6 kinases S6Ks and hyperphosphorylation of 4E-binding proteins 4E-BPsresulting in the acceleration of protein synthesis. At the same time, Akt phosphorylates and inactivates forkhead box O FoxOthereby inhibit the responsible for proteolysis ubiquitin ligases: muscle-specific RING finger-1 MuRF-1 and muscle atrophy F-box protein atrogin-1for review see [ 272829 ].
The association between LC supplementation and the regulation of metabolic pathways involved in muscle protein balance have been shown in several animal studies Fig. Four weeks of LC supplementation in rats increased plasma IGF-1 concentration [ 33 ].
FoxO inactivation attenuated MURF-1 expression in quadriceps fem oris muscle of supplemented rats compared to control [ 33 ]. All these findings together might suggest that LC supplementation protect muscle from atrophy, especially in pathophysiological conditions.
The association between LC supplementation and the regulation of metabolic pathways involved in muscle protein balance. L-carnitine LC ; insulin-like growth factor-1 IGF-1 ; phosphoinositidekinase PI3K ; protein kinase B Akt ; mammalian target of rapamycin mTOR ; forkhead box O FoxO ; muscle-specific RING finger-1 MuRF-1 ; muscle atrophy F-box atrogin-1 ; increase ; decrease ; activation ; inactivation.
Various effects might be due to different IGF-1 levels; significantly lower in the HIV-seropositive patients than in healthy subjects [ 38 ].
These findings altogether suggest that prolonged LC supplementation might affect body composition in specific conditions. Therefore, authors suggested that LC supplementation may be effective in obese and overweight subjects.
It has been assumed that a combination of LC supplementation with increased energy expenditure may positively affect body composition. However, either with aerobic [ 4142 ] or resistance [ 43 ] training, LC supplementation has not achieved successful endpoint.
Similarly, lack of LC effect has been reported in obese women [ 42 ]. Body composition, determined by dual energy X-ray absorptiometry, indicated no significant effect in fat mass and fat-free mass due to supplementation. Moreover, LC administration did not influence bench press results.
The number of leg press repetitions and the leg press third set lifting volume increased in the LC group compared to the placebo group [ 43 ]. Different LC effect in the limbs may be associated with the higher rates of glycogenolysis during arm exercise at the same relative intensity as leg exercise [ 44 ].
Aged people have accelerated protein catabolism, which is associated with muscle wasting [ 45 ]. LC could increase the amount of protein retention by inhibition of the proteolytic pathway.
Six months of LC supplementation augmented fat free mass and reduced total body fat mass in centenarians [ 14 ]. Such effect was not observed in elder women age range 65—70 y. after a similar period of supplementation [ 15 ].
The effectiveness of LC supplementation may result from the age-wise distribution of sarcopenia. The prevalence of sarcopenia increased steeply with age, reaching Muscle damage may occur during exercise, especially eccentric exercise. In the clearance of damaged tissues assist free radicals produced by neutrophils.
Therefore, among other responses to exercise, neutrophils are released into the circulation. While neutrophil-derived reactive oxygen species ROS play an important role in breaking down damaged fragments of the muscle tissue, ROS produced in excess may also contribute to oxidative stress for review see [ 4748 ].
Based on the assumption that LC may provide cell membranes protection against oxidative stress [ 49 ], it has been hypothesized that LC supplementation would mitigate exercise-induced muscle damage and improve post-exercise recovery.
Since plasma LC elevates following 2 weeks of supplementation [ 2122 ], short protocols of supplementation may be considered as effective in attenuating post-exercise muscle soreness. It has been shown, through magnetic resonance imaging technique that muscle disruption after strenuous exercise was reduced by LC supplementation [ 3751 ].
This effect was accompanied by a significant reduction in released cytosolic proteins such as myoglobin and creatine kinase [ 505253 ] as well as attenuation in plasma marker of oxidative stress - malondialdehyde [ 515354 ].
Furthermore, 9 weeks of LC supplementation in conjunction with resistance training revealed a significant increase of circulating total antioxidant capacity and glutathione peroxidase activity and decrease in malondialdehyde concentration [ 43 ].
In Rebouche et al. Similar observations were noted in later human studies [ 5657 ], with the peak serum TMAO observed within hours following oral administration of the tracer [ 56 ]. Prolonged LC treatment elevates fasting plasma TMAO [ 1617185859 ].
Three months of oral LC supplementation in healthy aged women induced ten-fold increase of fasting plasma TMAO, and this level remained elevated for the further 3 months of supplementation [ 16 ].
Four months after cessation of LC supplementation, plasma TMAO reached a pre-supplementation concentration, which was stable for the following 8 months [ 60 ].
In Wang et al. Since diets high in red meat have been strongly related to heart disease and mortality [ 62 ], LC has been proposed as the red meat nutrient responsible for atherosclerosis promotion [ 8 ]. As a potential link between red meat consumption and the increasing risk of cardiovascular disease, TMAO has been indicated [ 8 ].
Numerous later studies have shown the association between increased plasma TMAO levels with a higher risk of cardiovascular events [ 63646566 ]. The recent meta-analyses indicated that in patients with high TMAO plasma level, the incidence of major adverse cardiovascular events was significantly higher compared with patients with low TMAO levels [ 67 ], and that all-cause mortality increased by 7.
The rise of plasma TMAO was on average three-fold compared with white meat and non-meat diets [ 70 ]. Conversely, habitual consumption of red, processed or white meat did not affect plasma TMAO in German adult population [ 71 ].
Similarly, a minor increase in plasma TMAO was observed following red meat and processed meat consumption in European multi-center study [ 72 ].
