Novel Multi-Ingredient Supplement Facilitates Weight Loss and Improves Body Composition in Overweight and Obese Individuals: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: Despite the growing recognition of the obesity crisis, its rates continue to rise. The current first-line therapies, such as dietary changes, energy restriction, and physical activity, are typically met with poor adherence. Novel nutritional interventions can address the root causes of obesity, including mitochondrial dysfunction, and facilitate weight loss. OBJECTIVE: The objective of this study was to investigate the effects of a multi-ingredient nutritional supplement designed to facilitate mitochondrial function and metabolic health outcomes over a 12 wk period. METHODS: Fifty-five overweight and/or obese participants (age (mean ± SEM): 26 ± 1; body mass index (BMI) (kg/m2): 30.5 ± 0.6) completed this double-blind, placebo-controlled clinical trial. Participants were randomized to 12 wks of daily consumption of multi-ingredient supplement (MIS; n = 28; containing 50 mg forskolin, 500 mg green coffee bean extract, 500 mg green tea extract, 500 mg beet root extract, 400 mg α-lipoic acid, 200 IU vitamin E, and 200 mg CoQ10) or control placebo (PLA, n = 27; containing microcrystalline cellulose) matched in appearance. The co-primary outcomes were bodyweight and fat mass (kg) changes. The secondary outcomes included other body composition measures, plasma markers of obesity, fatty liver disease biomarkers, resting energy metabolism, blood pressure, physical performance, and quality of life. The post-intervention differences between MIS and PLA were examined via ANCOVA which was adjusted for the respective pre-intervention variables. RESULTS: After adjustment for pre-intervention data, there was a significant difference in weight (p < 0.001) and fat mass (p < 0.001) post-intervention between the PLA and MIS treatment arms. Post-intervention weight and fat mass were significantly lower in MIS. Significant post-intervention differences corrected for baseline were found in markers of clinical biochemistry (AST, p = 0.017; ALT, p = 0.008), molecular metabolism (GDF15, p = 0.028), and extracellular vesicle-associated miRNA species miR-122 and miR-34a in MIS (p < 0.05). CONCLUSIONS: Following the 12 wks of MIS supplementation, weight and body composition significantly improved, concomitant with improvements in molecular markers of liver health and metabolism.

A Multi-Ingredient Supplement Protects against Obesity and Infertility in Western Diet-Fed Mice.

The Western diet (WD) predisposes to bodyweight gain and obesity and is linked to mitochondrial dysfunction, oxidative damage, inflammation, and multisystem disease, even affecting the reproductive organs, fertility, and pregnancy outcomes. In this study, we investigated the effects of multi-ingredient supplementation (MIS) with antioxidants, phytonutrients, and vitamins ('Fertility Enhancer'; FE) on white adipose tissue (WAT) expansion, nonalcoholic fatty liver disease (NAFLD), and infertility in WD-fed C57BL/6J mice. Five-month-old male (M) and female (F) mice were fed a low-fat diet (LF) or a high fat/sucrose WD (HF) for six weeks, followed by six weeks of LF (3.64 kcal/g), HF (4.56 kcal/g), or HF combined with FE (4.50 kcal/g). A sub-set of animals were sacrificed at 12 weeks, while the remainder were harem-mated in a 1:2 male-to-female ratio, and singly housed during the gestational period. Two-way, factorial ANOVA analysis revealed a main effect of diet on bodyweight (BW), total body fat, % body fat, white adipose tissue mass, and liver lipid content (all p < 0.001), driven by the anti-obesogenic effects of the 'Fertility Enhancer'. Similarly, a main effect of diet was found on PGC1-α mRNA levels (p < 0.05) and mitochondrial protein content (p < 0.001) in perigonadal WAT, with PGC1-α induction and higher complex II and complex III expression in FE vs. HF animals. Copulatory plug counts were higher in FE vs. HE couples (30% vs. 6%), resulting in more litters (4 vs. 0) and higher copulatory success (67% vs. 0%). Although the trends of all histology outcomes were suggestive of a benefit from the FE diet, only the number of atretic follicles and testicular mass were significant. Ovarian IL-1ß mRNA induction was significantly attenuated in the FE group (p < 0.05 vs. HF) with CASP1 attenuation trending lower (p = 0.09 vs. HF), which is indicative of anti-inflammatory benefits of the 'Fertility Enhancer.' We conclude that supplementation with specific phytonutrients, antioxidants, and vitamins may have utility as an adjunctive therapy for weight management, fatty liver disease, and infertility in overweight and obese couples.

