Using polyphenol derivatives to prevent muscle wasting.

PURPOSE OF REVIEW: To highlight recent evidence for the ability of polyphenols and their derivatives to reduce muscle wasting in different pathological states. RECENT FINDINGS: From January 2016 to August 2017, four articles dealt with the effects of polyphenols on muscle wasting, which were all carried out in mice. The four studies found that polyphenols reduced muscle mass loss associated with cancer cachexia, acute inflammation or sciatic nerve section. One study even showed that muscle mass was totally preserved when rutin was added to the diet of mice undergoing cancer cachexia. The beneficial effects of polyphenols on muscle wasting were mainly due to a reduction in the activation of the nuclear factor-kappa B pathway, a lower oxidative stress level and a better mitochondrial function. In addition, urolithin B was found to have a testosterone-like effect and to favorably regulate muscle protein balance. SUMMARY: During the last 20 months, additional data have been collected about the beneficial effects of rutin, curcumin, quercetin, ellagitanins and urolithin B to limit the loss of muscle mass associated with several pathological states. However, currently, scientific evidence lacks for their use as nutraceuticals in human.

Pomegranate extract prevents skeletal muscle of mice against wasting induced by acute TNF-α injection.

SCOPE: We investigated whether punicalagin-rich pomegranate extract (PE) protects skeletal muscle of mice against inflammation induced by an acute injection of TNF-α. RESULTS: Mice fed with PE or standard chow during 6 wk were injected with TNF-α (100 ng/g) or vehicle and sacrificed 6 h later. Prior supplementation with PE prevented the loss of tibialis anterior mass induced by TNF-α. In skeletal muscle, the activation of the NF-κB signaling and the induction of cytokines mRNA were reduced in mice having received PE. In those mice, the activity of the Akt/mTORC1 pathway and the protein synthesis were maintained after TNF-α injection whereas markers involved in the ubiquitin proteasome pathway were less activated. As urolithin A was the only punicalagin metabolite detectable in plasma of mice supplemented with PE, we performed in vitro experiments using a murine cell line (C2C12) to provide evidence that urolithin A is likely the active compound protecting skeletal muscle against TNF-α-induced inflammation. CONCLUSION (FOCUS ON NUTRITIONAL RELEVANCE): These results suggest that supplementation with a punicalagin-rich PE may protect skeletal muscle against an acute inflammation.

Potential harmful effects of dietary supplements in sports medicine.

PURPOSE OF REVIEW: The purpose of this article is to collect the most recent data regarding the safety of well-known or emerging dietary supplements used by athletes. RECENT FINDINGS: From January 2014 to April 2016, about 30 articles have been published in the field. New data show that 90% of sports supplements contain trace of estrogenic endocrine disruptors, with 25% of them having a higher estrogenic activity than acceptable. About 50% of the supplements are contaminated by melamine, a source of nonprotein nitrogen. Additional data accumulate toward the safety of nitrate ingestion. In the last 2 years, the safety of emerging supplements such as higenamine, potentially interesting to lose weight, creatine nitrate and guanidinoacetic acid has been evaluated but still needs further investigation. SUMMARY: The consumption of over-the-counter supplements is very popular in athletes. Although most supplements may be considered as safe when taking at the recommended doses, athletes should be aware of the potential risks linked to the consumption of supplements. In addition to the risks linked to overdosage and cross-effects when combining different supplements at the same time, inadvertent or deliberate contamination with stimulants, estrogenic compounds, diuretics or anabolic agents may occur.

Recommendations for Healthy Nutrition in Female Endurance Runners: An Update.

The purpose of this review is to present the basic principles of a healthy nutrition in female endurance runner enriched by the latest scientific recommendations. Female endurance runners are a specific population of athletes who need to take specifically care of daily nutrition due to the high load of training and the necessity to keep a rather low body mass. This paradoxical situation can create some nutritional imbalances and deficiencies. Female endurance athletes should pay attention to their total energy intake, which is often lower than their energy requirement. The minimal energy requirement has been set to 45 kcal/kg fat free mass/day plus the amount of energy needed for physical activity. The usual recommended amount of 1.2-1.4 g protein/kg/day has recently been questioned by new findings suggesting that 1.6 g/kg/day would be more appropriate for female athletes. Although a bit less sensitive to carbohydrate loading than their male counterparts, female athletes can benefit from this nutritional strategy before a race if the amount of carbohydrates reaches 8 g/kg/day and if their daily total energy intake is sufficient. A poor iron status is a common issue in female endurance runners but iron-enriched food as well as iron supplementation may help to counterbalance this poor status. Finally, they should also be aware that they may be at risk for low calcium and vitamin D levels.

Pomegranate and green tea extracts protect against ER stress induced by a high-fat diet in skeletal muscle of mice.

