Journal of Physiology-London最新文献

We previously reported that elevated expression of phospholipid hydroperoxide glutathione peroxidase 4, an enzyme that regulates membrane lipid hydroperoxides, can mitigate sarcopenia in mice. However, it is still unknown whether a pharmacological intervention designed to modulate lipid hydroperoxides might be an effective strategy to reduce sarcopenia in aged mice. Here we asked whether a newly developed compound, CMD-35647 (CMD), can reduce muscle atrophy induced by sciatic nerve transection. We treated mice daily with vehicle or CMD (15 mg/kg, i.p. injection) starting 1 day prior to denervation. CMD treatment reduced hydroperoxide generation and blunted muscle atrophy by over 17% in denervated muscle. To test whether CMD can reduce ageing-induced muscle atrophy and weakness, we treated mice with either vehicle or CMD (15 mg/kg, i.p. injection) 3 days per week for 8 months, starting at 18 months of age until 26 months of age. We measured muscle mass, functional status of neuromuscular junctions, muscle contractile function and mitochondrial function in control and CMD-treated 26-month-old female mice. Treatment with CMD conferred protection against muscle atrophy in both tibialis anterior and extensor digitorum longus that was associated with maintenance of fibre size of MHC 2b and 2x fibres. Mitochondrial respiration was also protected in CMD-treated mice. We also found that muscle force generation was protected with CMD treatment despite denervation in ∼25% of the muscle fibres. Overall, this study shows that pharmacological interventions designed to reduce lipid hydroperoxides might be effective for preventing sarcopenia. KEY POINTS: Sarcopenia in aged mice is associated with muscle loss, contractile dysfunction, denervation, and reduced mitochondrial respiration. CMD-35647 is a pharmocological compound that can neutralize lipid hydroperoxides. 8 month treatment of CMD-35647 mitigated muscle atrophy in tibialis anterior and extensor digitorum longus. 8 month treatment of CMD-35647 improved muscle function in aged mice independent of the neuromuscular junction. Aged mice treated with CMD-35647 had greater respiration in red gastrocnemius muscle when compared to vehicle treated mice.

Bipolar cells are vertebrate retinal interneurons conveying signals from rod and cone photoreceptors to amacrine and ganglion cells. Bipolar cells are found in all vertebrates and have many structural and molecular affinities with photoreceptors; they probably appeared very early during vertebrate evolution in conjunction with rod and cone progenitors. There are two types of bipolar cells, responding to central illumination with depolarization (ON) or hyperpolarization (OFF). In most vertebrate species, rod signals are conveyed to specialized rod bipolar cells, which sum signals from many rods and facilitate detection at the visual threshold. Lamprey, which diverged from all other vertebrates in the late Cambrian, have both rod ON and rod OFF bipolar cells, but mammals have only rod ON cells. Rod signals in mammals are conveyed to output neurons indirectly via AII (or A2) amacrine cells, which synapse onto cone ON and cone OFF bipolar-cells and then to ganglion cells. These findings raise the question of when during retinal evolution rod OFF bipolar cells were lost. Because physiological recordings have been made from rod OFF bipolar cells in both cartilaginous fishes (dogfish) and urodeles (salamanders), rod OFF bipolar cells and their circuits must have been retained in vertebrate progenitors at least until the Devonian. Recent evidence showing that zebrafish retina processes rod signals similar to those in mammals indicates that rod OFF bipolar cells were lost at least twice. The sole utilization of rod ON bipolar cells may have provided a selective advantage from increased signal-to-noise discrimination near the visual threshold. KEY POINTS: Rods and cones have many structural and molecular similarities to bipolar cells, which are retinal interneurons conveying signals from photoreceptors to the retinal output. Bipolar cells can be either ON (centre depolarizing) or OFF (centre hyperpolarizing) and either rod or cone dominant. Lamprey, which diverged from all other vertebrates 500 million years ago, have both ON and OFF bipolar cells, which can each be either rod or cone dominant. We argue that this configuration of separate rod/cone bipolar-cell pathways is representative of early vertebrates. Rod ON and rod OFF bipolars persisted at least until the progenitors of amphibians in the Devonian, but mammals and teleost fishes have only rod ON bipolar cells and convey rod OFF signals via a specialized amacrine cell. We argue that rod OFF bipolar cells were lost in at least two different lineages during vertebrate evolution, probably to increase the signal-to-noise of rod vision.