The Acute Effect of Multi-Ingredient Antioxidant Supplementation following Ionizing Radiation.

Radiation exposure is an undeniable health threat encountered in various occupations and procedures. High energy waves in ionizing radiation cause DNA damage and induce reactive oxygen species (ROS) production, which further exacerbate DNA, protein, and lipid damage, increasing risk of mutations. Although endogenous antioxidants such as superoxide dismutase have evolved to upregulate and neutralize ROS, exogenous dietary antioxidants also have the potential to combat ionizing radiation (IR)-induced ROS production. We evaluated a cocktail of ingredients (AOX) purported to have antioxidant and mitochondrial protective properties on the acute effects of IR. We show that IR stimulates DNA damage through phosphorylation of DNA repair proteins in the heart, brain, and liver of mice. AOX showed partial protection in brain and liver, through a lack of significant activation in given repair proteins. In addition, AOX attenuated the IR-induced increase in NF-kß mRNA and protein expression in brain and liver. Lastly, cytochrome c oxidase complex transcripts were significantly higher in heart and brain following radiation, which was also diminished by prior ingestion of AOX. Together, our findings suggest that a multi-ingredient AOX supplement may attenuate the IR-induced cellular damage response and represents a feasible and cost-effective preventative supplement for at-risk populations of radiation exposure.

Nutritional co-therapy with 1,3-butanediol and multi-ingredient antioxidants enhances autophagic clearance in Pompe disease.

Alglucosidase alpha is an orphan drug approved for enzyme replacement therapy (ERT) in Pompe disease (PD); however, its efficacy is limited in skeletal muscle because of a partial blockage of autophagic flux that hinders intracellular trafficking and enzyme delivery. Adjunctive therapies that enhance autophagic flux and protect mitochondrial integrity may alleviate autophagic blockage and oxidative stress and thereby improve ERT efficacy in PD. In this study, we compared the benefits of ERT combined with a ketogenic diet (ERT-KETO), daily administration of an oral ketone precursor (1,3-butanediol; ERT-BD), a multi-ingredient antioxidant diet (ERT-MITO; CoQ10, α-lipoic acid, vitamin E, beetroot extract, HMB, creatine, and citrulline), or co-therapy with the ketone precursor and multi-ingredient antioxidants (ERT-BD-MITO) on skeletal muscle pathology in GAA-KO mice. We found that two months of 1,3-BD administration raised circulatory ketone levels to ≥1.2 mM, attenuated autophagic buildup in type 2 muscle fibers, and preserved muscle strength and function in ERT-treated GAA-KO mice. Collectively, ERT-BD was more effective vs. standard ERT and ERT-KETO in terms of autophagic clearance, dampening of oxidative stress, and muscle maintenance. However, the addition of multi-ingredient antioxidants (ERT-BD-MITO) provided the most consistent benefits across all outcome measures and normalized mitochondrial protein expression in GAA-KO mice. We therefore conclude that nutritional co-therapy with 1,3-butanediol and multi-ingredient antioxidants may provide an alternative to ketogenic diets for inducing ketosis and enhancing autophagic flux in PD patients.

A Novel Multi-Ingredient Supplement Activates a Browning Program in White Adipose Tissue and Mitigates Weight Gain in High-Fat Diet-Fed Mice.

