Skeletal Muscle Carnitine Research Articles

Evaluation of taurine and carnitine concentrations in whole blood, plasma, skeletal muscle and cardiac muscle in dogs.

Little is known about how plasma and whole blood taurine and plasma carnitine correlate to concentrations in skeletal and cardiac muscle and the effects of diet in dogs. The purpose of this study was to evaluate the correlation among plasma, skeletal and cardiac muscle carnitine and taurine and whole blood taurine and determine the effect of diet. The study protocol was approved by the Pet Food Solutions Institutional Animal Care and Use Committee. Thirty-three mixed-breed hounds and 32 beagles were evaluated at Day 0 then removed from their baseline diet and randomized to a test diet: high animal protein, grain-inclusive (HA-GI), low animal protein, grain-free (LA-GF), low animal protein, grain-inclusive (LA-GI), or high animal protein, grain-free (HA-GF). Blood was drawn every 30 days and endomyocardial (mixed breeds only) and skeletal muscle biopsies were collected at Days 0 and 180. The correlations between plasma and whole blood taurine, or plasma carnitine and skeletal and cardiac muscle concentrations were weak (p < 0.01-0.05). Mixed-breed hounds had increased (p = 0.029) whole blood taurine compared to beagles. Plasma taurine was lower with diet HA-GF, (p = 0.009) however, all diets had increased taurine from Day 0 and were, on average within the laboratory reference range. Dogs fed the HA-GI diet had increased cardiac muscle carnitine esters (p = 0.014). Increased carnitine esters were also appreciated in cardiac muscle in all diets from Day 0 to 180 (p = 0.0001). On Day 180 mixed-breed hounds had increased skeletal total carnitine (p < 0.001) compared to all time points and breeds. This study observed no correlation between plasma, whole blood, skeletal and cardiac muscle taurine concentrations but noted some effects between time, breed and diet.

The Effect of L-Carnitine Supplementation on Sportive Performance

L-carnitine is a derivative of two essential amino acids synthesized in the liver and kidneys that our body needs for energy. In the bioenergetics of skeletal muscle, carnitine plays crucial roles. A severe reduction in muscular activity is associated with skeletal muscle carnitine insufficiency. Since L-carnitine supplement is known as a fat burner, its use among athletes has become more common in recent years. This review's objective is to assess the potential mechanistic effects of L-carnitine supplementation on athletic performance. In this context, the literature in the SportDiscus, EMBASE, PubMed and Google Scholar databases was scanned during a 15-year period to gather the data from the publications screened within the scope of SCI, SCI-Expanded, and ESCI. Consequently, it may be argued that taking carnitine supplementation improves athletic performance through a number of processes; including the maintenance of glycogen.

Sex-specific maturation of muscle metabolites carnosine, creatine, and carnitine over puberty: a longitudinal follow-up study.

Due to the invasiveness of a muscle biopsy, there is fragmentary information on the existence and possible origin of a sexual dimorphism in the skeletal muscle concentrations of the energy delivery-related metabolites carnosine, creatine, and carnitine. As these metabolites can be noninvasively monitored by proton magnetic resonance spectroscopy, this technique offers the possibility to investigate if sexual dimorphisms are present in an adult reference population and if these dimorphisms originated during puberty using a longitudinal design. Concentrations of carnosine, creatine, and carnitine were examined using proton magnetic resonance spectroscopy in the soleus and gastrocnemius muscles of an adult reference population of female (n = 50) and male adults (n = 50). For the longitudinal follow-up over puberty, 29 boys and 28 girls were scanned prepuberty. Six years later, 24 boys and 24 girls were rescanned postpuberty. A sexual dimorphism was present in carnosine and creatine, but not carnitine, in the adult reference population. Carnosine was 28.5% higher in the gastrocnemius (P < 0.001) and carnosine and creatine were respectively 19.9% (P < 0.001) and 18.2% (P < 0.001) higher in the soleus of male when compared with female adults. Through puberty, carnosine increased more in male subjects compared with female subjects, both in the gastrocnemius (+10.43% and -10.83%, respectively; interaction effect: P = 0.002) and in the soleus (+24.30% and +5.49%, respectively; interaction effect: P = 0.012). No significant effect of puberty was found in either creatine (interaction effect: P = 0.307) or carnitine (interaction effect: P = 0.066). A sexual dimorphism in the adult human muscle is present in carnosine and creatine, but not in carnitine.NEW & NOTEWORTHY This is the first study to investigate sexual dimorphisms in skeletal muscle carnosine, creatine, and carnitine concentrations in a substantial adult reference population (n = 100). A sexual dimorphism is present in both carnosine and creatine at adult age. The origin of the sexual dimorphisms is investigated using a longitudinal design over puberty in 24 males and 24 females. The sexual dimorphism in carnosine originated partly during puberty for carnosine, but not for creatine.

