L-carnitine supplementation for muscle weakness and fatigue in children with neurofibromatosis type 1: A Phase 2a clinical trial.

Reduced muscle tone, muscle weakness, and physical fatigue can impact considerably on quality of life for children with neurofibromatosis type 1 (NF1). Human muscle biopsies and mouse models of NF1 deficiency in muscle show intramyocellular lipid accumulation, and preclinical data have indicated that L-carnitine supplementation can ameliorate this phenotype. The aim of this study is to examine whether daily L-carnitine supplementation is safe and feasible, and will improve muscle strength and reduce fatigue in children with NF1. A 12-week Phase 2a trial was conducted using 1000 mg daily oral levocarnitine tartrate supplementation. Recruited children were between 8 and 12 years old with a clinical diagnosis of NF1, history of muscle weakness and fatigue, and naïve to L-carnitine. Primary outcomes were safety (self-reporting, biochemical testing) and compliance. Secondary outcomes included plasma acylcarnitine profiles, functional measures (muscle strength, long jump, handwriting speed, 6-minute-walk test [6MWT]), and parent-reported questionnaires (PedsQL™, CBCL/6-18). Six children completed the trial with no self-reported adverse events. Biochemical tests for kidney and liver function were normal, and the average compliance was 95%. Plasma acylcarnitine levels were low, but within a range not clinically linked to carnitine deficiency. For strength measures, there was a mean 53% increase in dorsiflexion strength (95% confidence interval [CI] 8.89-60.75; p = 0.02) and mean 66% increase in plantarflexion strength (95% CI 12.99-134.1; p = 0.03). In terms of muscle performance, there was a mean 10% increase in long jump distance (95% CI 2.97-16.03; p = 0.01) and 6MWT distance (95% CI 5.88-75.45; p = 0.03). Comparison with the 1000 Norms Project data showed a significant improvement in Z-score for all of these measures. Parent reports showed no negative impact on quality of life, and the perceived benefits led to the majority of individuals remaining on L-carnitine after the study. Twelve weeks of L-carnitine supplementation is safe and feasible in children with NF1, and a Phase 3 trial should confirm the efficacy of treatment.

Dietary casein, egg albumin, and branched-chain amino acids attenuate phosphate-induced renal tubulointerstitial injury in rats.

Dietary phosphate intake is closely correlated with protein intake. However, the effects of the latter on phosphate-induced organ injuries remain uncertain. Herein, we investigated the effects of low (10.8%), moderate (23.0%), and high (35.2%) dietary casein and egg albumin administration on phosphate-induced organ injuries in rats. The moderate and high casein levels suppressed renal tubulointerstitial fibrosis and maintained mitochondrial integrity in the kidney. The serum creatinine levels were suppressed only in the high casein group. Phosphate-induced muscle weakness was also ameliorated by high dietary casein. The urinary and fecal phosphate levels in the early experiment stage showed that dietary casein did not affect phosphate absorption from the intestine. High dietary egg albumin showed similar kidney protective effects, while the egg albumin effects on muscle weakness were only marginally significant. As the plasma branched-chain amino acid levels were elevated in casein- and egg albumin-fed rats, we analyzed their effects. Dietary supplementation of 10% branched-chain amino acids suppressed phosphate-induced kidney injury and muscle weakness. Although dietary protein restriction is recommended in cases of chronic kidney disease, our findings indicate that the dietary casein, egg albumin, and branched-chain amino acid effects might be reconsidered in the era of a phosphate-enriched diet.

Effects of 21 days of bed rest and whey protein supplementation on plantar flexor muscle fatigue resistance during repeated shortening contractions.