We investigated the effects of a novel multi-ingredient supplement comprised of polyphenol antioxidants and compounds known to facilitate mitochondrial function and metabolic enhancement (ME) in a mouse model of obesity. In this study, 6-week-old male C57/BL6J mice were placed on a high-fat diet (HFD; ~60% fat) for 6 weeks, with subsequent allocation into experimentalgroups for 4 weeks: HFD control, HFD + ME10 (10 components), HFD + ME7 (7 components), HFD + ME10 + EX, HFD + EX (where '+EX' animals exercised 3 days/week), and chow-fed control. After the intervention, HFD control animals had significantly greater body weight and fat mass. Despite the continuation of HFD, animals supplemented with multi-ingredient ME or who performed exercise training showed an attenuation of fat mass and preservation of lean body mass, which was further enhanced when combined (ME+EX). ME supplementation stimulated the upregulation of white and brown adipose tissue mRNA transcripts associated with mitochondrial biogenesis, browning, fatty acid transport, and fat metabolism. In WAT depots, this was mirrored by mitochodrial oxidative phosphorylation (OXPHOS) protein expression, and increased in vivo fat oxidation measured via CLAMS. ME supplementation also decreased systemic and local inflammation markers. Herein, we demonstrated that novel multi-ingredient nutritional supplements induced significant fat loss independent of physical activity while preserving muscle mass in obese mice. Mechanistically, these MEs appear to act by inducing a browning program in white adipose tissue and decreasing other pathophysiological impairments associated with obesity, including mitochondrial respiration alterations induced by HFD.

A Five-Ingredient Nutritional Supplement and Home-Based Resistance Exercise Improve Lean Mass and Strength in Free-Living Elderly.

Old age is associated with lower physical activity levels, suboptimal protein intake, and desensitization to anabolic stimuli, predisposing for age-related muscle loss (sarcopenia). Although resistance exercise (RE) and protein supplementation partially protect against sarcopenia under controlled conditions, the efficacy of home-based, unsupervised RE (HBRE) and multi-ingredient supplementation (MIS) is largely unknown. In this randomized, placebo-controlled and double-blind trial, we examined the effects of HBRE/MIS on muscle mass, strength, and function in free-living, older men. Thirty-two sedentary men underwent twelve weeks of home-based resistance band training (3 d/week), in combination with daily intake of a novel five-nutrient supplement ('Muscle5'; M5, n = 16, 77.4 ± 2.8 y) containing whey, micellar casein, creatine, vitamin D, and omega-3 fatty acids, or an isocaloric/isonitrogenous placebo (PLA; n = 16, 74.4 ± 1.3 y), containing collagen and sunflower oil. Appendicular and total lean mass (ASM; +3%, TLM; +2%), lean mass to fat ratios (ASM/% body fat; +6%, TLM/% body fat; +5%), maximal strength (grip; +8%, leg press; +17%), and function (5-Times Sit-to-Stand time; -9%) were significantly improved in the M5 group following HBRE/MIS therapy (pre vs. post tests; p < 0.05). Fast-twitch muscle fiber cross-sectional areas of the quadriceps muscle were also significantly increased in the M5 group post intervention (Type IIa; +30.9%, Type IIx, +28.5%, p < 0.05). Sub-group analysis indicated even greater gains in total lean mass in sarcopenic individuals following HBRE/MIS therapy (TLM; +1.65 kg/+3.4%, p < 0.05). We conclude that the Muscle5 supplement is a safe, well-tolerated, and effective complement to low-intensity, home-based resistance exercise and improves lean mass, strength, and overall muscle quality in old age.

Nutrition and exercise in Pompe disease.

The current standard of care for Pompe disease (PD) is the administration of enzyme replacement therapy (ERT). Exercise and nutrition are often considered as complementary strategies rather than "treatments" per se. Nutritional assessment is important in patients with locomotor disability because the relative hypodynamia limits energy expenditure and thus the total amount of energy must be reduced to avoid obesity. A lower total energy intake often leads to lower protein and micronutrient intake. Consequently, ensuring that Pompe patients are tested for and replaced for deficiencies (protein, vitamin D, vitamin B12, etc.) is an important aspect of care. Furthermore, given the role of autophagy in the pathophysiology of PD and the fact that fasting induces autophagy, it is important that strategies such as nutritional timing and amino acid intake (L-arginine, L-leucine) be evaluated as therapies. Exercise interventions have been shown to improve six-minute walk testing distance by more than what was seen in the seminal ERT study in late-onset PD. Exercise therapy can also activate autophagy, and this is likely another component of its efficacy. The current review will evaluate the theoretical and practical aspects of nutrition and exercise as therapies for patients with PD.

ß-Alanine Supplementation Does Not Augment the Skeletal Muscle Adaptive Response to 6 Weeks of Sprint Interval Training.