Untargeted Metabolomic Characteristics of Skeletal Muscle Dysfunction in Rabbits Induced by a High Fat Diet.

Simple SummaryIn the present study, we performed an untargeted metabolomic analysis of skeletal muscle of rabbits and found that the skeletal muscle of rabbits fed a high-fat diet is rich in many metabolites, most of which are associated with type 2 diabetes and metabolic syndrome. In this paper, the mechanism of action of these metabolites in skeletal muscle and the metabolic pathways that interfere with the normal operation mechanism of the body are described and presented in the form of charts. Finally, we found that skeletal muscle-rich phospholipids, long-chain carnitine, histidine, carnosine, and tetrahydrocortisone may be potential markers for type 2 diabetes and metabolic syndrome, and may serve as potential therapeutic targets for related diseases in the future.Type 2 diabetes and metabolic syndrome caused by a high fat diet (HFD) have become public health problems worldwide. These diseases are characterized by the oxidation of skeletal muscle mitochondria and disruption of insulin resistance, but the mechanisms are not well understood. Therefore, this study aims to reveal how high-fat diet causes skeletal muscle metabolic disorders. In total, 16 weaned rabbits were randomly divided into two groups, one group was fed a standard normal diet (SND) and the other group was fed a high fat diet (HFD) for 5 weeks. At the end of the five-week experiment, skeletal muscle tissue samples were taken from each rabbit. Untargeted metabolomic analysis was performed using ultra-performance liquid chromatography combined with mass spectrometry (UHPLC-MS/MS). The results showed that high fat diet significantly altered the expression levels of phospholipids, LCACs, histidine, carnosine, and tetrahydrocorticosterone in skeletal muscle. Principal component analysis (PCA) and least squares discriminant analysis (PLS-DA) showed that, compared with the SND group, skeletal muscle metabolism in HFD group was significantly up-regulated. Among 43 skeletal muscle metabolites in the HFD group, phospholipids, LCACs, histidine, carnosine, and tetrahydrocorticosteroids were identified as biomarkers of skeletal muscle metabolic diseases, and may become potential physiological targets of related diseases in the future. Untargeted metabonomics analysis showed that high-fat diet altered the metabolism of phospholipids, carnitine, amino acids and steroids in skeletal muscle of rabbits. Notably, phospholipids, LCACs, histidine, carnopeptide, and tetrahydrocorticosteroids block the oxidative capacity of mitochondria and disrupt the oxidative capacity of glucose and the fatty acid-glucose cycle in rabbit skeletal muscle.

Increasing skeletal muscle carnitine content in older individuals increases whole-body fat oxidation during moderate-intensity exercise.