PURPOSE: Space flight and bed rest (BR) lead to a rapid decline in exercise capacity. Whey protein plus potassium bicarbonate diet-supplementation (NUTR) could attenuate this effect by improving oxidative metabolism. We evaluated the impact of 21-day BR and NUTR on fatigue resistance of plantar flexor muscles (PF) during repeated shortening contractions, and whether any change was related to altered energy metabolism and muscle oxygenation. METHODS: Ten healthy men received a standardized isocaloric diet with (n = 5) or without (n = 5) NUTR. Eight bouts of 24 concentric plantar flexions (30 s each bout) with 20 s rest between bouts were employed. PF muscle size was assessed by means of peripheral quantitative computed tomography. PF muscle volume was assessed with magnetic resonance imaging. PF muscle force, contraction velocity, power and surface electromyogram signals were recorded during each contraction, as well as energy metabolism (31P nuclear magnetic resonance spectroscopy) and oxygenation (near-infrared spectroscopy). Cardiopulmonary parameters were measured during an incremental cycle exercise test. RESULTS: BR caused 10-15% loss of PF volume that was partly recovered 3 days after re-ambulation, as a consequence of fluid redistribution. Unexpectedly, PF fatigue resistance was not affected by BR or NUTR. BR induced a shift in muscle metabolism toward glycolysis and some signs of impaired muscle oxygen extraction. NUTR did not attenuate the BR-induced-shift in energy metabolism. CONCLUSIONS: Twenty-one days' BR did not impair PF fatigue resistance, but the shift to glycolytic metabolism and indications of impaired oxygen extraction may be early signs of developing reduced muscle fatigue resistance.

Response to Early Coenzyme Q10 Supplementation Is not Sustained in CoQ10 Deficiency Caused by CoQ2 Mutation.

BACKGROUND: COQ2 mutations cause a rare infantile multisystemic disease with heterogeneous clinical features. Promising results have been reported in response to Coenzyme Q10 treatment, especially for kidney involvement, but little is known about the long-term outcomes. METHODS: We report four new patients from two families with the c.437G→A (p.Ser146Asn) mutation in COQ2 and the outcomes of two patients after long-term coenzyme Q10 treatment. RESULTS: Index cases from two families presented with vomiting, nephrotic range proteinuria, and diabetes in early infancy. These patients were diagnosed with coenzyme Q10 deficiency and died shortly after diagnosis. Siblings of the index cases later presented with neonatal diabetes and proteinuria and were diagnosed at the first day of life. Coenzyme Q10 treatment was started immediately. The siblings responded dramatically to coenzyme Q10 treatment with normalized glucose and proteinuria levels, but they developed refractory focal clonic seizures beginning at three months of life that progressed to encephalopathy. CONCLUSIONS: In our cohort with CoQ10 deficiency, neurological involvement did not improve with oral coenzyme Q10 treatment despite the initial recovery from the diabetes and nephrotic syndrome.

Soymilk Improves Muscle Weakness in Young Ovariectomized Female Mice.

Estrogens play a key role in an extensive range of physiological functions in various types of tissues throughout the body in females. We previously showed that estrogen insufficiency caused muscle weakness that could be rescued by estrogen administration in a young female ovariectomized (OVX) mouse model. However, long-term estrogen replacement therapy increases risks of breast cancer and cardiovascular diseases. Soymilk contains plant-based protein and isoflavones that exert estrogen-like activity. Here we examined the effects of prolonged soymilk intake on muscle and its resident stem cells, called satellite cells, in the estrogen-insufficient model. Six-week-old C57BL/6 OVX female mice were fed with a dried soymilk-containing diet. We found that prolonged soymilk intake upregulated grip strength in OVX mice. Correspondingly, cross-sectional area of tibialis anterior muscle was significantly increased in OVX mice fed with soymilk. Furthermore, soymilk diet mitigated dysfunction of satellite cells isolated from OVX mice. Thus, these results indicated that prolonged soymilk intake is beneficial for improving muscle weakness in an estrogen-insufficient state in females.

Skeletal muscle metabolism is impaired during exercise in glycogen storage disease type III.

OBJECTIVE: Glycogen storage disease type IIIa (GSDIIIa) is classically regarded as a glycogenosis with fixed weakness, but we hypothesized that exercise intolerance in GSDIIIa is related to muscle energy failure and that oral fructose ingestion could improve exercise tolerance in this metabolic myopathy. METHODS: We challenged metabolism with cycle-ergometer exercise and measured substrate turnover and oxidation rates using stable isotope methodology and indirect calorimetry in 3 patients and 6 age-matched controls on 1 day, and examined the effect of fructose ingestion on exercise tolerance in the patients on another day. RESULTS: Total fatty acid oxidation rates during exercise were higher in patients than controls, 32.1 (SE 1.2) vs 20.7 (SE 0.5; range 15.8-29.3) µmol/kg/min (p = 0.048), and oxidation of carbohydrates was lower in patients, 1.0 (SE 5.4) vs 38.4 (SE 8.0; range 23.0-77.1) µmol/kg/min (p = 0.024). Fructose ingestion improved exercise tolerance in the patients. CONCLUSION: Similar to patients with McArdle disease, in whom muscle glycogenolysis is also impaired, GSDIIIa is associated with a reduced skeletal muscle oxidation of carbohydrates and a compensatory increase in fatty acid oxidation, and fructose ingestion improves exercise tolerance. Our results indicate that GSDIIIa should not only be viewed as a glycogenosis with fixed skeletal muscle weakness, but should also be considered among the glycogenoses presenting with exercise-related dynamic symptoms caused by muscular energy deficiency. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that ingestion of fructose improves exercise tolerance in patients with GSDIIIa.

