Klaus Müller

Mitochondrial impairment in patients and asymptomatic mutation carriers of Huntington's disease

Huntingtons disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the IT‐15 gene; however, it remains unknown how the mutation leads to selective neurodegeneration. Several lines of evidence suggest impaired mitochondrial function as a component of the neurodegenerative process in HD. We assessed energy metabolism in the skeletal muscle of 15 HD patients and 12 asymptomatic mutation carriers in vivo using 31P magnetic resonance spectroscopy. Phosphocreatine recovery after exercise is a direct measure of ATP synthesis and was slowed significantly in HD patients and mutation carriers in comparison to age‐ and gender‐matched healthy controls. We found that oxidative function is impaired to a similar extent in manifest HD patients and asymptomatic mutation carriers. Our findings suggest that mitochondrial dysfunction is an early and persistent component of the pathophysiology of HD.

L-carnitine and creatine in Friedreich’s ataxia. A randomized, placebo-controlled crossover trial

Summary.Impaired oxidative phosphorylation is a crucial factor in the pathogenesis of Friedreich’s ataxia (FA). L-carnitine and creatine are natural compounds that can enhance cellular energy transduction. We performed a placebo-controlled triple-phase crossover trial of L-carnitine (3u2009g/d) and creatine (6.75u2009g/d) in 16 patients with genetically confirmed FA. Primary outcome measures were mitochondrial ATP production measured as phosphocreatine recovery by 31Phosphorus magnetic resonance spectroscopy, neurological deficits assessed by the international co-operative ataxia rating scale and cardiac hypertrophy in echocardiography. After 4 months on L-carnitine phosphocreatine recovery was improved compared to baseline (pu2009<u20090.03, t-test) but comparison to placebo and creatine effects did not reach significance (pu2009=u20090.06, F-test). Ataxia rating scale and echocardiographic parameters remained unchanged. Creatine had no effect in FA patients. L-carnitine is a promising substance for the treatment of FA patients, and larger trials are warranted.

Breakdown of adenine nucleotide pool in fatiguing skeletal muscle in McArdle's disease: a noninvasive 31P-MRS and EMG study.

Energy metabolism and electrical muscle activity were studied in the calf muscles of 19 patients with proven McArdles disease and in 25 healthy subjects. Phosphorus magnetic resonance spectroscopy and surface electromyography (S‐EMG) were performed during two isometric muscle contractions of 3 min at 30% maximum voluntary contraction, one performed during normal perfusion and the other during applied ischemia. After about 1 min of ischemic muscle contraction in diseased muscle a significant acceleration in phosphocreatine breakdown was observed, along with a significant decrease in adenosine triphosphate. During both contractions the absence of glycolysis was shown by a significant alkalinization. Furthermore, in patients we observed a greater increase in the S‐EMG amplitude than in control subjects. We conclude that early on during moderate exercise, a small number of muscle fibers reach metabolic depletion, indicated by a reduction in the adenine nucleotide pool. An increasing number of motor units, which are still in a high‐energy state, are continuously recruited to compensate for muscle fatigue. This functional compartmentation may contribute to the pathophysiology of exercise intolerance in McArdles disease. Muscle Nerve 27: 728–736, 2003

Energy metabolism in human calf muscle performing isometric plantar flexion superimposed by 20-Hz vibration

Vibration training is commonly expected to induce an active muscle contraction via a complex reflex mechanism. In calf muscles of 20 untrained subjects, the additional energy consumption in response to vibration superimposed on an isometric contraction was examined by 31P magnetic resonance spectroscopy and by near infrared spectroscopy. Subjects performed 3xa0min of isometric plantar flexion exercise at 40% MVC under four conditions: with (VIB) and without (CON) superimposed 20xa0Hz vibration at ±2xa0mm amplitude, both combined with or without arterial occlusion (AO). After contraction under all conditions, the decreases in oxygenated haemoglobin were not significantly different. After VIBxa0+xa0AO consumption of ATP was increased by 60% over CONxa0+xa0AO, visible by significant decreases in [PCr] and intracellular pH (Pxa0<xa00.05). The additional energy consumption by vibration was not detectable under natural perfusion. Probably without AO the additional energy consumption by vibration was compensated by oxidative phosphorylation enabled by additional perfusion.