Intramyocellular lipid (IMCL) utilization is impaired in older individuals, and IMCL accumulation is associated with insulin resistance. We hypothesized that increasing muscle total carnitine content in older men would increase fat oxidation and IMCL utilization during exercise, and improve insulin sensitivity. Fourteen healthy older men (69 ± 1 year, BMI 26.5 ± 0.8 kg/m2) performed 1 h of cycling at 50% VO2max and, on a separate occasion, underwent a 60 mU/m2/min euglycaemic hyperinsulinaemic clamp before and after 25 weeks of daily ingestion of a 220 ml insulinogenic beverage (44.4 g carbohydrate, 13.8 g protein) containing 4.5 g placebo (n = 7) or L‐carnitine L‐tartrate (n = 7). During supplementation, participants performed twice‐weekly cycling for 1 h at 50% VO2max. Placebo ingestion had no effect on muscle carnitine content or total fat oxidation during exercise at 50% VO2max. L‐carnitine supplementation resulted in a 20% increase in muscle total carnitine content (20.1 ± 1.2 to 23.9 ± 1.7 mmol/kg/dm; p < 0.01) and a 20% increase in total fat oxidation (181.1 ± 15.0 to 220.4 ± 19.6 J/kg lbm/min; p < 0.01), predominantly due to increased IMCL utilization. These changes were associated with increased expression of genes involved in fat metabolism (ACAT1, DGKD & PLIN2; p < 0.05). There was no change in resting insulin‐stimulated whole‐body or skeletal muscle glucose disposal after supplementation. This is the first study to demonstrate that a carnitine‐mediated increase in fat oxidation is achievable in older individuals. This warrants further investigation given reduced lipid turnover is associated with poor metabolic health in older adults.

The effects of exercise on skeletal and heart muscle citrate synthase and carnitine palmitoyltransferase mRNA expressions in high-calorie fed rats.

In this study, the effect of high-calorie feeding and aerobic exercise on skeletal and cardiac muscle citrate synthase (CS), carnitine palmitoyltransferase-I (CPT-I), and -II (CPT-II) mRNA expressions were evaluated. Genetically non-obese rats were grouped as normal-high calorie and sedentary-exercising. Gastrocnemius-soleus and heart muscles' CS, CPT-I, and CPT-II expressions and skeletal muscles' histopathological characteristics were evaluated. High-fat diet had increased body weight by 10% and aerobic exercise did not make any difference. Skeletal muscle CS expression was increased significantly in normal-calorie exercising group. Exercise and high-fat diet did not change CPT-I and CPT-II expressions in both heart and skeletal muscle. Histopathological evaluations demonstrated increased cytoplasmic lipid droplets in high-calorie fed sedentary rats, and exercise had reduced lipid droplets in skeletal muscle. Also, both mitochondria and nuclei distribution were impaired in high-calorie groups. In conclusion, aerobic exercise without food restriction was not enough to make significant changes in fat transportation mechanism into skeletal and heart muscle.

L-carnitine infusion does not alleviate lipid-induced insulin resistance and metabolic inflexibility.

BackgroundLow carnitine status may underlie the development of insulin resistance and metabolic inflexibility. Intravenous lipid infusion elevates plasma free fatty acid (FFA) concentration and is a model for simulating insulin resistance and metabolic inflexibility in healthy, insulin sensitive volunteers. Here, we hypothesized that co-infusion of L-carnitine may alleviate lipid-induced insulin resistance and metabolic inflexibility.MethodsIn a randomized crossover trial, eight young healthy volunteers underwent hyperinsulinemic-euglycemic clamps (40mU/m2/min) with simultaneous infusion of saline (CON), Intralipid (20%, 90mL/h) (LIPID), or Intralipid (20%, 90mL/h) combined with L-carnitine infusion (28mg/kg) (LIPID+CAR). Ten volunteers were randomized for the intervention arms (CON, LIPID and LIPID+CAR), but two dropped-out during the study. Therefore, eight volunteers participated in all three intervention arms and were included for analysis.ResultsL-carnitine infusion elevated plasma free carnitine availability and resulted in a more pronounced increase in plasma acetylcarnitine, short-, medium-, and long-chain acylcarnitines compared to lipid infusion, however no differences in skeletal muscle free carnitine or acetylcarnitine were found. Peripheral insulin sensitivity and metabolic flexibility were blunted upon lipid infusion compared to CON but L-carnitine infusion did not alleviate this.ConclusionAcute L-carnitine infusion could not alleviated lipid-induced insulin resistance and metabolic inflexibility and did not alter skeletal muscle carnitine availability. Possibly, lipid-induced insulin resistance may also have affected carnitine uptake and may have blunted the insulin-induced carnitine storage in muscle. Future studies are needed to investigate this.