Sprint interval training (SIT), repeated bouts of high-intensity exercise, improves skeletal muscle oxidative capacity and exercise performance. ß-alanine (ß-ALA) supplementation has been shown to enhance exercise performance, which led us to hypothesize that chronic ß-ALA supplementation would augment work capacity during SIT and augment training-induced adaptations in skeletal muscle and performance. Twenty-four active but untrained men (23 ± 2 yr; VO2peak = 50 ± 6 mL · kg(-1) · min(-1)) ingested 3.2 g/day of ß-ALA or a placebo (PLA) for a total of 10 weeks (n = 12 per group). Following 4 weeks of baseline supplementation, participants completed a 6-week SIT intervention. Each of 3 weekly sessions consisted of 4-6 Wingate tests, i.e., 30-s bouts of maximal cycling, interspersed with 4 min of recovery. Before and after the 6-week SIT program, participants completed a 250-kJ time trial and a repeated sprint test. Biopsies (v. lateralis) revealed that skeletal muscle carnosine content increased by 33% and 52%, respectively, after 4 and 10 weeks of ß-ALA supplementation, but was unchanged in PLA. Total work performed during each training session was similar across treatments. SIT increased markers of mitochondrial content, including cytochome c oxidase (40%) and ß-hydroxyacyl-CoA dehydrogenase maximal activities (19%), as well as VO2peak (9%), repeated-sprint capacity (5%), and 250-kJ time trial performance (13%), but there were no differences between treatments for any measure (p < .01, main effects for time; p > .05, interaction effects). The training stimulus may have overwhelmed any potential influence of ß-ALA, or the supplementation protocol was insufficient to alter the variables to a detectable extent.

Beneficial effects of resveratrol on respiratory chain defects in patients' fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling.

Mitochondrial respiratory chain (RC) disorders are the most prevalent inborn metabolic diseases and remain without effective treatment to date. Up-regulation of residual enzyme activity has been proposed as a possible therapeutic approach in this group of disorders. As resveratrol (RSV), a natural compound, was proposed to stimulate mitochondrial metabolism in rodents, we tested the effect of this compound on mitochondrial functions in control or in Complex I (CI)- or Complex IV (CIV)-deficient patients' fibroblasts. We show that RSV stimulates the expression of a panel of proteins representing structural subunits or assembly factors of the five RC complexes, in control fibroblasts. In moderate RC-deficient patients' cells, RSV treatment increases the amount of mutated proteins and stimulates residual enzyme activities. In these patients' cells, we establish that up-regulation of RC enzyme activities induced by RSV translates into increased cellular O2 consumption rates and results in the correction of RC deficiencies. Importantly, RSV also prevents the accumulation of lactate that occurred in RC-deficient fibroblasts. Different complementary approaches demonstrate that RSV induces a mitochondrial biogenesis that might underlie the increase in mitochondrial capacities. Finally, we showed that, in human fibroblasts, RSV stimulated mitochondrial functions mainly in a SIRT1- and AMPK-independent manner and that its effects rather involved the estrogen receptor (ER) and estrogen-related receptor alpha (ERRα) signaling pathways. These results represent the first demonstration that RSV could have a beneficial effect on inborn CI and CIV deficiencies from nuclear origin, in human fibroblasts and might be clinically relevant for the treatment of some RC deficiencies.

Creatine for treating muscle disorders.