: L-carnitine and muscle fatigue| L-Carnitine | Savitha S, Panneerselvam C. Several clinical trials conducted in the s examined the effect of acetyl-L-carnitine ALCAR treatment on the cognitive performance of patients clinically diagnosed with Alzheimer's disease. Oral L-carnitine supplementation increases trimethylamine-N-oxide but reduces markers of vascular injury in hemodialysis patients. Three studies had no control arm, eight studies were open-label , and eight studies included fewer than participants. Hepatic encephalopathy refers to the occurrence of a spectrum of neuropsychiatric signs or symptoms in individuals with acute or chronic liver disease |
| Carnitine Deficiency | Cedars-Sinai | In contrast, L -carnitine had no effect on chromogranin A or subjective fatigue. These results suggest that citric acid reduces physiological stress and attenuates physical fatigue, whereas L -carnitine does not. Already have an account? Sign in here. Journal of Clinical Biochemistry and Nutrition. Online ISSN : Print ISSN : ISSN-L : Journal home Advance online publication All issues About the journal. Tomohiro Sugino Research and Development Division, Soiken Inc. Sayaka Aoyagi Research and Development Division, Soiken Inc. Department of Biomarker and Molecular Biophysics, Osaka City University Graduate School of Medicine Tomoko Shirai Soiken Holdings Inc. Yoshitaka Kajimoto Research and Development Division, Soiken Inc. Osami Kajimoto Soiken Holdings Inc. Wachter S, Vogt M, Kreis R, Boesch C, Bigler P, Hoppeler H, Krahenbuhl S. 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| L-Carnitine | Linus Pauling Institute | Oregon State University | Journal of Clinical Biochemistry and Nutrition. Online ISSN : Print ISSN : ISSN-L : Journal home Advance online publication All issues About the journal. Tomohiro Sugino Research and Development Division, Soiken Inc. Sayaka Aoyagi Research and Development Division, Soiken Inc. Department of Biomarker and Molecular Biophysics, Osaka City University Graduate School of Medicine Tomoko Shirai Soiken Holdings Inc. Yoshitaka Kajimoto Research and Development Division, Soiken Inc. Osami Kajimoto Soiken Holdings Inc. Corresponding author. Keywords: physical fatigue , citric acid , L -carnitine , chromogranin A , cycle ergometer. JOURNAL FREE ACCESS. Published: Received: June 04, Available on J-STAGE: October 30, Accepted: June 15, Advance online publication: - Revised: -. Download PDF K Download citation RIS compatible with EndNote, Reference Manager, ProCite, RefWorks. Article overview. References Related articles 0. Figures 0. Content from these authors. A meta-analysis of 17 randomized , placebo -controlled studies in a total of 1, participants with heart failure found that oral L-carnitine 1. Angina pectoris is chest pain that occurs when the coronary blood supply is insufficient to meet the metabolic needs of the heart muscle as with ischemic heart disease; see the page on Angina Pectoris In a prospective cohort study in over 4, participants with suspected angina pectoris, elevated concentrations of certain acylcarnitine intermediates in blood were associated with fatal and non-fatal acute myocardial infarction In early studies, the addition of oral L-carnitine or propionyl-L-carnitine to pharmacologic therapy for chronic stable angina modestly improved exercise tolerance and decreased electrocardiographic signs of ischemia during exercise testing in some angina patients In this study, propionyl-L-carnitine decreased myocardial ischemia, evidenced by significant reductions in ST-segment depression and left ventricular end-diastolic pressure In peripheral arterial disease , atherosclerosis of the arteries that supply the lower extremities may diminish blood flow to the point that the metabolic needs of exercising muscles are not sufficiently met, thereby leading to ischemic leg or hip pain known as claudication see the page on Intermittent Claudication in Peripheral Arterial Disease Several clinical trials have found that treatment with propionyl-L-carnitine improves exercise tolerance in some patients with intermittent claudication. Two systematic reviews of interventions concluded that the modest benefit of propionyl-L-carnitine on walking performance was equivalent or superior to that obtained with drugs approved for claudication in the US e. Both L-carnitine loss into the dialysate and impaired synthesis by the kidneys contribute to a progressive carnitine deficiency in patients with end-stage renal disease ESRD undergoing hemodialysis The low clearance of long-chain acylcarnitine molecules leads to a high acylcarnitine-to-L-carnitine ratio that has been associated with a higher risk of cardiovascular mortality Carnitine depletion in patients undergoing hemodialysis may lead to various conditions, such as muscle weakness and fatigue, plasma lipid abnormalities, and refractory anemia. A systematic review and meta-analysis of 31 randomized controlled trials in a total of 1, patients with ESRD found that L-carnitine treatment — administered either orally or intravenously — resulted in reductions of serum C-reactive protein a marker of inflammation and predictor of mortality in patients undergoing hemodialysis and LDL - cholesterol , although the latter was not deemed to be clinically relevant There was no effect of L-carnitine on other serum lipids i. The US National Kidney Foundation did not recommend routine administration of L-carnitine to subjects undergoing dialysis yet encouraged the development of trials in patients with select symptoms that do not respond to standard therapy, i. The use of certain antiretroviral agents nucleoside analogs has been associated with an increased risk of developing peripheral neuropathy in HIV -positive individuals 77, Small, uncontrolled, open-label intervention studies have suggested a beneficial effect of acetyl-L-carnitine ALCAR in patients with painful neuropathies. An early uncontrolled study found that 10 