PURPOSE: We tested the hypothesis that polyphenol-rich extracts can reduce endoplasmic reticulum (ER) stress induced by a high-fat diet (HFD) in skeletal muscle of mice. METHODS: Mice were randomly assigned to four groups receiving during 20 weeks either a standard chow control (CTRL), or a HFD supplemented, or not, with pomegranate (HFD + P) or green tea (HFD + GT) extracts. After the nutritional intervention, mice were killed and gastrocnemius muscles were taken. Proteins and mRNA were measured by Western blot and RT-qPCR, respectively. RESULTS: Body weight gain and visceral fat were higher in HFD, HFD + P and HFD + GT than in CTRL. The markers of the unfolded protein response BiP, XBP1u, XBP1s and ATF4 were higher only in HFD. In HFD + P and HFD + GT, this increase was not observed except for CHOP, which was elevated in all HFD groups. HFD increased also markers of ubiquitin-proteasome pathway, autophagy and oxidative stress, which were kept low in HFD + P and HFD + GT groups. CONCLUSION: Our data provide evidence for a protective effect of pomegranate and green tea extracts against ER stress, oxidative stress and protein degradation induced by HFD in skeletal muscle. They give arguments for a usefulness of these natural nutritional compounds to fight against cellular dysfunctions related to fat excess.

Hepatic n-3 polyunsaturated fatty acid depletion promotes steatosis and insulin resistance in mice: genomic analysis of cellular targets.

Patients with non-alcoholic fatty liver disease are characterised by a decreased n-3/n-6 polyunsaturated fatty acid (PUFA) ratio in hepatic phospholipids. The metabolic consequences of n-3 PUFA depletion in the liver are poorly understood. We have reproduced a drastic drop in n-3 PUFA among hepatic phospholipids by feeding C57Bl/6J mice for 3 months with an n-3 PUFA depleted diet (DEF) versus a control diet (CT), which only differed in the PUFA content. DEF mice exhibited hepatic insulin resistance (assessed by euglycemic-hyperinsulinemic clamp) and steatosis that was associated with a decrease in fatty acid oxidation and occurred despite a higher capacity for triglyceride secretion. Microarray and qPCR analysis of the liver tissue revealed higher expression of all the enzymes involved in lipogenesis in DEF mice compared to CT mice, as well as increased expression and activation of sterol regulatory element binding protein-1c (SREBP-1c). Our data suggest that the activation of the liver X receptor pathway is involved in the overexpression of SREBP-1c, and this phenomenon cannot be attributed to insulin or to endoplasmic reticulum stress responses. In conclusion, n-3 PUFA depletion in liver phospholipids leads to activation of SREBP-1c and lipogenesis, which contributes to hepatic steatosis.

Functional food for exercise performance: fact or foe?

PURPOSE OF REVIEW: To present food components showing evidence for improved sport performance in the light of the scientific literature from the past 2 years. RECENT FINDINGS: Appropriate nutrition is essential for sport performance. Nutritional products containing carbohydrates, proteins, vitamins, and minerals have been widely used by athletes to provide something extra to the daily allowance. Currently, the field of interest is shifting from macronutrients and fluids to physiologically active isolated food components. Several of them have been demonstrated to improve sport performance at a higher level than expected with a well balanced diet. In the present review, we will focus on the benefits of creatine, caffeine, branched-chain amino acids, and more particularly leucine, beta-alanine, bicarbonate, and glycerol ingestion on exercise performance. SUMMARY: A bulk of products are sold on the market labeled with various performance benefit statements without any scientific evidence. These food components are often used without a full understanding or evaluation of the potential benefits and risks associated with their use. There is thus a real need to classify food components on the basis of their evidence-based effectiveness.

Effects of resistance exercise with and without creatine supplementation on gene expression and cell signaling in human skeletal muscle.

To test the hypothesis that creatine supplementation would enhance the anabolic responses of muscle cell signaling and gene expression to exercise, we studied nine subjects who received either creatine or a placebo (maltodextrin) for 5 days in a double-blind fashion before undergoing muscle biopsies: at rest, immediately after exercise (10 x 10 repetitions of one-leg extension at 80% 1 repetition maximum), and 24 and 72 h later (all in the morning after fasting overnight). Creatine supplementation decreased the phosphorylation state of protein kinase B (PKB) on Thr308 at rest by 60% (P < 0.05) and that of eukaryotic initiation factor 4E-binding protein on Thr37/46 (4E-BP1) by 30% 24 h postexercise (P < 0.05). Creatine increased mRNA for collagen 1 (alpha(1)), glucose transporter-4 (GLUT-4), and myosin heavy chain I at rest by 250%, 45%, and 80%, respectively, and myosin heavy chain IIA (MHCIIA) mRNA immediately after exercise by 70% (all P < 0.05). Immediately after exercise, and independent of creatine, mRNA for muscle atrophy F-box (MAFbx), MHCIIA, peroxisome proliferator-activated receptor gamma coactivator-1alpha, and interleukin-6 were upregulated (60-350%; P < 0.05); the phosphorylation state of p38 both in the sarcoplasm and nucleus were increased (12- and 25-fold, respectively; both P < 0.05). Concurrently, the phosphorylation states of PKB (Thr308) and 4E-BP1 (Thr37/46) were decreased by 50% and 75%, respectively (P < 0.05). Twenty-four hours postexercise, MAFbx, myostatin, and GLUT-4 mRNA expression decreased below preexercise values (-35 to -50%; P < 0.05); calpain 1 mRNA increased 70% 72 h postexercise (P < 0.05) and at no other time. In conclusion, 5 days of creatine supplementation do not enhance anabolic signaling but increase the expression of certain targeted genes.

