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

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 (3 g/d) and creatine (6.75 g/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 (p<0.03, t-test) but comparison to placebo and creatine effects did not reach significance (p=0.06, 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.

Adipose tissue thickness affects in vivo quantitative near-IR spectroscopy in human skeletal muscle.

The influence of adipose tissue thickness (ATT) on near-IR spectroscopy (NIRS) measurements in vivo was studied in the human flexor digitorum superficialis muscle at rest and during sustained isometric handgrip exercise. NIRS was used for the quantitative measurement of muscle O(2) consumption (mV.O(2)) and forearm blood flow (FBF) in 78 healthy subjects. Skinfold thickness ranged from 1.4 to 8.9 mm within the group. Resting mV.O(2) was 0.11+/-0.04 ml of O(2).min(-1).100 g(-1), and FBF was 1.28+/-0.82 ml.min(-1).100 ml(-1). There was a negative correlation (r=-0.70, P< or =0.01), indicating a decrease in mV.O(2) with increasing ATT. mV.O(2) in the 10 leanest subjects appeared to be twice as high as that in the 10 subjects with the highest ATT. A poor correlation (r=0.29, P< or =0.01) was found between ATT and FBF. The gender difference that we found for mV.O(2) was due to the difference in ATT between female and male subjects. No correlation was found between maximum voluntary contraction and mV.O(2), nor between maximum voluntary contraction and ATT, indicating that the contraction force did not confound our results. These results show that ATT has a substantial confounding influence on in vivo NIRS measurements, and that it is essential to incorporate this factor into future NIRS muscle studies in order to justify comparisons between different groups. To facilitate such comparisons, upper and lower boundaries for normal values of mV.O(2) and FBF in relation to ATT are presented.

Blood flow and muscle oxygen uptake at the onset and end of moderate and heavy dynamic forearm exercise.

We hypothesized that forearm blood flow (FBF) during moderate intensity dynamic exercise would meet the demands of the exercise and that postexercise FBF would quickly recover. In contrast, during heavy exercise, FBF would be inadequate causing a marked postexercise hyperemia and sustained increase in muscle oxygen uptake (VO(2musc)). Six subjects did forearm exercise (1-s contraction/relaxation, 1-s pause) for 5 min at 25 and 75% of peak workload. FBF was determined by Doppler ultrasound, and O(2) extraction was estimated from venous blood samples. In moderate exercise, FBF and VO(2musc) increased within 2 min to steady state. Rapid recovery to baseline suggested adequate O(2) supply during moderate exercise. In contrast, FBF was not adequate during heavy dynamic exercise. Immediately postexercise, there was an approximately 50% increase in FBF. Furthermore, we observed for the first time in the recovery period an increase in VO(2musc) above end-exercise values. During moderate exercise, O(2) supply met requirements, but with heavy forearm exercise, inadequate O(2) supply during exercise caused accumulation of a large O(2) deficit that was repaid during recovery.

Performance of near-infrared spectroscopy in measuring local O(2) consumption and blood flow in skeletal muscle.

The aim of this study was to investigate local muscle O(2) consumption (muscV(O(2))) and forearm blood flow (FBF) in resting and exercising muscle by use of near-infrared spectroscopy (NIRS) and to compare the results with the global muscV(O(2)) and FBF derived from the well-established Fick method and plethysmography. muscV(O(2)) was derived from 1) NIRS using venous occlusion, 2) NIRS using arterial occlusion, and 3) the Fick method [muscV(O(2(Fick)))]. FBF was derived from 1) NIRS and 2) strain-gauge plethysmography. Twenty-six healthy subjects were tested at rest and during sustained isometric handgrip exercise. Local variations were investigated with two independent and simultaneously operating NIRS systems at two different muscles and two measurement depths. muscV(O(2)) increased more than fivefold in the active flexor digitorum superficialis muscle, and it increased 1.6 times in the brachioradialis muscle. The average increase in muscV(O(2(Fick))) was twofold. FBF increased 1.4 times independent of the muscle or the method. It is concluded that NIRS is an appropriate tool to provide information about local muscV(O(2)) and local FBF because both place and depth of the NIRS measurements reveal local differences that are not detectable by the more established, but also more global, Fick method.

The effect of electrical stimulation on leg muscle pump activity in spinal cord-injured and able-bodied individuals.

The purpose of this study was to examine the difference in: (1) effective muscle pump activity (MPA) between voluntary and electrically (ES) induced contractions in able-bodied subjects (ABS); and (2) ES-induced MPA between spinal cord-injured (SCI) individuals and ABS. MPA was measured as relative volume changes in the calf using strain-gauge plethysmography during repeated muscle contractions in the supine position while venous outflow was impeded by a thigh cuff inflated to a range of pressures. Ten SCI individuals and ten ABS participated in this study. ABS showed no significant difference between voluntary and electrically induced MPA [58.1 (18.4)% versus 67.7 (8.7)%, respectively]. SCI individuals showed a significantly lower ES-induced MPA than ABS [21.5 (15.9)% versus 67.7 (8.7)%, respectively]. The low MPA in SCI individuals may be explained by: (1) extensive leg muscle atrophy and/or (2) an "atrophic" vascular system in the legs. The electrical current level seemed to influence MPA (43 mA, 21.5% versus 60 mA, 30.8%) for SCI individuals, whereas no influence of muscle contraction rate on MPA was observed in ABS. The results of this study demonstrate that although ES-induced leg muscle contractions result in adequate MPA in ABS, it leads to significantly less effective MPA in SCI individuals.

Quantitative near-infrared spectroscopy discriminates between mitochondrial myopathies and normal muscle.

Five patients with chronic progressive external ophthalmoplegia (CPEO) and 27 healthy controls were examined by near-infrared spectroscopy (NIRS) for the noninvasive and direct quantitative measurement of muscle oxygen consumption and forearm blood flow. NIRS measurements were obtained in rest and during static isometric handgrip exercise at 10% of the maximum voluntary contraction (MVC) force. A significantly decreased oxygen consumption at rest as well as during exercise was found in patients with CPEO. Our results suggest that NIRS is able to discriminate between CPEO patients and healthy controls, which makes NIRS a valuable tool in the diagnostic workup of patients suspected to have a mitochondrial myopathy.

Quantitative measurement of oxygen consumption and forearm blood flow in patients with mitochondrial myopathies.

Five patients with chronic progressive external ophthalmoplegia (CPEO) and 27 healthy controls were examined by near-infrared spectroscopy (NIRS) for the non-invasive and direct quantitative measurement of muscle oxygen consumption during rest as well as during static isometric handgrip exercise at 10% of their maximum voluntary contraction. In patients with CPEO, we found a significantly decreased oxygen consumption during exercise, but more remarkably already during rest. Our results suggest that NIRS is able to discriminate between CPEO patients and healthy controls, which makes NIRS a promising tool in the diagnostic work-up of patients suspected of a mitochondrial myopathy.