out of 16 HIV-positive subjects with painful neuropathy reported improvement after three weeks of intravenous or intramuscular ALCAR treatment Results from another uncontrolled intervention in 21 HIV-positive patients suggested that long-term two to four years oral ALCAR supplementation 1. Large-scale, controlled studies are needed before any conclusions can be drawn. Advanced stages of diabetic peripheral neuropathy can lead to recurrent foot ulcers and infections, and eventually amputations A systematic review 87 identified three placebo -controlled interventions that examined the effect of oral supplementation with acetyl-L-carnitine ALCAR; 1. Low-quality evidence suggested a lower level of pain with ALCAR, as measured with a visual scale analog. Low-quality evidence from another trial that compared the effect of ALCAR 1. A few randomized , double-blind , placebo -controlled trials have examined whether ALCAR might help prevent or treat chemotherapy -induced peripheral neuropathy. A trial in participants with either ovarian cancer or castration-resistant prostate cancer found no evidence that ALCAR 1g every 3 days given with the anticancer drug sagopilone for up to six cycles of treatment reduced the overall risk of peripheral neuropathy compared to a placebo However, ALCAR reduced the risk of high-grade sagopilone-induced neuropathy A follow-up study reported that the negative impact of week treatment with ALCAR was still observed at week 52; however, no differences between ALCAR and placebo were apparent at week Improvements in electrophysiological parameters were also observed with ALCAR treatment The results from these trials are conflicting and thus difficult to interpret. The efficacy of ALCAR in the prevention and treatment of chemotherapy-induced peripheral neuropathy remains to be established A meta-analysis identified 12 randomized controlled trials , including participants, that examined the effect of ALCAR on symptoms of depression Another meta-analysis of trials that compared the safety profile of antidepressants found evidence of fewer adverse effects, and consequently, better adherence to treatment with ALCAR compared to placebo and in contrast to classical pharmaceutical agents The metabolomic profiling of acylcarnitine molecules showed variations in serum concentrations of subjects along the continuum from cognitively healthy to affected by Alzheimer's disease Several clinical trials conducted in the s examined the effect of acetyl-L-carnitine ALCAR treatment on the cognitive performance of patients clinically diagnosed with Alzheimer's disease. Early, small trials suggested a beneficial effect of ALCAR with respect to cognitive decline , whereas later, larger trials found little-to-no effect compared to placebo However, a systematic review highlighted differences in methodologies between early and later studies that make it difficult to compare results A meta-analysis of 21 trials found that ALCAR was superior to placebo in several psychometric tests assessing global patient functioning, attention, memory, and some intellectual functions Hepatic encephalopathy refers to the occurrence of a spectrum of neuropsychiatric signs or symptoms in individuals with acute or chronic liver disease Subclinical hepatic encephalopathy may not feature any symptoms beyond abnormal behavior on psychometric tests or symptoms that are nonspecific in nature. In contract, overt hepatic encephalopathy can present with disorientation, obvious personality change, inappropriate behavior, somnolence, stupor, confusion, and coma Changes in mental status are thought to be caused by the liver failing to detoxify neurotoxic compounds like ammonia. A systematic review of five placebo -controlled trials conducted by one group of investigators examined the effect of acetyl-L-carnitine ALCAR in participants with cirrhosis and portal hypertension high blood pressure in the portal vein and presenting with either subclinical or overt hepatic encephalopathy. ALCAR was found to significantly reduce blood ammonium concentration compared to placebo. However, none of the trials reported on serious adverse outcomes, including mortality. Additionally, the evidence was too limited to assess the impact on quality of life or mental and physical fatigue. Fatigue is not uncommon in people who have undergone chemotherapy and survived cancer , with fatigue symptoms depending on the specific type of cancer and treatment. Cancer-related fatigue can persist well beyond the end of chemotherapy and be associated with cognitive and functional decline, insomnia, depression, and a reduction in the quality of life A systematic review and meta-analysis identified 12 intervention studies that assessed the effect of L-carnitine or ALCAR on cancer-related fatigue reported as a primary or secondary outcome in cancer survivors Three studies had no control arm, eight studies were open-label , and eight studies included fewer than participants. Overall, only three studies were deemed of good quality. The meta-analysis of these three randomized , double-blind , placebo -controlled trials found no effect of L-carnitine 0. L-Carnitine is concentrated in the epididymis , where sperm mature and acquire their motility An early cross-sectional study of fertile and infertile men found that L-carnitine concentrations in semen were positively correlated with the number of sperm, the percentage of motile sperm, and the percentage of normal appearing sperm in the sample , suggesting that L-carnitine may play an important role in male fertility. In both trials, the effect of carnitine was greater in the most severe cases of asthenozoospermia reduced sperm motility at baseline , However, a pooled analysis of the two trials that employed ALCAR found no significant effect of ALCAR and L-carnitine on sperm concentration, motility, and morphology Evidence from larger scale clinical trials is still needed to determine whether L-carnitine and ALCAR