The effects of L-carnitine supplementation in athletic performance

Summary Objectives This review aims to analyze the available data, mainly the most recent, regarding L-carnitine supplementation and exercise performance, in order to understand if L-carnitine can still be considered an ergogenic supplement. Moreover, it also aims to briefly analyze other potential uses, more specifically the effects on weight loss, recovery after exercise and aging. News A literature search, using the online scientific databases PubMed and Scopus, was conducted to identify studies related to L-carnitine supplementation and athletic performance. The discovery that skeletal muscle carnitine content can be increased through oral supplementation in humans represented a significant progress in this area. More recently, due to this discovery, new research has been done to investigate whether L-carnitine supplementation could have an impact on fuel metabolism. However, the inconsistency of results led to a change in the focus of research, shifting towards the investigation of the impact L-carnitine could have on the process of recovery after exercise and on aging. Prospects and projects In future research, this new area needs to be more explored. Nevertheless, the study of the L-carnitine supplementation impact on fuel selection during exercise should continue and it is crucial to use athletes. Conclusion Despite some performance benefits have been demonstrated, more research needs to be done. Presently, the available data is still not enough to widely recommend the use of L-carnitine supplements with the aim of improving exercise performance.

Novel role of carnitine in skeletal muscle revealed using dynamics analysis

Novel role of carnitine in skeletal muscle revealed using dynamics analysis

Skeletal Muscle Acute and Chronic Metabolic Response to Essential Amino Acid Supplementation in Hypertriglyceridemic Older Adults

BackgroundSupplementation with essential amino acids (EAAs) + arginine is a promising nutritional approach to decrease plasma triglyceride (TG) concentrations, which are an independent risk factor for ischemic heart disease. ObjectiveThe objective of this study was to examine the effects of 8 wk of EAA supplementation on skeletal muscle basal metabolite concentrations and changes in metabolic response to acute EAA intake, with an emphasis on mitochondrial metabolism, in adults with elevated TGs to better understand the mechanisms of lowering plasma TGs. MethodsOlder adults with elevated plasma TG concentrations were given 22 g EAAs to ingest acutely before and after an 8-wk EAA supplementation period. Skeletal muscle biopsy samples were collected before and after acute EAA intake, both pre- and postsupplementation (4 biopsy samples), and targeted metabolomic analyses of organic acids and acylcarnitines were conducted on the specimens. ResultsAcute EAA intake resulted in increased skeletal muscle acylcarnitine concentrations associated with oxidative catabolism of the supplement components, with the largest increases found in acylcarnitines of branched-chain amino acid oxidative catabolism, including isovaleryl-carnitine (2200%) and 2-methylbutyryl-carnitine (2400%). The chronic EAA supplementation resulted in a 19% decrease in plasma TGs along with accumulation of long-chain acylcarnitines myristoyl- (90%) and stearoyl- (120%) carnitine in skeletal muscle and increases in succinyl-carnitine (250%) and the late-stage tricarboxylic acid cycle intermediates fumarate (44%) and malate (110%). ConclusionsSupplementation with EAAs shows promise as an approach for moderate reduction in plasma TGs. Changes in skeletal muscle metabolites suggest incomplete fatty acid oxidation and increased anaplerosis, which suggests a potential bottleneck in fatty acid metabolism.

Does skeletal muscle carnitine availability influence fuel selection during exercise?

Fat and carbohydrate are the major fuel sources utilised for oxidative, mitochondrial ATP resynthesis during human skeletal muscle contraction. The relative contribution of these two substrates to ATP resynthesis and total energy expenditure during exercise can vary substantially, and is predominantly determined by fuel availability and exercise intensity and duration. For example, the increased ATP demand that occurs with an increase in exercise intensity is met by increases in both fat and carbohydrate oxidation up to an intensity of approximately 60-70 % of maximal oxygen consumption. When exercise intensity increases beyond this workload, skeletal muscle carbohydrate utilisation is accelerated, which results in a reduction and inhibition of the relative and absolute contribution of fat oxidation to total energy expenditure. However, the precise mechanisms regulating muscle fuel selection and underpinning the decline in fat oxidation remain unclear. This brief review will primarily address the theory that a carbohydrate flux-mediated reduction in the availability of muscle carnitine to the mitochondrial enzyme carnitine palmitoyltransferase 1, a rate-limiting step in mitochondrial fat translocation, is a key mechanism for the decline in fat oxidation during high-intensity exercise. This is discussed in relation to recent work in this area investigating fuel metabolism at various exercise intensities and taking advantage of the discovery that skeletal muscle carnitine content can be nutritionally increased in vivo in human subjects.

