Paul Van Hecke

Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism

HIF prolyl hydroxylases (PHD1–3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparα pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2α and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress.

Visual Motion Processing Investigated Using Contrast Agent-Enhanced fMRI in Awake Behaving Monkeys

To reduce the information gap between human neuroimaging and macaque physiology and anatomy, we mapped fMRI signals produced by moving and stationary stimuli (random dots or lines) in fixating monkeys. Functional sensitivity was increased by a factor of approximately 5 relative to the BOLD technique by injecting a contrast agent (monocrystalline iron oxide nanoparticle [MION]). Areas identified as motion sensitive included V2, V3, MT/V5, vMST, FST, VIP, and FEF (with moving dots), as well as V4, TE, LIP, and PIP (with random lines). These regions sensitive for moving dots are largely in agreement with monkey single unit data and (except for V3A) with human fMRI results. Moving lines activate some regions that have not been previously implicated in motion processing. Overall, the results clarify the relationship between the motion pathway and the dorsal stream in primates.

Motion-responsive regions of the human brain

Abstract Functional magnetic resonance imaging was used to map motion responsive regions of the human brain by contrasting passive viewing of moving and stationary randomly textured patterns. Regions were retained as motion responsive if they reached significance either in the group analysis or in the majority of hemispheres in single-subject analysis. They include well-known regions, such as V1, hMT/V5+, and hV3A, but also several occipito-temporal, occipito-parietal, parietal, and frontal regions. The time course of the activation was similar in most of these regions. Motion responses were nearly identical for binocular and monocular presentations. Flicker-induced-activation introduced a dichotomy amongst these motion responsive regions. Early occipital and occipito-temporal regions responded well to flicker, while flicker responses gradually vanished as one moved to occipito-parietal and then parietal regions. Finally, over a more than four-fold range, stimulus diameter had little effect on the motion activations, except in V1.

Internal vs external generation of movements: differential neural pathways involved in bimanual coordination performed in the presence or absence of augmented visual feedback.

It is commonly agreed that a functional dissociation with respect to the internal vs external control of movements exists for several brain regions. This has, however, only been tested in relation to the timing and preparation of motor responses, but not to ongoing movement control. Using functional magnetic resonance imaging (fMRI), the present study addressed the neuroanatomical substrate of the internal-external control hypothesis by comparing regional brain activation for cyclical bimanual movements performed in the presence or absence of augmented visual feedback. Subjects performed a bimanual movement pattern, either with the help of on-line visual feedback of the movements (externally guided coordination) or with the eyes closed on the basis of an internal representation of the movement pattern (internally generated coordination). Visual control and baseline rest conditions were also added. Results showed a clear functional dissociation within the network involved in movement coordination. The hMT/V5+, the superior parietal cortex, the premotor cortex, the thalamus, and cerebellar lobule VI showed higher activation levels when movements were guided by visual feedback. Conversely, the basal ganglia, the supplementary motor area, cingulate motor cortex, the inferior parietal, frontal operculum, and cerebellar lobule IV-V/dentate nucleus showed higher involvement when movements were internally generated. Consequently, the present findings suggest the existence of distinct cortico-cortical and subcortico-cortical neural pathways for externally (augmented feedback) and internally guided cyclical bimanual movements. This provides a neurophysiological account for the beneficial effect of providing augmented visual feedback to optimize movements in normal and motor disordered patients.

Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans

1 We investigated the effect of oral creatine supplementation during leg immobilization and rehabilitation on muscle volume and function, and on myogenic transcription factor expression in human subjects. 2 A double‐blind trial was performed in young healthy volunteers (n=22). A cast was used to immobilize the right leg for 2 weeks. Thereafter the subjects participated in a knee‐extension rehabilitation programme (3 sessions week−1, 10 weeks). Half of the subjects received creatine monohydrate (CR; from 20 g down to 5 g daily), whilst the others ingested placebo (P; maltodextrin). 3 Before and after immobilization, and after 3 and 10 weeks of rehabilitation training, the cross‐sectional area (CSA) of the quadriceps muscle was assessed by NMR imaging. In addition, an isokinetic dynamometer was used to measure maximal knee‐extension power (Wmax), and needle biopsy samples taken from the vastus lateralis muscle were examined to asses expression of the myogenic transcription factors MyoD, myogenin, Myf5, and MRF4, and muscle fibre diameters. 4 Immobilization decreased quadriceps muscle CSA (∼10 %) and Wmax (∼25 %) by the same magnitude in both groups. During rehabilitation, CSA and Wmax recovered at a faster rate in CR than in P (P < 0.05 for both parameters). Immobilization changed myogenic factor protein expression in neither P nor CR. However, after rehabilitation myogenin protein expression was increased in P but not in CR (P < 0.05), whilst MRF4 protein expression was increased in CR but not in P (P < 0.05). In addition, the change in MRF4 expression was correlated with the change in mean muscle fibre diameter (r=0.73, P < 0.05). 5 It is concluded that oral creatine supplementation stimulates muscle hypertrophy during rehabilitative strength training. This effect may be mediated by a creatine‐induced change in MRF4 and myogenin expression.