Evaluación de la actividad física en la población general; cuestionarios validados / Physical activity assessment in the general population; validated self-report methods

Los cuestionarios auto-administrados han sido comúnmente utilizados en los estudios con grandes cohortes, con el fin de evaluar la actividad física de sus participantes. Como consecuencia de ello, existe una considerable cantidad de evidencias científicas sobre el efecto protector de la actividad física sobre la salud. Sin embargo, los estudios de validación que utilizan métodos objetivos, cómo métodos de referencia o «Gold Standard», para la cuantificación de la actividad física o el gasto energético (el agua doblemente marcada, los acelerómetros, los podómetros, etc.), indican que la precisión de los cuestionarios es limitada. Los cuestionarios de actividad física pueden fallar especialmente al estimar la actividad física no vigorosa, y suelen centrarse de forma específica en el ejercicio planificado (ir en bicicleta, correr, andar,…) y no suelen recoger las actividades de la vida diaria y movimientos de intensidad baja no planificada. Por ello, la estimación del gasto energético a partir de estos datos no es muy recomendable. Por otro lado, y a pesar de que los métodos objetivos deberían ser la primera elección a la hora de evaluar la actividad física, los cuestionarios se mantienen todavía como herramientas válidas y con muchas ventajas. Una de las ventajas es la buena implementación para estudios epidemiológicos y su bajo coste. Además, este tipo de instrumentos están específicamente diseñados y validados para diferentes grupos de edad y proporcionan información valiosa e importante, sobre todo, del patrón de actividad física. Sin embargo, aún son necesarios futuros estudios que investiguen en métodos más precisos para medir la actividad física respecto a la que proporcionan los cuestionarios. Podemos concluir que probablemente un método mixto que combine los métodos objetivos y subjetivos, y que incluya nuevos sistemas y registros electrónicos, sería lo más recomendable (AU)

Self-reported questionnaires have been commonly used to assess physical activity levels in large cohort studies. As a result, strong and convincing evidences that physical activity can protect health are widely recognized. However, validation studies using objective measures of physical activity or energy expenditure (double labelled water, accelerometers, pedometers, etc.) indicate that the accuracy and precision of survey techniques are limited. Physical activity questionnaires could fail in estimating particularly non-vigorous physical activity. They have a disproportionate focus on volitional type exercise (i.e. biking, jogging, and walking), while not capturing the activities of daily living and low to moderate intensity movements. Energy expenditure estimates from these data are not recommended. On the other hand, despite objective tools should be the measurement of choice to assess PA level, self-reported questionnaires remain valid, and have many advantages. i.e. low costs. These kind of recalls are designed and validated for different age groups and provide value and important information, mainly about physical activity pattern. Future studies will require more precision and accuracy in physical activity measurement than those provided by traditional survey methods. We can conclude that probably a mixed approach that combines both the objective and subjective techniques involving novel devices and electronic capture of physical activity questionnaires will be more effective (AU)

Association between coenzyme Q10 and glucose transporter (GLUT1) deficiency.