Importance of the skeletal muscle carnitine stores in fuel selection

Importance of the skeletal muscle carnitine stores in fuel selection

Exercise with weight loss improves adipose tissue and skeletal muscle markers of fatty acid metabolism in postmenopausal women.

ObjectiveThe effects of six-months weight loss (WL) versus aerobic exercise training (AEX)+WL on fat and skeletal muscle markers of fatty acid metabolism were determined in normal (NGT) and impaired (IGT) glucose tolerant African-American and Caucasian postmenopausal women with overweight/obesity.MethodsFat (gluteal and abdominal) lipoprotein lipase (LPL), and skeletal muscle LPL, acyl-CoA synthase (ACS), β-hydroxacyl-CoA dehydrogenase, carnitine palmitoyltransferase (CPT-1), and citrate synthase (CS) activities were measured at baseline (n=104) and before and after WL (n=34) and AEX+WL (n=37).ResultsAfter controlling for age and race, muscle LPL and CPT-1 were lower in IGT, and the ratios of fat/muscle LPL activity were higher in IGT compared to NGT. Muscle LPL was related to insulin sensitivity (M), and inversely related to G120, fasting insulin, and HOMA-IR. AEX+WL decreased abdominal fat LPL and increased muscle LPL, ACS, and CS. The ratios of fat/muscle LPL decreased after AEX+WL. The change in VO2max was related to the changes in LPL, ACS, and CS and inversely related to the changes in fat/muscle LPL activity ratios.ConclusionsSix-month AEX+WL, and not WL alone, is capable of enhancing skeletal muscle fatty acid metabolism in postmenopausal African-American and Caucasian women with NGT, IGT, and overweight/obesity.

Increasing skeletal muscle carnitine availability does not alter the adaptations to high‐intensity interval training

Increasing skeletal muscle carnitine availability alters muscle metabolism during steady-state exercise in healthy humans. We investigated whether elevating muscle carnitine, and thereby the acetyl-group buffering capacity, altered the metabolic and physiological adaptations to 24weeks of high-intensity interval training (HIIT) at 100% maximal exercise capacity (Wattmax ). Twenty-one healthy male volunteers (age 23±2years; BMI 24.2±1.1kg/m2 ) performed 2×3minute bouts of cycling exercise at 100% Wattmax , separated by 5minutes of rest. Fourteen volunteers repeated this protocol following 24weeks of HIIT and twice-daily consumption of 80g carbohydrate (CON) or 3g l-carnitine+carbohydrate (CARN). Before HIIT, muscle phosphocreatine (PCr) degradation (P<.0001), glycogenolysis (P<.0005), PDC activation (P<.05), and acetylcarnitine (P<.005) were 2.3-, 2.1-, 1.5-, and 1.5-fold greater, respectively, in exercise bout two compared to bout 1, while lactate accumulation tended (P<.07) to be 1.5-fold greater. Following HIIT, muscle free carnitine was 30% greater in CARN vs CON at rest and remained 40% elevated prior to the start of bout 2 (P<.05). Following bout 2, free carnitine content, PCr degradation, glycogenolysis, lactate accumulation, and PDC activation were all similar between CON and CARN, albeit markedly lower than before HIIT. VO2max , Wattmax , and work output were similarly increased in CON and CARN, by 9, 15, and 23% (P<.001). In summary, increased reliance on non-mitochondrial ATP resynthesis during a second bout of intense exercise is accompanied by increased carnitine acetylation. Augmenting muscle carnitine during 24weeks of HIIT did not alter this, nor did it enhance muscle metabolic adaptations or performance gains beyond those with HIIT alone.