Brain Areas Involved in Interlimb Coordination: A Distributed Network

Whereas behavioral studies have made significant contributions toward the identification of the principles governing the coordination of limb movements, little is known about the role of higher brain areas that are involved in interlimb coordination. Functional magnetic resonance imaging (fMRI) was used to reveal the brain areas activated during the cyclical coordination of ipsilateral wrist and foot movements. Six normal subjects performed five different tasks that were presented in a random order, i.e., isolated flexion-extension movements of the right wrist (WRIST) and right foot (FOOT), cyclical coordination of wrist and foot according to the isodirectional (ISODIR) and nonisodirectional (NON-ISODIR) mode, and rest (REST). All movements were auditory paced at 66 beats/min. During the coordination of both limb segments, a distributed network was identified showing activation levels in the supplementary motor area (SMA), cingulate motor cortex (CMC), premotor cortex (PMC), primary sensorimotor cortex (M1/S1), and cerebellum that exceeded the sum of the activations observed during the isolated limb movements. In addition, coordination of the limb movements in different directions was associated with extra activation of the SMA as compared to movements in the same direction. It is therefore concluded that the SMA is substantially involved in the coordination of the nonhomologous limbs as part of a distributed motor network. Accordingly, the long-standing exclusive association that has been made between this medial frontal area and bimanual (homologous) coordination needs to be abandoned and extended towards other forms of interlimb coordination (nonhomologous).

Human cortical regions involved in extracting depth from motion.

We used functional magnetic resonance imaging (fMRI) to investigate brain regions involved in extracting three-dimensional structure from motion. A factorial design included two-dimensional and three-dimensional structures undergoing rigid and nonrigid motions. As predicted from monkey data, the human homolog of MT/V5 was significantly more active when subjects viewed three-dimensional (as opposed to two-dimensional) displays, irrespective of their rigidity. Human MT/V5+ (hMT/V5+) is part of a network with right hemisphere dominance involved in extracting depth from motion, including a lateral occipital region, five sites along the intraparietal sulcus (IPS), and two ventral occipital regions. Control experiments confirmed that this pattern of activation is most strongly correlated with perceived three-dimensional structure, in as much as it arises from motion and cannot be attributed to numerous two-dimensional image properties or to saliency.

Attention to 3-D Shape, 3-D Motion, and Texture in 3-D Structure from Motion Displays

We used fMRI to directly compare the neural substrates of three-dimensional (3-D) shape and motion processing for realistic textured objects rotating in depth. Subjects made judgments about several different attributes of these objects, including 3-D shape, the 3-D motion, and the scale of surface texture. For all of these tasks, we equated visual input, motor output, and task difficulty, and we controlled for differences in spatial attention. Judgments about 3-D shape from motion involve both parietal and occipito-temporal regions. The processing of 3-D shape is associated with the analysis of 3-D motion in parietal regions and the analysis of surface texture in occipito-temporal regions, which is consistent with the different behavioral roles that are typically attributed to the dorsal and ventral processing streams.

Lateralization of brain activity during lower limb joints movement. An fMRI study.

Studies of unilateral finger movement in right-handed subjects have shown asymmetrical patterns of activation in primary motor cortex and subcortical regions. In order to investigate the existence of an analogous pattern during lower limb joints movements, functional magnetic resonance imaging (fMRI) was used. Eighteen healthy, right leg dominant volunteers participated in a motor block design study, performing unilateral right and left repetitive knee, ankle and toes flexion/extension movements. Aiming to relate lower limb joints activation to the well-described patterns of finger movement, serial finger-to-thumb opposition was also assessed. All movements were auditory paced at 72 beats/min (1.2 Hz). Brain activation during movement of the nondominant joints was more bilateral than during the same movement performed with the dominant joints. Finger movement had a stronger lateralized pattern of activation in comparison with lower limb joints, implying a different functional specialization. Differences were also evident between the joints of the lower limb. Ankle and toes movements elicited the same extend of MR signal change in the majority of the examined brain regions, whereas knee joint movement was associated with a different pattern. Finally, lateralization index in primary sensorimotor cortex and basal ganglia was significantly affected by the main effect of dominance, whereas the lateralization index in cerebellum was significantly affected by the joint main effect, demonstrating a lateralization index increase from proximal to distal joints.

Phosphocreatine resynthesis is not affected by creatine loading

PURPOSE Oral creatine supplementation has been shown to improve power output during high intensity intermittent muscle contractions. Facilitated muscle phosphocreatine (PCr) resynthesis, by virtue of elevated intracellular PCr concentration, might contribute to this ergogenic action. Therefore, the effect of creatine loading (C: 25 g X d(-1) for 5 d) on muscle PCr breakdown and resynthesis and muscle performance during high intensity intermittent muscle contractions was investigated. METHODS A double-blind randomized cross-over study was performed in young healthy male volunteers (N = 9). 31P-NMR spectroscopy of the m. gastrocnemius and isokinetic dynamometry of knee-extension torque were performed before and after 2 and 5 d of either placebo (P) or C administration. RESULTS Compared with P, 2 and 5 d of C increased (P < 0.05) resting muscle PCr concentration by 11% and 16%, respectively. Furthermore, torque production during maximal intermittent knee extensions, including the first bout of contractions, was increased (P < 0.05) by 5-13% by either 2 or 5 d of C. However, compared with P, the rate of PCr breakdown and resynthesis during intermittent isometric contractions of the calf was not significantly affected by C. CONCLUSION Creatine loading raises muscle PCr concentration and improves performance during rapid and dynamic intermittent muscle contractions. Creatine loading does not facilitate muscle PCr resynthesis during intermittent isometric muscle contractions.