BACKGROUND: Progressive muscle weakness is a main symptom of most hereditary and acquired muscle diseases. Creatine improves muscle performance in healthy individuals. This is an update of our 2007 Cochrane review that evaluated creatine treatment in muscle disorders. Previous updates were in 2009 and 2011. OBJECTIVES: To evaluate the efficacy of creatine compared to placebo for the treatment of muscle weakness in muscle diseases. SEARCH METHODS: On 11 September 2012, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL (2012, Issue 9 in The Cochrane Library), MEDLINE (January 1966 to September 2012) and EMBASE (January 1980 to September 2012) for randomised controlled trials (RCTs) of creatine used to treat muscle diseases. SELECTION CRITERIA: RCTs or quasi-RCTs of creatine treatment compared to placebo in hereditary muscle diseases or idiopathic inflammatory myopathies. DATA COLLECTION AND ANALYSIS: Two authors independently applied the selection criteria, assessed trial quality and extracted data. We obtained missing data from investigators. MAIN RESULTS: A total of 14 trials, including 364 randomised participants, met the selection criteria. The risk of bias was low in most studies. Only one trial had a high risk of selection, performance and detection bias. No new studies were identified at this update.Meta-analysis of six trials in muscular dystrophies including 192 participants revealed a significant increase in muscle strength in the creatine group compared to placebo, with a mean difference of 8.47%; (95% confidence intervals (CI) 3.55 to 13.38). Pooled data of four trials including 115 participants showed that a significantly higher number of participants felt better during creatine treatment compared to placebo with a risk ratio of 4.51 (95% CI 2.33 to 8.74). One trial in 37 participants with idiopathic inflammatory myopathies also showed a significant improvement in functional performance. No trial reported any clinically relevant adverse event.In metabolic myopathies, meta-analyses of three cross-over trials including 33 participants revealed no significant difference in muscle strength. One trial reported a significant deterioration of activities of daily living (mean difference 0.54 on a 1 to 10 scale; 95% CI 0.14 to 0.93) and an increase in muscle pain during high-dose creatine treatment in McArdle disease. AUTHORS' CONCLUSIONS: High quality evidence from RCTs shows that short- and medium-term creatine treatment increases muscle strength in muscular dystrophies. There is also evidence that creatine improves functional performance in muscular dystrophy and idiopathic inflammatory myopathy. Creatine is well tolerated in these people. High quality but limited evidence from RCTs does not show significant improvement in muscle strength in metabolic myopathies. High-dose creatine treatment impaired activities of daily living and increased muscle pain in McArdle disease.

Massage therapy attenuates inflammatory signaling after exercise-induced muscle damage.

Massage therapy is commonly used during physical rehabilitation of skeletal muscle to ameliorate pain and promote recovery from injury. Although there is evidence that massage may relieve pain in injured muscle, how massage affects cellular function remains unknown. To assess the effects of massage, we administered either massage therapy or no treatment to separate quadriceps of 11 young male participants after exercise-induced muscle damage. Muscle biopsies were acquired from the quadriceps (vastus lateralis) at baseline, immediately after 10 min of massage treatment, and after a 2.5-hour period of recovery. We found that massage activated the mechanotransduction signaling pathways focal adhesion kinase (FAK) and extracellular signal-regulated kinase 1/2 (ERK1/2), potentiated mitochondrial biogenesis signaling [nuclear peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)], and mitigated the rise in nuclear factor κB (NFκB) (p65) nuclear accumulation caused by exercise-induced muscle trauma. Moreover, despite having no effect on muscle metabolites (glycogen, lactate), massage attenuated the production of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and reduced heat shock protein 27 (HSP27) phosphorylation, thereby mitigating cellular stress resulting from myofiber injury. In summary, when administered to skeletal muscle that has been acutely damaged through exercise, massage therapy appears to be clinically beneficial by reducing inflammation and promoting mitochondrial biogenesis.

Greater stimulation of myofibrillar protein synthesis with ingestion of whey protein isolate v. micellar casein at rest and after resistance exercise in elderly men.

We aimed to determine the effect of consuming pure isolated micellar casein or pure whey protein isolate on rates of myofibrillar protein synthesis (MPS) at rest and after resistance exercise in elderly men. Healthy elderly men (72 (sem 1) years; BMI 26·4 (sem 0·7) kg/m²) were divided into two groups (n 7 each) who received a primed, constant infusion of l-[ring-¹³C6]phenylalanine to measure MPS at rest and during 4 h of exercise recovery. Participants performed unilateral leg resistance exercise followed by the consumption of isonitrogenous quantities (20 g) of casein or whey. Blood essential amino acids and leucine concentration peaked 60 min post-drink and were greater in amplitude after whey protein ingestion (both, P < 0·05). MPS in the rested leg was 65 % higher (P = 0·002) after ingestion of whey (0·040 (sem 0·003) %/h) when compared with micellar casein (0·024 (sem 0·002) %/h). Similarly, resistance exercise-stimulated rates of MPS were greater (P < 0·001) after whey ingestion (0·059 (sem 0·005) %/h) v. micellar casein (0·035 (sem 0·002) %/h). We conclude that ingestion of isolated whey protein supports greater rates of MPS than micellar casein both at rest and after resistance exercise in healthy elderly men. This result is probably related to a greater hyperaminoacidaemia or leucinaemia with whey ingestion.