Carnitine-related hypoglycemia caused by 3\xa0days of pivalate antibiotic therapy in a patient with severe muscular dystrophy: a case report

BackgroundLong-term treatment with antibiotics containing pivalic acid may decrease serum carnitine concentration and can sometimes be associated with severe hypoglycemia and encephalopathy in infants. Little has been reported, however, on severe hypocarnitinemia induced by acute administration in older children.Case presentationWe describe a 6-year-old Japanese girl with Fukuyama-type congenital muscular dystrophy who lost consciousness after 3 days of treatment with an antibiotic containing pivalic acid (cefditoren pivoxil). Investigations at the onset of unconsciousness revealed hypoglycemia (free plasma glucose concentration: 31 mg/dL) and hypocarnitinemia (serum free carnitine concentration: 6.2 μmol/L). Intravenous administration of glucose rapidly improved her symptoms without any complications. Serum free carnitine concentration was 29.0 μmol/L immediately prior to the initiation of cefditoren pivoxil. Computed tomography scanning showed severe peripheral skeletal muscle atrophy, indicating the likelihood of decreased carnitine stores in skeletal muscle.ConclusionsAlthough serum carnitine concentration can appear deceptively normal, skeletal muscle carnitine stores can be reduced in patients with severe muscular atrophy. Even a short course of a pivalate-containing antibiotic can lead to life-threatening hypocarnitinemia in older children with severe muscular dystrophy.

Increasing Skeletal Muscle Carnitine Availability During High Intensity Interval Training

Increasing skeletal muscle carnitine availability increases pyruvate dehydrogenase (PDC) flux during continuous exercise at 80% maximal aerobic capacity (VO2max−), as evidenced by greater free carnitine acetylation [1]. Whether free carnitine availability is limiting to PDC flux and mitochondrial ATP production during consecutive bouts of more intense exercise is unclear. If it is, then increasing carnitine availability during high‐intensity interval training (HIT) could serve to enhance the gains to this type of exercise.In seven healthy male volunteers (age 23 ± 4 years; BMI 23.6 ± 2.0 kg/m2; VO2max 48 ± 6 ml/kg/min) we determined skeletal muscle carnitine, PDC activation status, glycogenolysis and non‐mitochondrial ATP production (NMAP; from changes in phosphocreatine [PCr], lactate and ATP concentrations) during two 3 minute bouts of cycling exercise at 100% VO2max separated by 5 minutes recovery (Study A). In a further 14 volunteers (23.2 ± 1.1 years; 24.4 ± 0.9 kg/m2; 41.6 ± 2.1 ml/kg/min) we subsequently investigated the effects of twice daily L‐carnitine (1.5 g) and carbohydrate (80 g) supplementation (CARN) during 24 weeks of HIT (3×3 min at 100% VO2max thrice weekly), versus HIT with carbohydrate alone (CON; Study B). In addition to the same outcome measures in study A, study B included VO2max, work output, and mechanical efficiency. Both studies were approved by local ethics committeeIn study A, muscle free carnitine declined similarly by 33% and 41%, whilst PDC activation increased 3 and 5‐fold, during bout one and bout two, respectively. Glycogenolysis tended to increase 2‐fold (54 ± 14 [bout one] vs. 99 ± 18 [bout two] mmol/kg dw; P=0.1) and although NMAP was not significantly different between bouts (158 ± 14 [bout one] vs. 110 ± 40 [bout two] mmol/kg dw; P=0.29), PCr degradation was 2‐fold greater during bout two (29 ± 9 [bout one] vs. 61 ± 8 [bout two] mmol/kg dw; P&lt;0.05).In study B, the change in muscle total carnitine following HIT was greater in CARN than CON (1.5 ± 0.7 [CARN] vs. −0.9 ± 0.6 [CON] mmol/kg dw; P&lt;0.05), resulting in elevated free carnitine concentrations in CARN throughout bout one and prior to the start of bout two compared to CON (P&lt;0.05). During bout one, NMAP was significantly lower following training in CARN (P&lt;0.05) but not CON, whilst glycogenolysis was unchanged in both groups. During bout two, the HIT‐induced reduction in NMAP (~60%; P&lt;0.01) and glycogenolysis (~60%; P&lt;0.05) was similar between CON and CARN. Likewise, the overall improvements in VO2max (11% [CON] vs. 8% [CARN]) and work output (28% [CON] vs. 18% [CARN]) following HIT were similar between groups. However, mechanical efficiency increased in CARN only, such that the change from baseline was greater than in CON (1.9 ± 0.8 [CARN] and −0.2 ± 0.7% [CON]; P&lt;0.05).This novel data demonstrate that mitochondrial ATP production declines during a second bout of intense fixed workload cycling. However, increasing muscle carnitine availability during a 24 week period of HIT does not prevent this decline, despite improving efficiency during a first bout. As such, increasing muscle carnitine did not enhance the gains in exercise performance and capacity beyond the robust adaptations observed here with HIT training alone.Support or Funding InformationBBSRC DTA Studentship