Kinetics of creatine ingested as a food ingredient.

The aim of the present study was to test if the consumption of creatine incorporated in food bars modifies creatine plasma kinetics, erythrocyte retention and loss in urine and in feces when compared with its consumption in the form of an aqueous solution (AS). Seventeen healthy young men ingested 2 g creatine either in the form of AS, or incorporated in a protein (PP)- or in a beta-glucan (BG)-rich food bar. Kinetics of plasma creatine was measured for 8-h duration and urinary excretion for 24 h. Then, the subjects received the same treatment thrice a day for 1 week at the end of which creatine contents were determined in erythrocytes and in feces (n = 4 for feces). The three crossover treatments were interspaced by a 40 +/- 1.2-day wash-out. Absorption of creatine was slowed down by 8-fold in the presence of BG (P < 0.001) and by 4-fold with PP (P < 0.001) whereas the velocity rate constant of elimination and the area under the curve were not modified. Urinary loss of creatine in the first 24 h following ingestion was 15 +/- 1.9% in AS and 14 +/- 2.2% in PP conditions (NS), whereas it was only 8 +/- 1.2% with BG (P = 0.004). Increase in creatine concentration in erythrocyte was similar in whatever form the creatine was ingested. Creatine seems to be totally absorbed since no creatine or creatinine was detectable in feces. No side effects were reported. In conclusion, ingestion of creatine combined with BG facilitates its retention by slowing down its absorption rate and reducing its urinary excretion.

Side effects of creatine supplementation in athletes.

CONTEXT: Allegations about side effects of creatine supplementation by athletes have been published in the popular media and scientific publications. PURPOSE: To examine the experimental evidence relating to the physiological effects of creatine supplementation. RESULTS: One of the purported effects of oral creatine supplementation is increased muscle mass. A review of the literature reveals a 1.0% to 2.3% increase in body mass, which is attributed to fat-free mass and, more specifically, to skeletal-muscle mass. Although it is unlikely that water retention can completely explain these changes, increase in muscle-protein synthesis has never been observed after creatine supplementation. Indirect evidence based on mRNA analyses suggests that transcription of certain genes is enhanced. Although the effect of creatine on muscle-protein synthesis seems irrefutable according to advertising, this allegation remains under debate in the scientific literature. The kidneys appear to maintain their functionality in healthy subjects who supplement with creatine, even over several months. CONCLUSION: The authors, however, think that creatine supplementation should not be used by an individual with preexisting renal disease and that risk should be evaluated before and during any supplementation period. Even if there is a slight increase in mutagenic agents (methylamine and formaldehyde) in urine after a heavy load of creatine (20 g/day), their excretion remains within a normal range. No data are currently available regarding the potential production of heterocyclic amines with creatine supplementation. In summary, the major risk for health is probably associated with the purity of commercially available creatine.

Effect of oral creatine supplementation on urinary methylamine, formaldehyde, and formate.

PURPOSE: It has been claimed that oral creatine supplementation might have potential cytotoxic effects on healthy consumers by increasing the production of methylamine and formaldehyde. Despite this allegation, there has been no scientific evidence obtained in humans to sustain or disprove such a detrimental effect of this widely used ergogenic substance. METHODS: Twenty young healthy men ingested 21 g of creatine monohydrate daily for 14 consecutive days. Venous blood samples and 24-h urine were collected before and after the 14th day of supplementation. Creatine and creatinine were analyzed in plasma and urine, and methylamine, formaldehyde, and formate were determined in 24-h urine samples. RESULTS: Oral creatine supplementation increased plasma creatine content 7.2-fold (P < 0.001) and urine output 141-fold (P < 0.001) with no effect on creatinine levels. Twenty-four-hour urine excretion of methylamine and formaldehyde increased, respectively, 9.2-fold (P = 0.001) and 4.5-fold (P = 0.002) after creatine feeding, with no increase in urinary albumin output (9.78 +/- 1.93 mg x 24 h(-1) before, 6.97 +/- 1.15 mg x 24 h(-1) creatine feeding). CONCLUSION: This investigation shows that short-term, high-dose oral creatine supplementation enhances the excretion of potential cytotoxic compounds, but does not have any detrimental effects on kidney permeability. This provides indirect evidence of the absence of microangiopathy in renal glomeruli.