17ß-estradiol attenuates exercise-induced neutrophil infiltration in men.

17ß-estradiol (E2) attenuates exercise-induced muscle damage and inflammation in some models. Eighteen men completed 150 eccentric contractions after random assignment to placebo (Control group) or E2 supplementation (Experimental group). Muscle biopsies and blood samples were collected at baseline, following 8-day supplementation and 3 h and 48 h after exercise. Blood samples were analyzed for sex hormone concentration, creatine kinase (CK) activity and total antioxidant capacity. The mRNA content of genes involved in lipid and cholesterol homeostasis [forkhead box O1 (FOXO1), caveolin 1, and sterol regulatory element binding protein-2 (SREBP2)] and antioxidant defense (SOD1 and -2) were measured by RT-PCR. Immunohistochemistry was used to quantify muscle neutrophil (myeloperoxidase) and macrophage (CD68) content. Serum E2 concentration increased 2.5-fold with supplementation (P < 0.001), attenuating neutrophil infiltration at 3 h (P < 0.05) and 48 h (P < 0.001), and the induction of SOD1 at 48 h (P = 0.02). Macrophage density at 48 h (P < 0.05) and SOD2 mRNA at 3 h (P = 0.01) increased but were not affected by E2. Serum CK activity was higher at 48 h for both groups (P < 0.05). FOXO1, caveolin 1 and SREBP2 expression were 2.8-fold (P < 0.05), 1.4-fold (P < 0.05), and 1.5-fold (P < 0.001) and higher at 3 h after exercise with no effect of E2. This suggests that E2 attenuates neutrophil infiltration; however, the mechanism does not appear to be lesser oxidative stress or membrane damage and may indicate lesser neutrophil/endothelial interaction.

Creatine for treating muscle disorders.

BACKGROUND: Progressive muscle weakness is a main symptom of most hereditary and acquired muscle diseases. Creatine improves muscle performance in healthy individuals. This is an update of our 2007 Cochrane review that evaluated creatine treatment in muscle disorders. OBJECTIVES: To evaluate the efficacy of creatine compared to placebo for the treatment of muscle weakness in muscle diseases. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialized Register (4 October 2010), the Cochrane Central Register of Controlled Trials (11 October 2010, Issue 4, 2010 in The Cochrane Library), MEDLINE (January 1966 to September 2010) and EMBASE (January 1980 to September 2010) for randomised controlled trials (RCT) of creatine used to treat muscle diseases. SELECTION CRITERIA: RCTs or quasi-RCTs of creatine treatment compared to placebo in hereditary muscle diseases or idiopathic inflammatory myopathies. DATA COLLECTION AND ANALYSIS: Two authors independently applied the selection criteria, assessed trial quality and extracted data. We obtained missing data from investigators. MAIN RESULTS: The updated searches identified two new studies. A total of 14 trials, including 364 randomised participants, met the selection criteria. Meta-analysis of six trials in muscular dystrophies including 192 participants revealed a significant increase in muscle strength in the creatine group compared to placebo, with a weighted mean difference of 8.47%; (95% confidence intervals (CI) 3.55 to 13.38). Pooled data of four trials including 115 participants showed that a significantly higher number of patients felt better during creatine treatment compared to placebo with a risk ratio of 4.51 (95% CI 2.33 to 8.74). One trial in 37 participants with idiopathic inflammatory myopathies also showed a significant improvement in functional performance. No trial reported any clinically relevant adverse event. In metabolic myopathies, meta-analyses of three cross-over trials including 33 participants revealed no significant difference in muscle strength. One trial reported a significant deterioration of ADL (mean difference 0.54 on a 1 to 10 scale; 95% CI 0.14 to 0.93) and an increase in muscle pain during high-dose creatine treatment in McArdle disease. AUTHORS' CONCLUSIONS: High quality evidence from RCTs shows that short- and medium-term creatine treatment increases muscle strength in muscular dystrophies. There is also evidence that creatine improves functional performance in muscular dystrophy and idiopathic inflammatory myopathy. Creatine is well tolerated in these people. High quality but limited evidence from RCTs does not show significant improvement in muscle strength in metabolic myopathies. High-dose creatine treatment impaired ADL and increased muscle pain in McArdle disease.