Protein ingestion acutely inhibits insulin-stimulated muscle carnitine uptake in healthy young men

Increasing skeletal muscle carnitine content represents an appealing intervention in conditions of perturbed lipid metabolism such as obesity and type 2 diabetes but requires chronic L-carnitine feeding on a daily basis in a high-carbohydrate beverage. We investigated whether whey protein ingestion could reduce the carbohydrate load required to stimulate insulin-mediated muscle carnitine accretion. Seven healthy men [mean ± SD age: 24 ± 5 y; body mass index (in kg/m(2)): 23 ± 3] ingested 80 g carbohydrate, 40 g carbohydrate + 40 g protein, or control (flavored water) beverages 60 min after the ingestion of 4.5 g L-carnitine tartrate (3 g L-carnitine; 0.1% (2)[H]3-L-carnitine). Serum insulin concentration, net forearm carnitine balance (NCB; arterialized-venous and venous plasma carnitine difference × brachial artery flow), and carnitine disappearance (Rd) and appearance (Ra) rates were determined at 20-min intervals for 180 min. Serum insulin and plasma flow areas under the curve (AUCs) were similarly elevated by carbohydrate [4.5 ± 0.8 U/L · min (P < 0.01) and 0.5 ± 0.6 L (P < 0.05), respectively] and carbohydrate+protein [3.8 ± 0.6 U/L · min (P < 0.01) and 0.4 ± 0.6 L (P = 0.05), respectively] consumption, respectively, compared with the control visit (0.04 ± 0.1 U/L · min and -0.5 ± 0.2 L). Plasma carnitine AUC was greater after carbohydrate+protein consumption (3.5 ± 0.5 mmol/L · min) than after control and carbohydrate visits [2.1 ± 0.2 mmol/L · min (P < 0.05) and 1.9 ± 0.3 mmol/L · min (P < 0.01), respectively]. NCB AUC with carbohydrate (4.1 ± 3.1 μmol) was greater than during control and carbohydrate-protein visits (-8.6 ± 3.0 and -14.6 ± 6.4 μmol, respectively; P < 0.05), as was Rd AUC after carbohydrate (35.7 ± 25.2 μmol) compared with control and carbohydrate consumption [19.7 ± 15.5 μmol (P = 0.07) and 14.8 ± 9.6 μmol (P < 0.05), respectively]. The insulin-mediated increase in forearm carnitine balance with carbohydrate consumption was acutely blunted by a carbohydrate+protein beverage, which suggests that carbohydrate+protein could inhibit chronic muscle carnitine accumulation.

Prevention of hyperphagia prevents ovariectomy-induced triacylglycerol accumulation in liver, but not plasma

Menopause is associated with higher plasma and liver triacylglycerol (TAG) and increased risk for cardiovascular disease. Lowering TAG in menopause may be beneficial; however, the mechanism underlying menopause-induced TAG accumulation is not clear. Ovariectomy is a model for menopause and is associated with metabolic alterations and hyperphagia. This study investigated the role of hyperphagia in ovariectomy-induced increases in blood and tissue TAG, as well as differences in lipid metabolism enzymes and resting metabolic measures. It was hypothesized that prevention of hyperphagia would restore blood and tissue TAG, enzyme expression, and metabolic measures to eugonadal levels. Ovariectomized rats were fed ad libitum (OVX + AL) or pair-fed (OVX + PF) relative to sham-operated rats (SHAM) to prevent hyperphagia. OVX + AL had higher TAG concentrations in liver and plasma than SHAM (60% and 50%, respectively), and prevention of hyperphagia in OVX + PF normalized TAG concentrations to SHAM levels in liver, but not plasma. OVX + AL also had 141% higher hepatic stearoyl-CoA desaturase 1 which was almost completely normalized to SHAM levels by pair-feeding, suggesting normalization of hepatic lipid storage. In contrast, skeletal muscle carnitine palmitoyl transferase 1 was 40% lower in OVX + AL than SHAM and was intermediate in OVX + PF, suggesting lower muscle fatty acid oxidation that may underlie the higher plasma TAG in OVX. No differences were seen in energy expenditure, VO2, or VCO2. Overall, this study indicates that prevention of hyperphagia resulting from ovarian hormone withdrawal normalizes hepatic TAG to eugonadal levels but has no effect on ovariectomy-induced increases in plasma TAG.

