The Journal of physiology
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The Journal of physiology · Sep 2020
Desmin prevents muscle wasting, exaggerated weakness and fragility, and fatigue in dystrophic mdx mouse.
Desmin, similar to dystrophin, is associated with costameric structures bridging sarcomeres to the extracellular matrix. Deletion of the desmin gene in mdx mice [double knockout (DKO) mice] induces marked muscle weakness and fatigue resistance compared to mdx mice. Muscle fragility (higher susceptibility to contraction-induced injury) was also aggravated in DKO mice compared to mdx mice. By contrast to mdx mice, the DKO mice did not undergo muscle hypertrophy. Desmin cDNA transfer with adeno-associated virus in newborn mdx mice reduced muscle weakness. Overall, desmin plays important and beneficial roles in muscle wasting, performance and fragility in dystrophic muscle. ⋯ Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease caused by dystrophin deficiency. Desmin, similar to dystrophin, is associated with costameric structures bridging sarcomeres to the extracellular matrix that contributes to muscle function. In the present study, we attempted to provide further insight into the roles of desmin, for which the expression is increased in the muscle from the mouse mdx DMD model. We show that a deletion of the desmin gene (Des) in mdx mice [double knockout (DKO) mice, mdx:desmin-/-] induces a marked muscle weakness; namely, a reduced absolute maximal force production and increased fatigue compared to that in mdx mice. Fragility (i.e. higher susceptibility to contraction-induced injury) was also aggravated in DKO mice compared to mdx mice, despite the promotion of supposedly less fragile muscle fibres in DKO mice, and this worsening of fragility was related to a decreased muscle excitability. Moreover, in contrast to mdx mice, the DKO mice did not undergo muscle hypertrophy, as indicated by smaller and fewer fibres, with a reduced percentage of centronucleated fibres, potentially explaining the severe muscle weakness. Notably, Desmin cDNA transfer with adeno-associated virus in newborn mdx mice improved specific maximal force normalized to muscle weight. Overall, desmin plays important and beneficial roles in muscle wasting, performance and fragility in dystrophic mdx mice, which differ, at least in part, from those observed in healthy muscle.
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The Journal of physiology · Sep 2020
Modulation of Kv3.1/Kv3.2 promotes gamma oscillations by rescuing Aβ-induced desynchronization of fast-spiking interneuron firing in an AD mouse model in vitro.
Gamma oscillations (30-80 Hz) are important for cognitive functions and depend on the synchronized activity of fast-spiking interneurons (FSN), which is crucial for network stability. Gamma oscillations are degraded in Alzheimer's disease (AD) patients exhibiting cognitive impairment, with the degree of cognitive decline correlating with the severity of gamma disruption in response to neurotoxic amyloid-beta peptide (Aβ). Small molecule compounds EX15 and RE01 modulate Kv3.1/Kv3.2 potassium channels on FSN, resulting in faster activation kinetics and increased firing frequency, suggesting direct consequences for cognition-relevant gamma oscillations, particularly in a situation where network activity is pathologically compromised in the presence of neurotoxic Aβ. Using electrophysiological techniques in an in vitro AD model, we found a significant effect of EX15 and RE01 with respect to counteracting toxic Aβ effects on neuronal dynamics, advocating for targeting FSN activity to rescue cognitive performance from impairment caused by neurodegenerative triggers. ⋯ Rhythmic electrical activity in neuronal networks such as gamma oscillations (30-80 Hz) underlies cognitive functions such as sensory perception, attention and memory. Gamma oscillations are disrupted in Alzheimer's disease (AD) patients and animal AD models, with the severity of cognitive decline correlating with the degree of rhythm disruption. Misfolded amyloid-β peptide (Aβ) is assumed to be a key trigger of AD pathology and has been show to de-synchronize action potential firing in fast-spiking interneurons (FSN), which is crucial for entraining neuronal network activity into the gamma rhythm. The synchronizing activity of FSN therefore has become one of the most suitable targets to counteract disease-driven degradation of gamma oscillations and consequent cognitive decline. EX15 and RE01 are small-molecule compounds that modulate Kv3.1/Kv3.2 potassium channels, resulting in faster activation kinetics and increased FSN firing frequency. In the present study, we investigated the potential pro-cognitive effects of EX15 and RE01 by testing their ability to modulate FSN activity during ongoing gamma oscillations in normal and Aβ-disrupted network states in mouse hippocampus in vitro. In the compromised, but not the uncompromised, network state with gamma oscillations partially disrupted by Aβ, both compounds improve gamma oscillation regularity by promoting re-synchronization of FSN action potential firing. Our data suggest a therapeutic potential for compounds such as EX15 and RE01, which can rescue normal action potential firing parameters in FSN, in the search for disease-modifying drug candidates counteracting the progressive dysfunction of neuronal network dynamics that underlies the cognitive impairment typical of AD and other cognitive brain disorders.
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The Journal of physiology · Sep 2020
Cardiovascular and cerebrovascular responses to cardio-respiratory events in preterm infants during the transitional period.