An Individual Patient Data Meta-Analysis on Characteristics and Outcome of Patients with Papillary Glioneuronal Tumor, Rosette Glioneuronal Tumor with Neuropil-Like Islands and Rosette Forming Glioneuronal Tumor of the Fourth Ventricle

Background and Purpose In 2007, the WHO classification of brain tumors was extended by three new entities of glioneuronal tumors: papillary glioneuronal tumor (PGNT), rosette-forming glioneuronal tumor of the fourth ventricle (RGNT) and glioneuronal tumor with neuropil-like islands (GNTNI). Focusing on clinical characteristics and outcome, the authors performed a comprehensive individual patient data (IPD) meta-analysis of the cases reported in literature until December 2012. Methods PubMed, Embase and Web of Science were searched for peer-reviewed articles reporting on PGNT, RGNT, and GNTNI using predefined keywords. Results 95 publications reported on 182 patients (PGNT, 71; GNTNI, 26; RGNT, 85). Median age at diagnosis was 23 years (range 4–75) for PGNT, 27 years (range 6–79) for RGNT, and 40 years (range 2–65) for GNTNI. Ninety-seven percent of PGNT and 69% of GNTNI were located in the supratentorial region, 23% of GNTNI were in the spinal cord, and 80% of RGNT were localized in the posterior fossa. Complete resection was reported in 52 PGNT (73%), 36 RGNT (42%), and 7 GNTNI (27%) patients. Eight PGNT, 3 RGNT, and 12 GNTNI patients were treated with chemo- and/or radiotherapy as the primary postoperative treatment. Follow-up data were available for 132 cases. After a median follow-up time of 1.5 years (range 0.2–25) across all patients, 1.5-year progression-free survival rates were 52±12% for GNTNI, 86±5% for PGNT, and 100% for RGNT. The 1.5-year overall-survival were 95±5%, 98±2%, and 100%, respectively. Conclusions The clinical understanding of the three new entities of glioneuronal tumors, PGNT, RGNT and GNTNI, is currently emerging. The present meta-analysis will hopefully contribute to a delineation of their diagnostic, therapeutic, and prognostic profiles. However, the available data do not provide a solid basis to define the optimum treatment approach. Hence, a central register should be established.

Impaired aerobic glycolysis in muscle phosphofructokinase deficiency results in biphasic post-exercise phosphocreatine recovery in 31P magnetic resonance spectroscopy

Using 31P magnetic resonance spectroscopy, energy metabolism in calf muscles of two patients with biochemically and genetically proven muscular phosphofructokinase deficiency, and an asymptomatic heterozygote was monitored during isometric foot plantarflexion performed under aerobic and anaerobic conditions and in the aerobic recovery phases. In the heterozygote only a moderate alteration from normal was found in terms of an elevated ATP demand during exercise. In the homozygote, hexose phosphates, indicated as phosphomonoesters, increased dramatically during contraction. Phosphomonoester accumulation resulted in consumption of free inorganic phosphate (P(i)). During ischemic exercise the absence of glycolytic ATP formation resulted in a linear time course of phosphocreatine breakdown and a moderate alkalinization. During the recovery, phosphocreatine resynthesis showed a biphasic time course, indicating that mitochondrial function itself was not directly affected. At first glance, the early depletion of P(i) below initial resting levels and the rate of phosphate splitting from sugar phosphates seemed to become the limiting factor for the rate of the oxidative phosphorylation and creatine kinase reaction. However, the actual concentrations of P(i) and ADP estimated at the onset of delay were too high to exclusively explain the dramatic delay in PCr resynthesis. For this reason, a reduced turnover of the citric acid cycle was assumed, which was caused by the complete absence of glycolysis in PFK deficiency patients. Furthermore, results from PFK deficiency patients were compared with previous findings from myophosphorylase deficiency patients in the literature.

Creatine supplementation results in elevated phosphocreatine/adenosine triphosphate (ATP) ratios in the calf muscle of athletes but not in patients with myopathies

In a recent article, Tarnopolsky and Beal described the potential benefit of oral creatine supplementation for symptomatic therapy for various muscle diseases. Creatine uptake by the muscle fibers results in an elevation of intracellular phosphocreatine (PCr) levels because of the equilibrium reaction of creatine kinase. The uptake is mediated by a creatine membrane transporter. However, reduced concentrations of this transporter protein were found in various neuromuscular disorders. The aim of this letter is to compare the effects of oral creatine supplementation on PCr levels in the calf muscles of sports students performing regular muscle training, of sedentary healthy subjects, and of patients with glycogen storage disease V (McArdle’s disease), chronic progressive external ophthalmoplegia, and X-chromosomal Beckertype muscular dystrophy. All supplementation studies followed a double-blind, placebo-controlled crossover design. The creatine dose and the duration of each treatment phase are summarized in the table. Noninvasive P magnetic resonance spectroscopy was performed with a 4.7T magnetic resonance instrument (81MHz for P) and a 5cm surface coil. P magnetic resonance spectra of the right calf were recorded at rest and analyzed for the integrals of the PCr and the -ATP signals. Integral values were corrected for partial spin saturation effects. ATP levels were assumed to be constant throughout the period. In conclusion, PCr/ATP ratios predominantly reflected alterations in PCr levels. The PCr/ATP ratio of nontreated sedentary control subjects (n 38) was 3.7 0.5. This ratio was significantly higher than the placebo values of the PCr/ATP ratio in sports students and in patients with chronic progressive external ophthalmoplegia and X-chromsomal Becker-type muscular dystrophy. Only the sports students profited from creatine supplementation by a significantly increased PCr/ATP ratio. In the sedentary healthy subjects (n 5) and in all patient groups, muscle PCr/ATP ratios were not significantly altered with creatine treatment. PCr concentrations in patient muscle were not augmented, although creatine serum concentrations were increased by the supplementation (data not shown) and patients with X-chromsomal Becker-type muscular dystrophy and chronic progressive external ophthalmoplegia exhibited a lower PCr/ATP ratio than healthy controls. In contrast to sports students, sedentary healthy subjects and patients did not perform regular physical training. In conclusion, physical exercise might be an essential prerequisite to stimulate the uptake of creatine in skeletal muscle fibers.