Effect of creatine supplementation on skeletal muscle of mdx mice.

Dystrophic mice (mdx) and their controls (C57/Bl10) were fed for 1 month with a diet with or without creatine (Cr) enrichment. Cr supplementation reduced mass (by 19%, P < 0.01) and mean fiber surface (by 25%, P < 0.05) of fast-twitch mdx muscles. In both strains, tetanic tension increased slightly (9.2%) without reaching statistical significance (P = 0.08), and relaxation time increased by 16% (P < 0.001). However, Cr had no protective effect on the other hallmarks of dystrophy such as susceptibility to eccentric contractions; large numbers of centrally nucleated fibers in tibialis anterior; and elevated total calcium content, which increased by 85% (P = 0.008) in gastrocnemius mdx muscles. In conclusion, Cr may be a positive intervention for improving function of dystrophic muscle.

No effect of creatine supplementation on human myofibrillar and sarcoplasmic protein synthesis after resistance exercise.

Muscle hypertrophy during resistance training is reportedly increased by creatine supplementation. Having previously failed to find an anabolic effect on muscle protein turnover at rest, either fed or fasted, we have now examined the possibility of a stimulatory effect of creatine in conjunction with acute resistance exercise. Seven healthy men (body mass index, 23 +/- 2 kg/m2, 21 +/- 1 yr, means +/- SE) performed 20 x 10 repetitions of leg extension-flexion at 75% one-repetition maximum in one leg, on two occasions, 4 wk apart, before and after ingesting 21 g/day creatine for 5 days. The subjects ate approximately 21 g maltodextrin + 6 g protein/h for 3 h postexercise. We measured incorporation of [1-13C]leucine into quadriceps muscle proteins in the rested and exercised legs. Leg protein breakdown (as dilution of [2H5]phenylalanine) was also assessed in the exercised and rested leg postexercise. Creatine supplementation increased muscle total creatine by approximately 21% (P < 0.01). Exercise increased the synthetic rates of myofibrillar and sarcoplasmic proteins by two- to threefold (P < 0.05), and leg phenylalanine balance became more positive, but creatine was without any anabolic effect.

Beneficial effects of creatine supplementation in dystrophic patients.

The effect of creatine (Cr) supplementation on muscle function and body composition of 12 boys with Duchenne muscular dystrophy and three with Becker dystrophy was evaluated by a randomized double-blind cross-over study (3 g Cr or maltodextrin daily for 3 months, with wash-out period of 2 months). After placebo, no change was observed in maximal voluntary contraction (MVC) and resistance to fatigue, whereas total joint stiffness (TJS) was increased by approximately 25% (P < 0.05). The patients receiving Cr did not show any change in TJS, improved MVC by 15% (P = 0.02), and almost doubled their resistance to fatigue (P < 0.001). In patients still independent of a wheelchair (n = 5), bone mineral density increased by 3% (P < 0.05), and urinary excretion of collagen type I cross-linking N-telopeptide declined to about one third (P < 0.001) after Cr. No adverse effect was observed. Thus, Cr may provide some symptomatic benefit in these patients.

Creatine supplementation has no effect on human muscle protein turnover at rest in the postabsorptive or fed states.

Dietary creatine supplementation is associated with increases in muscle mass, but the mechanism is unknown. We tested the hypothesis that creatine supplementation enhanced myofibrillar protein synthesis (MPS) and diminished muscle protein breakdown (MPB) in the fed state. Six healthy men (26 +/- 7 yr, body mass index 22 +/- 4 kg/m(2)) were studied twice, 2-4 wk apart, before and after ingestion of creatine (21 g/day, 5 days). We carried out two sets of measurements within 5.5 h of both MPS (by incorporation of [1-(13)C]leucine in quadriceps muscle) and MPB (as dilution of [1-(13)C]leucine or [(2)H(5)]phenylalanine across the forearm); for the first 3 h, the subjects were postabsorptive but thereafter were fed orally (0.3 g maltodextrin and 0.083 g protein. kg body wt(-1) x h(-1)). Creatine supplementation increased muscle total creatine by approximately 30% (P < 0.01). Feeding had significant effects, doubling MPS (P < 0.001) and depressing MPB by approximately 40% (P < 0.026), but creatine had no effect on turnover in the postabsorptive or fed states. Thus any increase in muscle mass accompanying creatine supplementation must be associated with increased physical activity.