Non-invasive simultaneous multiparametric monitoring allows the in vivo evaluation of cerebral and cardiovascular haemodynamic responses to different types of recurrent episodes of intermittent hypoxia and/or bradycardia, also defined as cardio-respiratory events (CRE), in preterm neonates during postnatal transition. By decreasing left cardiac output, bradycardia further contributes to cerebral hypoxia during CRE. The presence of a haemodynamically significant patent ductus arteriosus results in a deeper impairment of cerebral oxygen status in response to CRE, whereas the brain-sparing remodelling of the fetal circulation resulting from placental insufficiency is associated with more favourable haemodynamic responses to intermittent hypoxia. During transition, the haemodynamic impact of CRE is influenced not only by the event type, but also by specific clinical features; this highlights the importance of developing individualized approaches to reduce the hypoxic burden in this delicate phase. ⋯ The present observational prospective study aimed to investigate cerebral and cardiovascular haemodynamic responses to different types of cardio-respiratory events (CRE) in preterm infants during postnatal transition, as well as evaluate the impact of relevant clinical characteristics. Infants with gestational age (GA) <32 weeks and/or birth weight <1500 g were enrolled after birth. Cerebral oxygenation index (cTOI), fractional oxygen extraction (cFTOE), cardiac output (CO), cardiac contractility (iCON) and systemic vascular resistances (sVR) were simultaneously monitored over the first 72 h by near-infrared spectroscopy and electrical velocimetry. CRE were clustered into isolated bradycardia (IB), isolated desaturation (ID) and combined desaturation/bradycardia (DB). For each parameter, percentage changes from baseline (%Δ) were calculated. The impact of different CRE types and clinical variables on %Δ was evaluated with generalized estimating equations. In total, 1426 events were analysed. %ΔcTOI significantly differed among ID, IB and DB (P < 0.001), with the latter showing the greatest drop. %ΔcFTOE decreased significantly during DB (P < 0.001) and ID (P < 0.001) compared to IB. DB and IB were associated with more negative %ΔCO (P < 0.001) and more positive %ΔsVR (P < 0.001) compared to ID. A slight iCON reduction was observed during DB compared to ID (P = 0.043). Antenatal umbilical Doppler impairment, GA and the presence of a haemodynamically significant patent ductus arteriosus had a significant independent impact on %ΔcTOI, %ΔcFTOE and %ΔCO. During the transitional period, the haemodynamic responses to CRE are influenced by the event type and by specific neonatal characteristics, suggesting the importance of targeted individualized approaches for minimizing the risk of cerebral injury in the preterm population.
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The Journal of physiology · Sep 2020
Greater exercise tolerance in COPD during acute interval, compared to equivalent constant-load, cycle exercise: physiological mechanisms.
Exercise intolerance is common in chronic obstructive pulmonary disease (COPD) patients. In patients with COPD, we compared an interval exercise (IE) protocol (alternating 30 s at 100% peak work rate (WRpeak ) with 30 s at 50% WRpeak ) with moderate-intensity constant-load exercise (CLE) at 75% WRpeak , which yielded the same work rate. Exercise endurance time and total work output were almost twice as high for IE than CLE. At exercise isotime (when work completed was the same between IE and CLE), IE was associated with less dynamic hyperinflation, lower blood lactate concentration, and greater respiratory and locomotor muscle oxygenation, but there were no differences in ventilation or cardiac output. However, at the limit of tolerance for each modality, dynamic hyperinflation was not different between IE and CLE, while blood lactate remained lower and muscle oxygenation higher with IE. Taken together, these findings suggest that dynamic hyperinflation and not muscle-based factors dictate the limits of tolerance in these COPD patients. ⋯ The relative importance of ventilatory, circulatory and peripheral muscle factors in determining tolerance to exercise in patients with chronic obstructive pulmonary disease (COPD) is not known. In 12 COPD patients (forced expiratory volume in one second: 58 ± 17%pred.) we measured ventilation, cardiac output, dynamic hyperinflation, local muscle oxygenation, blood lactate and time to exhaustion during (a) interval exercise (IE) consisting of 30 s at 100% peak work rate alternating with 30 s at 50%, and (b) constant-load exercise (CLE) at 75% peak work rate, designed to produce the same average work rate. Exercise time was substantially longer during IE than CLE (19.5 ± 4.8 versus 11.4 ± 2.1 min, p = 0.0001). Total work output was therefore greater during IE than CLE (81.3 ± 27.7 versus 48.9 ± 23.8 kJ, p = 0.0001). Dynamic hyperinflation (assessed by changes from baseline in inspiratory capacity, ΔIC) was less during IE than CLE at CLE exhaustion time (isotime, p = 0.009), but was similar at exhaustion (ΔICCLE : -0.38 ± 0.10 versus ΔICIE : -0.33 ± 0.12 l, p = 0.102). In contrast, at isotime, minute ventilation, cardiac output and systemic oxygen delivery did not differ between protocols (P > 0.05). At exhaustion in both protocols, the vastus lateralis and intercostal muscle oxygen saturation were higher in IE than CLE (p = 0.014 and p = 0.0002, respectively) and blood lactate concentrations were lower (4.9 ± 2.4 mmol l-1 versus 6.4 ± 2.2 mmol l-1 , p = 0.039). These results suggest that (1) exercise tolerance with COPD is limited by dynamic hyperinflation; and (2) cyclically lower (50%) effort intervals in IE help to preserve muscle oxygenation and reduce metabolic acidosis compared with CLE at the same average work rate; but these factors do not appear to determine time to exhaustion.