Bolus arginine supplementation affects neither muscle blood flow nor muscle protein synthesis in young men at rest or after resistance exercise.

The aim of this study was to investigate the ergogenic potential of arginine on NO synthesis, muscle blood flow, and skeletal muscle protein synthesis (MPS). Eight healthy young men (22.1 ± 2.6 y, 1.79 ± 0.06 m, 76.6 ± 6.2 kg; mean ± SD) participated in 2 trials where they performed a bout of unilateral leg resistance exercise and ingested a drink containing either 10 g essential amino acids with 10 g l-arginine (ARG) or an isonitrogenous control (CON). Femoral artery blood flow of both the nonexercised and exercised leg was measured continuously using pulsed-wave Doppler ultrasound, while rates of mixed and myofibrillar MPS were determined using a primed continuous infusion of L-[ring-(13)C(6)] or L-[ring-(2)H(5)]phenylalanine. The plasma arginine concentration increased 300% during the ARG trial but not during the CON trial (P < 0.001). Plasma nitrate, nitrite, and endothelin-1, all markers of NO synthesis, did not change during either the ARG or CON trial. Plasma growth hormone increased to a greater degree after exercise in the ARG trial than CON trial (P < 0.05). Femoral artery blood flow increased 270% above basal in the exercised leg (P < 0.001) but not in the nonexercised leg, with no differences between the ARG and CON trials. Mixed and myofibrillar MPS were both greater in the exercised leg compared with the nonexercised leg (P < 0.001), but did not differ between the ARG and CON treatments. We conclude that an oral bolus (10 g) of arginine does not increase NO synthesis or muscle blood flow. Furthermore, arginine does not enhance mixed or myofibrillar MPS either at rest or after resistance exercise beyond that achieved by feeding alone.

Exercise training enhances the skeletal muscle response to radiation-induced oxidative stress.

Overproduction of reactive oxygen species (ROS) can damage cellular macromolecules and lead to cellular dysfunction or death. Exercise training induces beneficial adaptations in skeletal muscle that may reduce cellular damage from exposure to ROS. To determine the response of exercise-conditioned muscle to acute increases in ROS, four groups of mice were used: non-trained (NT, n = 12); NT + high-dose radiation (HDR, n = 3); exercise-trained (EX, n = 13, 3 days/week for 10 weeks, 10 m/min to 18 m/min); and EX + HDR (n = 3/group). Quadriceps muscle was harvested 3-5 days following the last exercise bout in the training program for measurement of antioxidant enzyme and metabolic enzyme activity. Total superoxide dismutase (41%), and manganese sodium oxide dismutase (51%) activities were significantly increased in radiation-challenged EX mice as compared with unchallenged EX mice (all P ≤ 0.05). No such increase was observed in NT mice. Citrate synthase (42%) and cytochrome c oxidase (38%) activities were both elevated in radiation-challenged EX mice as compared with unchallenged EX mice (both P < 0.05), and no such increase was observed in NT. We demonstrate that preconditioning skeletal muscle with EX enhances the response of antioxidant and mitochondrial enzymes to radiation.

Bacterial overgrowth syndrome in myotonic muscular dystrophy is potentially treatable.

Over one third of patients with myotonic muscular dystrophy type 1 (DM1) have gastrointestinal complaints. The cause is multifactorial, and treatment options are limited. Twenty DM1 patients with gastrointestinal symptoms were screened over a 2-year period using glucose breath hydrogen testing (GBHT) to evaluate the prevalence of small intestinal bacterial overgrowth (SIBO). Sixty-five percent of patients had a positive GBHT, and diarrhea was the most common presenting symptom. Ciprofloxacin was the most common antibiotic used for treatment, and 70% of patients reported a good response to the initial course of treatment. Although the causes of gastrointestinal symptoms in patients with DM1 are multifactorial, small intestinal bacterial overgrowth is an important diagnostic consideration that is easily diagnosed using glucose breath hydrogen testing and often shows a good response to treatment with common antibiotics.

A randomized trial of coenzyme Q10 in mitochondrial disorders.