could play a role in the treatment of male infertility. Frailty is a syndrome prevalent among geriatric populations and characterized by a functional decline and a loss of independence to perform the activities of daily living. Frailty in individuals may include at least three of the following symptoms: unintentional weight loss, exhaustion poor endurance , weakness low grip strength , slowness, and physical inactivity It is believed that early stages of frailty are amenable to interventions that could avert adverse outcomes, including the increased risk of hospitalization and premature death The suggestion that carnitine deficiency may lead to frailty through mitochondrial dysfunction has been examined in one trial. This randomized , double-blind , placebo -controlled trial in 58 older adults identified as "pre-frail" found an decrease in a Frailty Index score and an improvement in the hand grip test in individuals supplemented with L-carnitine 1. However, there was no difference in Frailty Index and hand grip test scores between supplemental L-carnitine and placebo groups. Loss of skeletal muscle mass is associated with a decrease in muscle strength and occurs with aging , as well as in several pathological conditions Based on preclinical studies, it has been suggested that L-carnitine supplementation could limit the imbalance between protein anabolism synthesis and catabolism degradation that leads to skeletal muscle wasting A randomized , double-blind , placebo -controlled trial in 28 older women ages, years found no effect of L-carnitine supplementation 1. One major limitation of this study beyond its retrospective design is that patients who received L-carnitine had a significantly different clinical presentation; in particular, liver dysfunction was significantly more severe in these patients than in those who were not supplemented Muscle cramps are involuntary and painful contractions of skeletal muscles. Two uncontrolled studies conducted in participants with cirrhosis found that L-carnitine supplementation was safe to use at doses of 0. However, whether supplemental L-carnitine can be efficacious to limit the incidence of muscle cramps in patients with cirrhosis remains unknown. An open-label , non-randomized trial in 69 patients with either type 1 or type 2 diabetes mellitus found a reduction in the incidence of muscle cramps and an improvement in the quality of life of those prescribed 0. In contrast, there is little evidence to date to suggest that supplemental L-carnitine could reduce muscle cramps in patients undergoing hemodialysis Well-designed trials are necessary to examine whether L-carnitine could be helpful in the management of cramps. Interest in the potential of L-carnitine supplementation to improve athletic performance is related to its important roles in energy metabolism. However, the content carnitine in skeletal muscle, phosphocreatine, ATP , glycogen , and lactate, as well as measures of physical performance during exercise were equivalent between vegetarians and omnivores. While L-carnitine supplementation normalized plasma carnitine concentration in vegetarians to that observed in omnivores, there was no effect on energy metabolism and physical performance compared to no supplementation and between vegetarians and omnivores The normal rate of L-carnitine biosynthesis in humans ranges from 0. Thus, a 70 kg 1b person would synthesize between 11 and 34 mg of carnitine per day. Meat, poultry, fish, and dairy products are the richest sources of L-carnitine, while fruit, vegetables, and grains contain relatively little L-carnitine. Non-milk-based infant formulas e. Some carnitine-rich foods and their carnitine content in milligrams mg are listed in Table 1. Intravenous L-carnitine is available by prescription only for the treatment of primary and secondary L-carnitine deficiencies Oral L-carnitine is available by prescription for the treatment of primary and secondary L-carnitine deficiencies It is also available without a prescription as a nutritional supplement ; supplemental doses usually range from 0. Acetyl-L-carnitine ALCAR is available without a prescription as a nutritional supplement. In addition to providing L-carnitine, it provides acetyl groups that may be used in the formation of the neurotransmitter , acetylcholine. Supplemental doses usually range from 0. Propionyl-L-carnitine is not approved by the US FDA for use as a drug to prevent or treat any condition. It is, however, available without prescription as a nutritional supplement. See Figure 1 for the chemical structures of L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine. In general, L-carnitine appears to be well tolerated; no toxic effects have been reported in relation to intakes of high doses of L-carnitine. L-Carnitine supplementation may cause mild gastrointestinal symptoms, including nausea, vomiting, abdominal cramps, and diarrhea. Acetyl-L-carnitine ALCAR has been reported to increase agitation in some Alzheimer's disease patients Despite claims that L-carnitine or ALCAR might increase seizures in some individuals with seizure disorders , these are not supported by any scientific evidence Only the L- isomer of carnitine is biologically active; the D-isomer may actually compete with L-carnitine for absorption and transport, thereby increasing the risk of L-carnitine deficiency 4. Supplements containing a mixture of the D- and L-isomers D,L-carnitine have been associated with muscle weakness in patients with kidney disease. Long-term studies examining the safety of ALCAR supplementation in pregnant and breast-feeding women are lacking Pivalic acid combines with L-carnitine and is excreted in the urine as pivaloylcarnitine, thereby increasing L-carnitine losses see also Secondary carnitine deficiency. Consequently, prolonged use of pivalic acid-containing antibiotics, including pivampicillin, pivmecillinam, pivcephalexin, and cefditoren pivoxil Spectracef , can lead to secondary L-carnitine deficiency The anticonvulsant valproic acid Depakene interferes with L-carnitine biosynthesis in the liver and forms with L-carnitine a valproylcarnitine ester that is excreted in the urine. However, L-carnitine supplements are necessary only in a subset of patients taking valproic acid. There is insufficient evidence to suggest that nucleoside analogs used in the treatment of HIV infection i. Originally written in by: Jane Higdon, Ph. Linus Pauling Institute Oregon State University. Updated in April by: Victoria J. Drake, Ph. Updated in July by: Barbara Delage, Ph. Reviewed in December by: Tory M. Hagen, Ph. Principal Investigator, Linus Pauling Institute Professor, Dept. of Biochemistry and Biophysics Helen P. Rumbel Professor for Healthy Aging Research Oregon State University. Rebouche CJ. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease. Fraenkel G, Friedman S. Vitam Horm. De Grandis D, Minardi C. Acetyl-L-carnitine levacecarnine in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebo-controlled study. Drugs R D. Seim H, Eichler K, Kleber H. L - -Carnitine and its precursor, gamma-butyrobetaine. In: Kramer K, Hoppe P, Packer L, eds. Nutraceuticals in Health and Disease Prevention. New York: Marcel Dekker, Inc. Kinetics, pharmacokinetics, and regulation of L-carnitine and acetyl-L-carnitine metabolism. Ann N Y Acad Sci. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Baltimore; Ascorbic acid and carnitine biosynthesis. Am J Clin Nutr. Evans AM, Fornasini G. Pharmacokinetics of L-carnitine. Clin Pharmacokinet. Lombard KA, Olson AL, Nelson SE, Rebouche CJ. Carnitine status of lactoovovegetarians and strict vegetarian adults and children. Rebouche CJ, Chenard CA. Metabolic fate of dietary carnitine in human adults: identification and quantification of urinary and fecal metabolites. J Nutr. Gross CJ, Henderson LM, Savaiano DA. Uptake of L-carnitine, D-carnitine and acetyl-L-carnitine by isolated guinea-pig enterocytes. Biochim Biophys Acta. Rebouche CJ, Lombard KA, Chenard CA. Renal adaptation to dietary carnitine in humans. In: Erdman JWJ, Macdonald IA, Zeisel SH, eds. Present Knowledge in Nutrition. McGrane MM. Carbohydrate metabolism--synthesis and oxidation. In: Stipanuk MH, ed. Biochemical and Physiological Aspects of Human Nutrition. Philadelphia: W. Saunders Co; Solarska K, Lewinska A, Karowicz-Bilinska A, Bartosz G. The antioxidant properties of carnitine in vitro. Cell Mol Biol Lett. Costell M, O'Connor JE, Grisolia S. Age-dependent decrease of carnitine content in muscle of mice and humans. Biochem Biophys Res Commun. Karlic H, Lohninger A, Laschan C, et al. Downregulation of carnitine acyltransferases and organic cation transporter OCTN2 in mononuclear cells in healthy elderly and patients with myelodysplastic syndromes. J Mol Med Berl. Hagen TM, Ingersoll RT, Wehr CM, et al. Acetyl-L-carnitine fed to old rats partially restores mitochondrial function and ambulatory activity. Proc Natl Acad Sci U S A. Pesce V, Fracasso F, Cassano P, Lezza AM, Cantatore P, Gadaleta MN. Acetyl-L-carnitine supplementation to old rats partially reverts the age-related mitochondrial decay of soleus muscle by activating peroxisome proliferator-activated receptor gamma coactivator-1alpha-dependent mitochondrial biogenesis. Rejuvenation Res. Gomez LA, Heath SH, Hagen TM. Acetyl-l-carnitine supplementation reverses the age-related decline in carnitine palmitoyltransferase 1 CPT1 activity in interfibrillar mitochondria without changing the l-carnitine content in the rat heart. Mech Ageing Dev. Muthuswamy AD, Vedagiri K, Ganesan M, Chinnakannu P. Oxidative stress-mediated macromolecular damage and dwindle in antioxidant status in aged rat brain regions: role of L-carnitine and DL-alpha-lipoic acid. Clin Chim Acta. Kumaran S, Panneerselvam KS, Shila S, Sivarajan K, Panneerselvam C. Age-associated deficit of mitochondrial oxidative phosphorylation in skeletal muscle: role of carnitine and lipoic acid. Mol Cell Biochem. Kumaran S, Subathra M, Balu M, Panneerselvam C. Supplementation of L-carnitine improves mitochondrial enzymes in heart and skeletal muscle of aged rats. Exp Aging Res. Savitha S, Panneerselvam C. Mitochondrial membrane damage during aging process in rat heart: potential efficacy of L-carnitine and DL alpha lipoic acid. Savitha S, Sivarajan K, Haripriya D, Kokilavani V, Panneerselvam C. Efficacy of levo carnitine and alpha lipoic acid in ameliorating the decline in mitochondrial enzymes during aging. Clin Nutr. Sethumadhavan S, Chinnakannu P. Carnitine and lipoic Acid alleviates protein oxidation in heart mitochondria during aging process. Sundaram K, Panneerselvam KS. Oxidative stress and DNA single strand breaks in skeletal muscle of aged rats: role of carnitine and lipoicacid. L-carnitine and alpha-lipoic acid improve age-associated decline in mitochondrial respiratory chain activity of rat heart muscle. J Gerontol A Biol Sci Med Sci. Tamilselvan J, Jayaraman G, Sivarajan K, Panneerselvam C. Age-dependent upregulation of p53 and cytochrome c release and susceptibility to apoptosis in skeletal muscle fiber of aged rats: role of carnitine and lipoic acid. Free Radic Biol Med. Aliev G, Liu J, Shenk JC, et al. Neuronal mitochondrial amelioration by feeding acetyl-L-carnitine and lipoic acid to aged rats. J Cell Mol Med. Olson AL, Nelson SE, Rebouche CJ. Low carnitine intake and altered lipid metabolism in infants. American Academy of Pediatrics, Committee on Nutrition. Soy protein-based formulas: recommendations for use in infant feeding. Frigeni M, Balakrishnan B, Yin X, et al. Functional and molecular studies in primary carnitine deficiency. Hum Mutat. Magoulas PL, El-Hattab AW. Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management. Orphanet J Rare Dis. Knottnerus SJG, Bleeker JC, Wust RCI, et al. Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle. Rev Endocr Metab Disord. Pons R, De Vivo DC. Primary and secondary carnitine deficiency syndromes. J Child Neurol. Gregory MJ, Schwartz GJ. Diagnosis and treatment of renal tubular disorders. Semin Nephrol. Calvani M, Benatti P, Mancinelli A, et al. Carnitine replacement in end-stage renal disease and hemodialysis. Stanley CA. Carnitine deficiency disorders in children. El-Gharbawy A, Vockley J. Inborn errors of metabolism with myopathy: defects of fatty acid oxidation and the carnitine shuttle system. Pediatr Clin North Am. Food and Nutrition Board, Institute of Medicine. Vitamin C. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington D. National Academy Press. Ringseis R, Keller J, Eder K. Mechanisms underlying the anti-wasting effect of L-carnitine supplementation under pathologic conditions: evidence from experimental and clinical studies. Eur J Nutr. Xu Y, Jiang W, Chen G, et al. L-carnitine treatment of insulin resistance: A systematic review and meta-analysis. Adv Clin Exp Med. Vidal-Casariego A, Burgos-Pelaez R, Martinez-Faedo C, et al. Metabolic effects of L-carnitine on type 2 diabetes mellitus: systematic review and meta-analysis. Exp Clin Endocrinol Diabetes. Asadi M, Rahimlou M, Shishehbor F, Mansoori A. The effect of l-carnitine supplementation on lipid profile and glycaemic control in adults with cardiovascular risk factors: A systematic review and meta-analysis of randomized controlled clinical trials. Parvanova A, Trillini M, Podesta MA, et al. Blood pressure and metabolic effects of acetyl-l-carnitine in type 2 diabetes: DIABASI randomized controlled trial. J Endocr Soc. Davini P, Bigalli A, Lamanna F, Boem A. Controlled study on L-carnitine therapeutic efficacy in post-infarction. Drugs Exp Clin Res. Xue YZ, Wang LX, Liu HZ, Qi XW, Wang XH, Ren HZ. L-carnitine as an adjunct therapy to percutaneous coronary intervention for non-ST elevation myocardial infarction. Cardiovasc Drugs Ther. Iyer R, Gupta A, Khan A, Hiremath S, Lokhandwala Y. Does left ventricular function improve with L-carnitine after acute myocardial infarction? J Postgrad Med. Tarantini G, Scrutinio D, Bruzzi P, Boni L, Rizzon P, Iliceto S. Metabolic treatment with L-carnitine in acute anterior ST segment elevation myocardial infarction. A randomized controlled trial. DiNicolantonio JJ, Lavie CJ, Fares H, Menezes AR, O'Keefe JH. L-carnitine in the secondary prevention of cardiovascular disease: systematic review and meta-analysis. Mayo Clin Proc. Trupp RJ, Abraham WT. Congestive heart failure. In: Rakel RE, Bope ET, eds. Conn's Current Therapy. New York: W. Sunders Company; Ruiz M, Labarthe F, Fortier A, et al. Circulating acylcarnitine profile in human heart failure: a surrogate of fatty acid metabolic dysregulation in mitochondria and beyond. Am J Physiol Heart Circ Physiol. Ueland T, Svardal A, Oie E, et al. Disturbed carnitine regulation in chronic heart failure--increased plasma levels of palmitoyl-carnitine are associated with poor prognosis. Int J Cardiol. Yoshihisa A, Watanabe S, Yokokawa T, et al. Associations between acylcarnitine to free carnitine ratio and adverse prognosis in heart failure patients with reduced or preserved ejection fraction. ESC Heart Fail. Song X, Qu H, Yang Z, Rong J, Cai W, Zhou H. Efficacy and safety of L-carnitine treatment for chronic heart failure: a meta-analysis of randomized controlled trials. Biomed Res Int. Strand E, Pedersen ER, Svingen GF, et al. Serum acylcarnitines and risk of cardiovascular death and acute myocardial infarction in patients with stable angina pectoris. J Am Heart Assoc. Cacciatore L, Cerio R, Ciarimboli M, et al. The therapeutic effect of L-carnitine in patients with exercise-induced stable angina: a controlled study. Cherchi A, Lai C, Angelino F, et al. Effects of L-carnitine on exercise tolerance in chronic stable angina: a multicenter, double-blind, randomized, placebo controlled crossover study. Int J Clin Pharmacol Ther Toxicol. Iyer RN, Khan AA, Gupta A, Vajifdar BU, Lokhandwala YY. L-carnitine moderately improves the exercise tolerance in chronic stable angina. J Assoc Physicians India. Bartels GL, Remme WJ, Pillay M, Schonfeld DH, Kruijssen DA. Effects of L-propionylcarnitine on ischemia-induced myocardial dysfunction in men with angina pectoris. Am J Cardiol. Mills JL. Peripheral arterial disease. Brevetti G, Perna S, Sabba C, Martone VD, Condorelli M. Propionyl-L-carnitine in intermittent claudication: double-blind, placebo-controlled, dose titration, multicenter study. J Am Coll Cardiol. Brevetti G, Diehm C, Lambert D. European multicenter study on propionyl-L-carnitine in intermittent claudication. Hiatt WR. Carnitine and peripheral arterial disease. Luo T, Li J, Li L, et al. A study on the efficacy and safety assessment of propionyl-L-carnitine tablets in treatment of intermittent claudication. Thromb Res. Santo SS, Sergio N, Luigi DP, et al. Effect of PLC on functional parameters and oxidative profile in type 2 diabetes-associated PAD. Diabetes Res Clin Pract. Brass EP, Koster D, Hiatt WR, Amato A. A systematic review and meta-analysis of propionyl-L-carnitine effects on exercise performance in patients with claudication. Vasc Med. Delaney CL, Spark JI, Thomas J, Wong YT, Chan LT, Miller MD. |