Changes in phosphocreatine concentration of skeletal muscle during high-intensity intermittent exercise in children and adults

PurposeThe aim of the present study was to test the hypotheses that a greater oxidative capacity in children results in a lower phosphocreatine (PCr) depletion, a faster PCr resynthesis and a lower muscle acidification during high-intensity intermittent exercise compared to adults.MethodsSixteen children (9.4xa0±xa00.5xa0years) and 16 adults (26.1xa0±xa00.3xa0years) completed a protocol consisting of a dynamic plantar flexion (10 bouts of 30-s exercise at 25xa0% of one repetition maximum separated by 20-s recovery), followed by 10xa0min of passive recovery. Changes of PCr, ATP, inorganic phosphate, and phosphomonoesters were measured by means of 31Phosphorous-magnetic resonance spectroscopy during and post-exercise.ResultsAverage PCr (percentage of [PCr] at initial rest (%[PCr]i)) at the end of the exercise (adults 17xa0±xa012xa0%[PCr]i, children 38xa0±xa017xa0%[PCr]i, Pxa0<xa00.01) and recovery periods (adults 37xa0±xa014xa0%[PCr]i, children 57xa0±xa017xa0%[PCr]i, Pxa0<xa00.01) was significantly lower in adults compared to children, induced by a stronger PCr decrease during the first exercise interval (adults −73xa0±xa010xa0%[PCr]i, children −55xa0±xa015xa0%[PCr]i, Pxa0<xa00.01). End-exercise pH was significantly higher in children compared to adults (children 6.90xa0+xa00.20, −0.14; adults 6.67xa0+xa00.23, −0.15, Pxa0<xa00.05).ConclusionsFrom our results we suggest relatively higher rates of oxidative ATP formation in children’s muscle for covering the ATP demand of high-intensity intermittent exercise compared to adults, enabling children to begin each exercise interval with significantly higher PCr concentrations and leading to an overall lower muscle acidification.

Relation between muscle mass, motor units and type of training in master athletes

The aim of this study was to measure the number of motor units and muscle mass in power‐trained and endurance‐trained master athletes compared with community‐dwelling older adults.

An Individual Patient Data Meta-Analysis on Characteristics, Treatments and Outcomes of Glioblastoma/ Gliosarcoma Patients with Metastases Outside of the Central Nervous System

Purpose To determine the characteristics, treatments and outcomes of patients with glioblastoma multiforme (GBM) or gliosarcoma (GS) and metastases outside of the central nervous system (CNS). Methods PubMed and Web of Science searches for peer-reviewed articles pertaining to GBM/ GS patients with metastatic dissemination were conducted using the keywords gliosarcoma, glioblastoma, GBM, metastasis, metastases and metastatic. Additionally, we performed hand search following the references from the selected papers. Cases with metastases to the CNS were excluded and evaluated in a separate study. Results 109 articles published between 1928 and 2013 were eligible. They reported on 150 patients. We observed a remarkable increase in the number of cases per decade over time. Median overall survival from diagnosis of metastasis (OSM+) was 6.0 ± 0.8 months and median overall survival from initial diagnosis (OSID) 13 ± 2.4 months. On univariate analyses, gender, age, the histological subtype, the time interval between initial diagnosis and diagnosis of metastasis and pulmonary involvement did not influence OSM+. We did not observe any substantial treatment progress. A comparison of the present cohort with 84 GBM/ GS patients with exclusive CNS dissemination suggests that metastases outside the CNS are related to a slightly more favorable outcome. Conclusions The occurrence of extra-CNS metastasis from GBM/ GS is associated with a dismal prognosis, however it seems to compare slightly favorable to CNS dissemination. Crucial treatment progress has not been achieved over recent decades. A central registry should be considered to consecutively gain more information about the ideal therapeutic approach.