Case reports and open-label studies suggest that coenzyme Q(10) (CoQ(10)) treatment may have beneficial effects in mitochondrial disease patients; however, controlled trials are warranted to clinically prove its effectiveness. Thirty patients with mitochondrial cytopathy received 1200 mg/day CoQ(10) for 60 days in a randomized, double-blind, cross-over trial. Blood lactate, urinary markers of oxidative stress, body composition, activities of daily living, quality of life, forearm handgrip strength and oxygen desaturation, cycle exercise cardiorespiratory variables, and brain metabolites were measured. CoQ(10) treatment attenuated the rise in lactate after cycle ergometry, increased (∽1.93 ml) VO(2)/kg lean mass after 5 minutes of cycling (P < 0.005), and decreased gray matter choline-containing compounds (P < 0.05). Sixty days of moderate- to high-dose CoQ(10) treatment had minor effects on cycle exercise aerobic capacity and post-exercise lactate but did not affect other clinically relevant variables such as strength or resting lactate.

Eccentric exercise activates novel transcriptional regulation of hypertrophic signaling pathways not affected by hormone changes.

Unaccustomed eccentric exercise damages skeletal muscle tissue, activating mechanisms of recovery and remodeling that may be influenced by the female sex hormone 17beta-estradiol (E2). Using high density oligonucleotide based microarrays, we screened for differences in mRNA expression caused by E2 and eccentric exercise. After random assignment to 8 days of either placebo (CON) or E2 (EXP), eighteen men performed 150 single-leg eccentric contractions. Muscle biopsies were collected at baseline (BL), following supplementation (PS), +3 hours (3H) and +48 hours (48H) after exercise. Serum E2 concentrations increased significantly with supplementation (P<0.001) but did not affect microarray results. Exercise led to early transcriptional changes in striated muscle activator of Rho signaling (STARS), Rho family GTPase 3 (RND3), mitogen activated protein kinase (MAPK) regulation and the downstream transcription factor FOS. Targeted RT-PCR analysis identified concurrent induction of negative regulators of calcineurin signaling RCAN (P<0.001) and HMOX1 (P = 0.009). Protein contents were elevated for RND3 at 3H (P = 0.02) and FOS at 48H (P<0.05). These findings indicate that early RhoA and NFAT signaling and regulation are altered following exercise for muscle remodeling and repair, but are not affected by E2.

Body composition and strength changes in women with milk and resistance exercise.

PURPOSE: We aimed to determine whether women consuming fat-free milk versus isoenergetic carbohydrate after resistance exercise would see augmented gains in lean mass and reductions in fat mass similar to what we observed in young men. METHODS: Young women were randomized to drink either fat-free milk (MILK: n = 10; age (mean +/- SD) = 23.2 +/- 2.8 yr; BMI = 26.2 +/- 4.2 kg x m(-2)) or isoenergetic carbohydrate (CON: n = 10; age = 22.4 +/- 2.4 yr; BMI = 25.2 +/- 3.8 kg x m(-2)) immediately after and 1 h after exercise (2 x 500 mL). Subjects exercised 5 d x wk(-1) for 12 wk. Body composition changes were measured by dual-energy x-ray absorptiometry, and subjects' strength and fasting blood were measured before and after training. RESULTS: CON gained weight after training (CON: +0.86 +/- 0.4 kg, P < 0.05; MILK: +0.50 +/- 0.4 kg, P = 0.29). Lean mass increased with training in both groups (P < 0.01), with a greater net gain in MILK versus CON (1.9 +/- 0.2 vs 1.1 +/- 0.2 kg, respectively, P < 0.01). Fat mass decreased with training in MILK only (-1.6 +/- 0.4 kg, P < 0.01; CON: -0.3 +/- 0.3 kg, P = 0.41). Isotonic strength increased more in MILK than CON (P < 0.05) for some exercises. Serum 25-hydroxyvitamin D increased in both groups but to a greater extent in MILK than CON (+6.5 +/- 1.1 vs +2.8 +/- 1.3 nM, respectively, P < 0.05), and parathyroid hormone decreased only in MILK (-1.2 +/- 0.2 pM, P < 0.01). CONCLUSIONS: Heavy, whole-body resistance exercise with the consumption of milk versus carbohydrate in the early postexercise period resulted in greater muscle mass accretion, strength gains, fat mass loss, and a possible reduction in bone turnover in women after 12 wk. Our results, similar to those in men, highlight that milk is an effective drink to support favorable body composition changes in women with resistance training.