| The bright and the dark sides of L-carnitine supplementation: a systematic review | The fatigue-inducing physical task consisted of workload trials on a cycle ergometer at fixed workloads for 2 h on 2 occasions. Before the physical load, salivary chromogranin A, measured as a physiological stress marker, was lower in the group given citric acid than in the group given placebo. Also, after the physical load, the subjective feeling of fatigue assessed with a visual analogue scale was lower in the citric acid group than in the placebo group. In contrast, L -carnitine had no effect on chromogranin A or subjective fatigue. These results suggest that citric acid reduces physiological stress and attenuates physical fatigue, whereas L -carnitine does not. Already have an account? Sign in here. Journal of Clinical Biochemistry and Nutrition. Online ISSN : Print ISSN : ISSN-L : Journal home Advance online publication All issues About the journal. Tomohiro Sugino Research and Development Division, Soiken Inc. Sayaka Aoyagi Research and Development Division, Soiken Inc. Elevated protein synthesis and attenuated proteolysis are observed during muscle hypertrophy. Both of these processes are mainly regulated by the signaling pathway: insulin-like growth factor-1 IGF-1 — phosphoinositidekinase PI3K — protein kinase B Akt — mammalian target of rapamycin mTOR. The activation of mTOR leads to phosphorylation and activation of S6 kinases S6Ks and hyperphosphorylation of 4E-binding proteins 4E-BPs , resulting in the acceleration of protein synthesis. At the same time, Akt phosphorylates and inactivates forkhead box O FoxO , thereby inhibit the responsible for proteolysis ubiquitin ligases: muscle-specific RING finger-1 MuRF-1 and muscle atrophy F-box protein atrogin-1 , for review see [ 27 , 28 , 29 ]. The association between LC supplementation and the regulation of metabolic pathways involved in muscle protein balance have been shown in several animal studies Fig. Four weeks of LC supplementation in rats increased plasma IGF-1 concentration [ 33 ]. FoxO inactivation attenuated MURF-1 expression in quadriceps fem oris muscle of supplemented rats compared to control [ 33 ]. All these findings together might suggest that LC supplementation protect muscle from atrophy, especially in pathophysiological conditions. The association between LC supplementation and the regulation of metabolic pathways involved in muscle protein balance. L-carnitine LC ; insulin-like growth factor-1 IGF-1 ; phosphoinositidekinase PI3K ; protein kinase B Akt ; mammalian target of rapamycin mTOR ; forkhead box O FoxO ; muscle-specific RING finger-1 MuRF-1 ; muscle atrophy F-box atrogin-1 ; increase ; decrease ; activation ; inactivation. Various effects might be due to different IGF-1 levels; significantly lower in the HIV-seropositive patients than in healthy subjects [ 38 ]. These findings altogether suggest that prolonged LC supplementation might affect body composition in specific conditions. Therefore, authors suggested that LC supplementation may be effective in obese and overweight subjects. It has been assumed that a combination of LC supplementation with increased energy expenditure may positively affect body composition. However, either with aerobic [ 41 , 42 ] or resistance [ 43 ] training, LC supplementation has not achieved successful endpoint. Similarly, lack of LC effect has been reported in obese women [ 42 ]. Body composition, determined by dual energy X-ray absorptiometry, indicated no significant effect in fat mass and fat-free mass due to supplementation. Moreover, LC administration did not influence bench press results. The number of leg press repetitions and the leg press third set lifting volume increased in the LC group compared to the placebo group [ 43 ]. Different LC effect in the limbs may be associated with the higher rates of glycogenolysis during arm exercise at the same relative intensity as leg exercise [ 44 ]. Aged people have accelerated protein catabolism, which is associated with muscle wasting [ 45 ]. LC could increase the amount of protein retention by inhibition of the proteolytic pathway. Six months of LC supplementation augmented fat free mass and reduced total body fat mass in centenarians [ 14 ]. Such effect was not observed in elder women age range 65—70 y. after a similar period of supplementation [ 15 ]. The effectiveness of LC supplementation may result from the age-wise distribution of sarcopenia. The prevalence of sarcopenia increased steeply with age, reaching Muscle damage may occur during exercise, especially eccentric exercise. In the clearance of damaged tissues assist free radicals produced by neutrophils. Therefore, among other responses to exercise, neutrophils are released into the circulation. While neutrophil-derived reactive oxygen species ROS play an important role in breaking down damaged fragments of the muscle tissue, ROS produced in excess may also contribute to oxidative stress for review see [ 47 , 48 ]. Based on the assumption that LC may provide cell membranes protection against oxidative stress [ 49 ], it has been hypothesized that LC supplementation would mitigate exercise-induced muscle damage and improve post-exercise recovery. Since plasma LC elevates following 2 weeks of supplementation [ 21 , 22 ], short protocols of supplementation may be considered as effective in attenuating post-exercise muscle soreness. It has been shown, through magnetic resonance imaging technique that muscle disruption after strenuous exercise was reduced by LC supplementation [ 37 , 51 ]. This effect was accompanied by a significant reduction in released cytosolic proteins such as myoglobin and creatine kinase [ 50 , 52 , 53 ] as well as attenuation in plasma marker of oxidative stress - malondialdehyde [ 51 , 53 , 54 ]. Furthermore, 9 weeks of LC supplementation in conjunction with resistance training revealed a significant increase of circulating total antioxidant capacity and glutathione peroxidase activity and decrease in malondialdehyde concentration [ 43 ]. In Rebouche et al. Similar observations were noted in later human studies [ 56 , 57 ], with the peak serum TMAO observed within hours following oral administration of the tracer [ 56 ]. Prolonged LC treatment elevates fasting plasma TMAO [ 16 , 17 , 18 , 58 , 59 ]. Three months of oral LC supplementation in healthy aged women induced ten-fold increase of fasting plasma TMAO, and this level remained elevated for the further 3 months of supplementation [ 16 ]. Four months after cessation of LC supplementation, plasma TMAO reached a pre-supplementation concentration, which was stable for the following 8 months [ 60 ]. In Wang et al. Since diets high in red meat have been strongly related to heart disease and mortality [ 62 ], LC has been proposed