Circulating mature red blood cells (RBCs) from patients and mice with sickle cell disease (SCD) abnormally retain mitochondria, a factor shown to contribute to the disease's pathobiology. To further understand the functional implications of RBC mitochondria retention in SCD, we used mitochondria inhibitors and metabolites/substrates from the tricarboxylic acid cycle, oxidative phosphorylation and glycolysis pathways (ADP, glutamate, malate, pyruvate, succinate or all metabolites combined) and examined RBC bioenergetics, reactive oxygen species (ROS) levels, calcium flux and hydration. In RBCs from sickle mice, mitochondria inhibition reduced ATP levels by 30%-60%, whereas control RBCs were unaffected. Conversely, in vitro treatment with metabolites/substrates known to stimulate mitochondria function increased RBC ATP levels and reduced RBC ROS, and these effects were notably more pronounced in sickle RBCs compared to those in control mice. In sickle RBCs, the increases in ATP and decreases in ROS were associated with greater decreases in RBC baseline calcium concentration and improvements in calcium flux. These changes also led to greater increases in RBC volume and hydration, and greater decreases in mean corpuscular haemoglobin concentration in sickle RBCs compared to control RBCs. These results propose a novel model of RBC metabolism in SCD, where retained mitochondria in circulating RBCs are functional and can significantly impact RBC bioenergetics, ATP production and RBC hydration and redox status. These in vitro findings could inform the development of in vivo strategies aimed at increasing RBC ATP, reducing RBC ROS, improving RBC hydration, which could decrease sickling and prove beneficial in SCD. KEY POINTS: Red blood cells (RBCs) from humans and mice with sickle cell disease (SCD) abnormally retain mitochondria. Mitochondria inhibitors lower ATP in circulating RBCs from sickle mice indicating that retained mitochondria contribute to ATP levels in sickle RBC. Metabolic stimulation of mitochondria function improves RBC bioenergetics, redox state and calcium flux, and increases RBC hydration. These data propose a new model of RBC metabolism in SCD, where in addition to glycolysis, retained mitochondria contribute to RBC ATP production. The effects of metabolic stimulation of RBCs resulting in improved RBC bioenergetics and hydration may prove beneficial in SCD.

In this study we have used a highly immersive virtual reality (VR) cycling environment where incongruence between virtual hill gradient (created by visual gradient and bike tilt angle) and actual workload (pedalling resistance) can experimentally manipulate perception of exercise effort. This therefore may provide a method to examine the role of effort perception in cardiorespiratory control during exercise. Twelve healthy untrained participants (7 men, age 26 ± 5 years) were studied during five visits. On visit 1 participants underwent cardiopulmonary exercise testing, and during subsequent visits (2-4) participants performed repeated hill climbs at different gradients (of 3%, 6% and 9% in counterbalanced order) with the actual workload 'congruent' with virtual hill gradient. On visit 5 participants completed three incongruent trials with virtual hill gradients of 3%, 6% and 9% but a fixed workload equal to that for the 6% climb (iVR3%, iVR6% and iVR9% trials). Despite no difference in power output, there was a significantly elevated rating of perceived exertion (RPE) and mean arterial blood pressure in iVR9% compared to iVR3% and iVR6%, although this effect decayed over time. There was no effect on any respiratory variable, and no significant reduction in RPE or cardiovascular responses was observed during the iVR3% trial. These data suggest that perception of effort and cardiovascular responses to exercise can be manipulated experimentally via virtual hill gradient (using visual and/or vestibular cues) in a VR environment. This work supports those previously showing the existence of a control mechanism which integrates perception of effort and the cardiovascular response to exercise in humans. KEY POINTS: We aimed to assess whether using a highly immersive virtual reality (VR) cycling environment to create incongruence between perceived effort (virtual hill gradient) and actual effort (pedal resistance) can manipulate cardiorespiratory responses to exercise. At an equivalent power output cycling up a steeper virtual hill produced greater ratings of perceived exertion (RPEs) and blood pressure responses compared to a virtual hill congruent to power output. This work suggests the existence of a control mechanism which integrates perception of exercise effort and the cardiovascular response to exercise, which can be experimentally manipulated by VR.