BACKGROUND: It has been demonstrated that glucose transporter (GLUT1) deficiency in a mouse model causes a diminished cerebral lipid synthesis. This deficient lipid biosynthesis could contribute to secondary CoQ deficiency. We report here, for the first time an association between GLUT1 and coenzyme Q10 deficiency in a pediatric patient. CASE PRESENTATION: We report a 15 year-old girl with truncal ataxia, nystagmus, dysarthria and myoclonic epilepsy as the main clinical features. Blood lactate and alanine values were increased, and coenzyme Q10 was deficient both in muscle and fibroblasts. Coenzyme Q10 supplementation was initiated, improving ataxia and nystagmus. Since dysarthria and myoclonic epilepsy persisted, a lumbar puncture was performed at 12 years of age disclosing diminished cerebrospinal glucose concentrations. Diagnosis of GLUT1 deficiency was confirmed by the presence of a de novo heterozygous variant (c.18+2T>G) in the SLC2A1 gene. No mutations were found in coenzyme Q10 biosynthesis related genes. A ketogenic diet was initiated with an excellent clinical outcome. Functional studies in fibroblasts supported the potential pathogenicity of coenzyme Q10 deficiency in GLUT1 mutant cells when compared with controls. CONCLUSION: Our results suggest that coenzyme Q10 deficiency might be a new factor in the pathogenesis of G1D, although this deficiency needs to be confirmed in a larger group of G1D patients as well as in animal models. Although ketogenic diet seems to correct the clinical consequences of CoQ deficiency, adjuvant treatment with CoQ could be trialled in this condition if our findings are confirmed in further G1D patients.

Elderly persons with ICU-acquired weakness: the potential role for ß-hydroxy-ß-methylbutyrate (HMB) supplementation?

Intensive care unit (ICU)-acquired weakness is common and characterized by muscle loss, weakness, and paralysis. It is associated with poor short-term outcomes, including increased mortality, but the consequences of reduced long-term outcomes, including decreased physical function and quality of life, can be just as devastating. ICU-acquired weakness is particularly relevant to elderly patients who are increasingly consuming ICU resources and are at increased risk for ICU-acquired weakness and complications, including mortality. Elderly patients often enter critical illness with reduced muscle mass and function and are also at increased risk for accelerated disuse atrophy with acute illness. Increasingly, intensivists and researchers are focusing on strategies and therapies aimed at improving long-term neuromuscular function. ß-Hydroxy-ß-methylbutyrate (HMB), an ergogenic supplement, has shown efficacy in elderly patients and certain clinical populations in counteracting muscle loss. The present review discusses ICU-acquired weakness, as well as the unique physiology of muscle loss and skeletal muscle function in elderly patients, and then summarizes the evidence for HMB in elderly patients and in clinical populations. We subsequently postulate on the potential role and strategies in studying HMB in elderly ICU patients to improve muscle mass and function.

Mitochondrial respiration without ubiquinone biosynthesis.

Ubiquinone (UQ), a.k.a. coenzyme Q, is a redox-active lipid that participates in several cellular processes, in particular mitochondrial electron transport. Primary UQ deficiency is a rare but severely debilitating condition. Mclk1 (a.k.a. Coq7) encodes a conserved mitochondrial enzyme that is necessary for UQ biosynthesis. We engineered conditional Mclk1 knockout models to study pathogenic effects of UQ deficiency and to assess potential therapeutic agents for the treatment of UQ deficiencies. We found that Mclk1 knockout cells are viable in the total absence of UQ. The UQ biosynthetic precursor DMQ9 accumulates in these cells and can sustain mitochondrial respiration, albeit inefficiently. We demonstrated that efficient rescue of the respiratory deficiency in UQ-deficient cells by UQ analogues is side chain length dependent, and that classical UQ analogues with alkyl side chains such as idebenone and decylUQ are inefficient in comparison with analogues with isoprenoid side chains. Furthermore, Vitamin K2, which has an isoprenoid side chain, and has been proposed to be a mitochondrial electron carrier, had no efficacy on UQ-deficient mouse cells. In our model with liver-specific loss of Mclk1, a large depletion of UQ in hepatocytes caused only a mild impairment of respiratory chain function and no gross abnormalities. In conjunction with previous findings, this surprisingly small effect of UQ depletion indicates a nonlinear dependence of mitochondrial respiratory capacity on UQ content. With this model, we also showed that diet-derived UQ10 is able to functionally rescue the electron transport deficit due to severe endogenous UQ deficiency in the liver, an organ capable of absorbing exogenous UQ.

Oral coenzyme Q10 supplementation improves clinical symptoms and recovers pathologic alterations in blood mononuclear cells in a fibromyalgia patient.