as the red meat nutrient responsible for atherosclerosis promotion [ 8 ]. As a potential link between red meat consumption and the increasing risk of cardiovascular disease, TMAO has been indicated [ 8 ]. Numerous later studies have shown the association between increased plasma TMAO levels with a higher risk of cardiovascular events [ 63 , 64 , 65 , 66 ]. The recent meta-analyses indicated that in patients with high TMAO plasma level, the incidence of major adverse cardiovascular events was significantly higher compared with patients with low TMAO levels [ 67 ], and that all-cause mortality increased by 7. The rise of plasma TMAO was on average three-fold compared with white meat and non-meat diets [ 70 ]. Conversely, habitual consumption of red, processed or white meat did not affect plasma TMAO in German adult population [ 71 ]. Similarly, a minor increase in plasma TMAO was observed following red meat and processed meat consumption in European multi-center study [ 72 ]. In the previous century, the underlined function of TMAO was the stabilization of proteins against various environmental stress factors, including high hydrostatic pressure [ 73 ]. TMAO was shown as widely distributed in sea animals [ 74 ], with concentration in the tissue increasing proportionally to the depth of the fishes natural environment [ 75 ]. Consequently, fish and seafood nutritional intake has a great impact on TMAO level in the human body [ 76 ], significantly elevating also plasma TMAO concentration [ 72 ]. Therefore, link between plasma TMAO and the risk of cardiovascular disease [ 8 ] seems like a paradox, since more fish in the diet reduces this risk [ 77 ]. Not only dietary modification may affect TMAO plasma levels. Due to TMAO excretion in urine [ 56 , 57 ], in chronic renal disease patients, TMAO elimination from the body fails, causing elevation of its plasma concentration [ 78 ]. Therefore, higher plasma TMAO in humans was suggested as a marker of kidney damage [ 79 ]. It is worthy to note that cardiovascular disease and kidney disease are closely interrelated [ 80 ] and diminished renal function is strongly associated with morbidity and mortality in heart failure patients [ 81 ]. Moreover, decreased TMAO urine excretion is associated with high salt dietary intake, increasing plasma TMAO concentration [ 82 ]. The relation between TMAO and chronic disease can be ambiguous, involving kidney function [ 79 ], disturbed gut-blood barrier [ 83 ], or flavin-containing monooxygenase 3 genotype [ 84 ]. Thus, whether TMAO is an atherogenic factor responsible for the development and progression of cardiovascular disease, or simply a marker of an underlined pathology, remains unclear [ 85 ]. Carnitine preparations administered orally can occasionally cause heart-burn or dyspepsia [ 86 ]. It is worthy to mention that Bakalov et al. The strength of this review is a focus on the period of LC treatment, very important aspect often missed in many articles dealing with this supplement. This limitation is also magnified by the varied design of the studies available including different supplementation protocols and outcome measures. There is also a high degree of heterogeneity among participants of the analyzed studies. Therefore, the results should be taken with caution, and more research is required before definitive recommendations. Lasting for several years opinion that LC supplementation does not change metabolism, especially exercise metabolism, is based mostly on short-term supplementation protocols. Nevertheless, LC is still used by elite [ 9 ] and sub-elite [ 10 ] athletes. Recent studies suggest that LC supplementation may elevate muscle TC content; therefore, modify muscle fuel metabolism and performance during the exercise. Due to insulin-mediated LC transport to the muscle, oral administration regimen should be combined with CHO. Because of LC poor bioavailability, it is likely that the supplementation protocol would take at least 3 months. Shorter period of supplementation may be effective in prevention of exercise-induced muscle damage, but not metabolic changes. On the other hand, it is also clear that prolonged LC supplementation elevates fasting plasma TMAO [ 16 , 17 , 18 , 58 , 59 ], compound supposed to be pro-atherogenic [ 61 ]. Therefore, additional studies focusing on long-term supplementation and its longitudinal effect on the TMAO metabolism and cardiovascular system are needed. Bremer J. Carnitine--metabolism and functions. Physiol Rev. Article CAS PubMed Google Scholar. Arenas J, Huertas R, Campos Y, Diaz AE, Villalon JM, Vilas E. Effects of L-carnitine on the pyruvate dehydrogenase complex and carnitine palmitoyl transferase activities in muscle of endurance athletes. FEBS Lett. Ringseis R, Keller J, Eder K. Mechanisms underlying the anti-wasting effect of L-carnitine supplementation under pathologic conditions: evidence from experimental and clinical studies. Eur J Nutr. Brass EP. Supplemental carnitine and exercise. Am J Clin Nutr. Wall BT, Stephens FB, Constantin-Teodosiu D, Marimuthu K, Macdonald IA, Greenhaff PL. 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| Carnitine (L-carnitine) Information | Mount Sinai - New York | L-Carnitine treatment reduces severity of physical and mental fatigue and increases cognitive functions in centenarians: a randomized and controlled clinical trial. Sites of action of carnitine and its derivatives on the cardiovascular system: interactions with membranes. AZT: In a laboratory study, L-carnitine supplements protected muscle tissue against toxic side effects from AZT, a medication used to treat HIV and AIDS. J Am Heart Assoc. Am J Physiol Heart Circ Physiol. Also, after the physical load, the subjective feeling of fatigue assessed with a visual analogue scale was lower in the citric acid group than in the placebo group. Male infertility: nutritional and environmental considerations. |
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