Differential epigenetic and transcriptional response of the skeletal muscle carnitine palmitoyltransferase 1B (CPT1B) gene to lipid exposure with obesity.

The ability to increase fatty acid oxidation (FAO) in response to dietary lipid is impaired in the skeletal muscle of obese individuals, which is associated with a failure to coordinately upregulate genes involved with FAO. While the molecular mechanisms contributing to this metabolic inflexibility are not evident, a possible candidate is carnitine palmitoyltransferase-1B (CPT1B), which is a rate-limiting step in FAO. The present study was undertaken to determine if the differential response of skeletal muscle CPT1B gene transcription to lipid between lean and severely obese subjects is linked to epigenetic modifications (DNA methylation and histone acetylation) that impact transcriptional activation. In primary human skeletal muscle cultures the expression of CPT1B was blunted in severely obese women compared with their lean counterparts in response to lipid, which was accompanied by changes in CpG methylation, H3/H4 histone acetylation, and peroxisome proliferator-activated receptor-δ and hepatocyte nuclear factor 4α transcription factor occupancy at the CPT1B promoter. Methylation of specific CpG sites in the CPT1B promoter that correlated with CPT1B transcript level blocked the binding of the transcription factor upstream stimulatory factor, suggesting a potential causal mechanism. These findings indicate that epigenetic modifications may play important roles in the regulation of CPT1B in response to a physiologically relevant lipid mixture in human skeletal muscle, a major site of fatty acid catabolism, and that differential DNA methylation may underlie the depressed expression of CPT1B in response to lipid, contributing to the metabolic inflexibility associated with severe obesity.

Effect of L-carnitine supplementation on the body carnitine pool, skeletal muscle energy metabolism and physical performance in male vegetarians.

More than 95% of the body carnitine is located in skeletal muscle, where it is essential for energy metabolism. Vegetarians ingest less carnitine and carnitine precursors and have lower plasma carnitine concentrations than omnivores. Principle aims of the current study were to assess the plasma and skeletal muscle carnitine content and physical performance of male vegetarians and matched omnivores under basal conditions and after L-carnitine supplementation. Sixteen vegetarians and eight omnivores participated in this interventional study with oral supplementation of 2 g L-carnitine for 12 weeks. Before carnitine supplementation, vegetarians had a 10% lower plasma carnitine concentration, but maintained skeletal muscle carnitine stores compared to omnivores. Skeletal muscle phosphocreatine, ATP, glycogen and lactate contents were also not different from omnivores. Maximal oxygen uptake (VO2max) and workload (P max) per bodyweight (bicycle spiroergometry) were not significantly different between vegetarians and omnivores. Sub-maximal exercise (75% VO2max for 1 h) revealed no significant differences between vegetarians and omnivores (respiratory exchange ratio, blood lactate and muscle metabolites). Supplementation with L-carnitine significantly increased the total plasma carnitine concentration (24% in omnivores, 31% in vegetarians) and the muscle carnitine content in vegetarians (13%). Despite this increase, P max and VO2max as well as muscle phosphocreatine, lactate and glycogen were not significantly affected by carnitine administration. Vegetarians have lower plasma carnitine concentrations, but maintained muscle carnitine stores compared to omnivores. Oral L-carnitine supplementation normalizes the plasma carnitine stores and slightly increases the skeletal muscle carnitine content in vegetarians, but without affecting muscle function and energy metabolism.