Robust preclinical models of asymmetric ventricular loading in late gestation reflecting conditions such as hypoplastic left heart syndrome are lacking. We characterized the morphometry and microvascular function of the hypoplastic left ventricle (LV) and remaining right ventricle (RV) in a sham-controlled late gestation fetal lamb model of impaired left ventricular inflow (ILVI). Singleton fetuses were instrumented at ∼120 days gestational age (dGA; term is ∼147 days) with vascular catheters, an aortic flow probe and a deflated left atrial balloon. Balloons in ILVI fetuses were inflated over the 8 day study until aortic output was eliminated; Sham balloons remained deflated. At the study end-point (∼134 dGA), cardiac function was assessed by echocardiography, microvascular perfusion of each free wall was measured by myocardial contrast echocardiography (MCE) and terminal morphometric data were collected. During the chronic study, flow through the ascending aorta of ILVI fetuses fell from 389 to -48 mL min^-1 with minimal changes to other haemodynamics or blood chemistry. End-point echocardiography and morphometry similarly showed significant and meaningful reductions in ILVI LV chamber volume and wall mass without statistically significant changes in RV size relative to Shams. MCE revealed modestly increased LV perfusion and profoundly increased RV perfusion in ILVI fetuses. Our model displays effective LV hypoplasia with preserved overall fetal health, and our finding of increased RV myocardial perfusion may indicate active vascular remodelling in response to the experimental lesion. KEY POINTS: Hypoplastic left heart syndrome can be caused by insufficient inflow of blood to the fetal left ventricle. We found that eliminating fetal left ventricular input for 8 days reduced left ventricular size and volume, with minimal effects on the right ventricle or overall fetal health. Blood and oxygen delivery increased significantly in the right ventricle and slightly in the hypoplastic left ventricle. Our results suggest functional and anatomical adaptation of the fetal coronary microvasculature to univentricular right heart conditions.

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental condition affecting a substantial number of children globally, characterized by diverse aetiologies, including genetic and environmental factors. Emerging research suggests that neurovascular dysregulation during development could significantly contribute to autism. This review synthesizes the potential role of vascular abnormalities in the pathogenesis of ASD and explores insights from studies on valproic acid (VPA) exposure during neural tube development. VPA, a widely used antiepileptic drug and mood stabilizer, crosses the placental barrier and impacts the developing fetal brain. Studies indicate that VPA disrupts normal angiogenesis by reducing the expression levels of vascular endothelial growth factor A (VEGFA) and its receptors, and purinergic signalling, which are crucial for both vascular and neural development. Such disruptions may lead to abnormalities in neuronal migration and pathfinding, potentially contributing to the neural and behavioural manifestations of ASD. Thus despite the relatively limited findings, improper vascularization of the neural tube appears to be a contributing factor in the pathogenesis of ASD, as also suggested by VPA studies. Integrating these insights, it is hypothesized that vascular factors should be considered in the aetiological analysis of idiopathic autism.

Both ageing and exercise training affect the neuromuscular junction (NMJ) structure. Morphological alterations in the NMJ have been considered to influence neuromuscular transmission and myofibre properties, but the direct link between the morphology and function has yet to be established. We measured the neuromuscular transmission, myofibre composition and NMJ structure of 5-month-old (young) and 24-month-old untrained (aged control) and trained (aged trained) mice. Aged trained mice were subjected to 2 months of endurance training before the measurement. Neuromuscular transmission was evaluated in vivo as the ratio of ankle plantar flexion torque evoked by the sciatic nerve stimulation to that by direct muscle stimulation. The torque ratio was significantly lower in aged mice than in young and aged trained mice at high-frequency stimulations, showing a significant positive correlation with voluntary grip strength. The degree of pre- to post-synaptic overlap of the NMJ was also significantly lower in aged mice and positively correlated with the torque ratio. We also found that the proportion of fast-twitch fibres in the soleus muscle decreased with age, and that age-related denervation occurred preferentially in fast-twitch fibres. Age-related denervation and a shift in myofibre composition were partially prevented by endurance training. These results suggest that age-related deterioration of the NMJ structure impairs neuromuscular transmission and alters myofibre composition, but these alterations can be prevented by structural amelioration of NMJ with endurance training. Our findings highlight the importance of the NMJ as a major determinant of age-related deterioration of skeletal muscles and the clinical significance of endurance training as a countermeasure. KEY POINTS: The neuromuscular junction (NMJ) plays an essential role in neuromuscular transmission and the maintenance of myofibre properties. We show that neuromuscular transmission is impaired with ageing but recovered by endurance training, which contributes to alterations in voluntary strength. Neuromuscular transmission is associated with the degree of pre- to post-synaptic overlap of the NMJ. Age-related denervation of fast-twitch fibres and a shift in myofibre composition toward a slower phenotype are partially prevented by endurance training. Our study provides substantial evidence that age-related and exercise-induced alterations in neuromuscular transmission and myofibre properties are associated with morphological changes in the NMJ.