Fibromyalgia (FM) is a chronic pain syndrome with unknown etiology. Recent studies have shown evidence demonstrating that mitochondrial dysfunction and oxidative stress may have a role in the pathophysiology of FM. Coenzyme Q10 (CoQ10) is an essential electron carrier in the mitochondrial respiratory chain and a strong antioxidant. Low CoQ10 levels have been detected in patients with FM, and a significant decrease of clinical symptoms has been reported after oral CoQ10 supplementation. In this report, we show the effect of CoQ10 treatment on clinical symptoms, blood mononuclear cells, and mitochondrial and oxidative stress markers from a woman with FM. After CoQ10 treatment, the patient reported a significant improvement of clinical symptoms. At the cellular level, CoQ10 treatment restored mitochondrial dysfunction and the mtDNA copy number, decreased oxidative stress, and increased mitochondrial biogenesis. Our results suggest that CoQ10 could be an alternative therapeutic approach for FM.

Osteomalacia as a result of vitamin D deficiency.

Osteomalacia is an end-stage bone disease of chronic and severe vitamin D or phosphate depletion of any cause. Its importance has increased because of the rising incidence of vitamin D deficiency. Yet, not all cases of osteomalacia are cured by vitamin D replacement, and furthermore, not all individuals with vitamin D deficiency develop osteomalacia. Although in the past osteomalacia was commonly caused by malabsorption, nutritional deficiency now is more common. In addition, recent literature suggests that nutritional vitamin D deficiency osteomalacia follows various bariatric surgeries for morbid obesity. Bone pain, tenderness, muscle weakness, and difficulty walking are all common clinical manifestations of osteomalacia. Diagnostic work-up involves biochemical assessment of vitamin D status and may also include a transiliac bone biopsy. Treatment is based on aggressive vitamin D repletion in most cases with follow-up biopsies if patients are started on antiresorptive or anabolic agents.

Moderately increased protein intake predominately from egg sources does not influence whole body, regional, or muscle composition responses to resistance training in older people.

UNLABELLED: The effects of increased dietary protein on resistance training (RT)-induced changes in body composition and skeletal muscle fiber size are uncertain in older people. OBJECTIVES: We hypothesized that the ingestion of more animal-based foods, especially eggs, to achieve a higher protein intake would enhance RT-induced changes in body composition. SETTING: West Lafayette, IN. PARTICIPANTS: 36 older people (age 61 +/- 1 y; mean +/- SEM). INTERVENTION: Subjects completed RT three d/wk for 12 weeks, and consumed omnivorous diets that contained either 0.9 +/- 0.1 (lower protein) or 1.2 +/- 0.0 (higher protein) g protein x kg(-1) x d(-1) (12 +/- 3 and 17 +/- 5% of energy intakes, respectively), with the higher protein intake achieved by consuming more eggs, meats, and dairy foods. The lower and higher protein diets contained 213 +/- 21 and 610 +/- 105 mg cholesterol/d, respectively. MEASUREMENTS: Strength, body composition, serum lipid-lipoprotein profile, urinary creatinine, skeletal muscle fiber type and size. RESULTS: Among all subjects, over time (i.e. with RT) body weight was unchanged, lean mass (1.1 +/- 0.2 kg) increased, and fat mass (-1.4 +/- 0.2 kg) decreased (all changes P < 0.05). Regional (i.e. trunk, legs, arms) lean mass increased and fat mass decreased. Whole body muscle mass (24-h urinary creatinine excretion) increased, but skeletal muscle (vastus lateralis) type 1, type 2a, and type 2x fiber cross-sectional areas did not change from baseline. Serum total and LDL cholesterol decreased (P < 0.05) and HDL cholesterol and triacylglycerol were unchanged. Dietary protein and cholesterol intakes did not influence these responses to RT. CONCLUSION: Consumption of diets that contained moderately higher protein and variable amounts of cholesterol did not differentially affect body composition, skeletal muscle fiber size, or serum lipid-lipoprotein profile responses to resistance training in older people.

Exercise, nutrition, and aging.

Advancing adult age is associated with profound changes in body composition. Age-related loss in skeletal muscle has been referred to as sarcopenia and is a direct cause of the age-related decreased in muscle strength. Resistance training is an effective means of preserving or increasing skeletal muscle mass and functional status in the elderly. In addition, resistance training has been demonstrated to increase energy requirements, protein retention, bone mass, and levels of physical activity in healthy elders as well as the very old and frail.