Pflugers Archiv : European journal of physiology最新文献

Prolonged bed rest or microgravity exposure, as experienced during spaceflight, profoundly impacts cardiac health. Yet, the molecular mechanisms driving these detrimental changes remain largely elusive. Hindlimb unloading (HLU), a model of simulated microgravity, induces endoplasmic-reticulum (ER) stress, and its role in maladaptive cardiac remodeling remains unknown. To investigate the impact of HLU, its underlying molecular mechanisms and the therapeutic potential of ER stress suppression, C57BL6 mice were assigned to grounded control (GC) or HLU group. HLU mice received daily vehicle or 4-phenylbutyrate (4-PBA), an ER stress inhibitor, for 21 days. Additionally, HL-1 cardiomyocytes were treated with the ER stress inducer thapsigargin, with or without 4-PBA, to explore the cross-communication between ER stress and mitochondrial and metabolic dysfunction in vitro. Cardiac transcriptomic analysis revealed significant gene dysregulation in HLU compared to GC hearts. In HLU hearts, downregulated genes were mainly enriched for mitochondrial function and metabolic pathways, while upregulated genes were linked to extracellular matrix (ECM) pathways. Conversely, HLU mice treated with 4-PBA showed upregulation of mitochondrial function-related genes and downregulation of ECM-related genes. The oxidative phosphorylation (OXPHOS), which was downregulated in HLU hearts, became one of the most upregulated pathways following 4-PBA treatment. Consistent with the in vivo findings, thapsigargin-induced ER stress significantly compromised mitochondrial function, whereas co-treatment with 4PBA significantly preserved mitochondrial function. Together, our findings strongly suggest that prolonged bed rest or microgravity exposure triggers ER stress-induced mitochondrial and metabolic dysfunction in the heart, and pharmacological suppression of ER stress limits these detrimental cellular effects.

Obesity is a leading global health issue, closely associated with a chronic low-grade inflammation termed metaflammation. Metaflammation is driven by immune cell reprogramming, particularly of macrophages. In white adipose tissue (WAT), obesity induces a shift from anti-inflammatory to pro-inflammatory macrophage phenotypes, contributing to insulin resistance and tissue fibrosis. Recent studies have also illuminated the role of macrophages in brown and beige adipose tissue (BAT and scWAT), where they influence thermogenic capacity. Beyond the adipose tissue, the liver is the other main metabolic organ impacted by obesity. Liver macrophages play a critical role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) by promoting inflammation, lipid accumulation, and fibrosis. This review highlights the role of macrophages in the development and regulation of metaflammation in metabolic organs.

Human locomotion in water involves unique forces (buoyancy, drag) influencing metabolic cost. However, a validated model integrating these forces to predict the cost of transport (COT) during shallow water walking (SWW) is lacking, and energetic optimization strategies remain unclear compared to terrestrial gaits. We measured the COT in nine healthy men during SWW across four immersion depths (knee to xiphoid) and four walking speeds (0.2-0.8 m/s). We developed and validated a physiomechanical model based on the mechanical work done against buoyancy-affected body weight and hydrodynamic drag. Using this model, we compared the energetics of SWW with swimming and dry land walking (including hypogravity conditions) and analyzed self-selected walking speeds. The minimum COT occurred at hip immersion depth (0.2 m/s), rather than at intermediate speeds, with the J-shaped relationship observed only at knee immersion depth. Metabolic power, in contrast, remained relatively constant during self-selected walking across immersion depths. An immersion depth threshold near the center of mass emerged, above which swimming becomes more economical than SWW. Our physiomechanical model accurately predicted the measured COT. The interplay between buoyancy and drag dictates SWW energetics, shifting optimization away from intermediate speeds common on dry land. From a physiological perspective, these findings quantify the energetic consequences of human locomotor adaptation to the unique mechanical challenges posed by aquatic environments. Furthermore, identifying an immersion depth threshold influencing the economical choice between walking and swimming provides new insights into human aquatic locomotor adaptations.

The ion channel TRPV2 has multiple roles in immunology, cancer, cardiovascular function and pain signaling. However, only few endogenous modulators of TRPV2 have been described. The phospholipase A2 (PLA2)-derived lipid lysophosphatidylcholine (LPC) was demonstrated to induce pain and itch by activating sensory neurons, and it seems to be a direct agonist of TRPV4 and TRPC5. Although LPC was suggested to modulate TRPV2, the molecular mechanisms for this effect remain unclear. Here we used patch clamp and calcium imaging techniques to investigate if and how TRPV2 is modulated by LPC. Rat, mouse and human TRPV2 were not directly activated by LPC. Instead, 10 µM LPC induced a TRPV2-independent calcium influx and irreversible inward currents in HEK 293T cells. However, 3 µM LPC induced a reversible potentiation of membrane currents induced by 2-APB, cannabidiol (CBD), probenecid (PBC) and weak acids, but not to heat. This sensitization of TRPV2 was robust in whole cell experiments, but not in cell-free inside-out or outside-out patches. A disruption of the actin cytoskeleton with cytochalasin D, but also the depletion of cholesterol or sphingomyelin from the cell membrane diminished the potentiating effects of LPC on TRPV2. In conclusion, we present novel data describing that the PLA2 downstream signaling lipid LPC amplifies TRPV2-mediated responses via indirect mechanisms that seem to involve a destabilization of lipid rafts and the actin cytoskeleton.

The myogenic response is an important regulatory mechanism under physiological as well as pathophysiological conditions. However, little is known about the myogenic response under pulsatile pressure conditions. Therefore, based on the known mechanisms governing the myogenic response induced by static pressure, we tested the hypothesis that a stronger myogenic response induced by pulsatile pressure is due to a larger increase of the intracellular calcium concentration and/or a higher calcium sensitivity of vessel tone. Rat small tail and gracilis arteries were studied using isobaric myography and FURA-2 fluorimetry. We found that in small tail arteries, the effect of pulsatile pressure on the myogenic response is determined by its systolic pressure, whereas in gracilis arteries, the effect of pulsatile pressure is determined by its mean pressure. Interestingly, the effect of pulsatile pressure on the intracellular calcium concentration in both vessels is determined by its systolic pressure. However, while calcium sensitivity of myogenic tone did not differ between static and pulsatile pressure conditions in small tail arteries, it was weaker under pulsatile pressure than under static pressure in gracilis arteries. In conclusion, a stronger myogenic response under pulsatile pressure conditions, i.e., the capability of a vessel to respond to systolic pressure, requires the vessel's ability to maintain and not lose the calcium sensitivity of myogenic tone compared to static pressure conditions.

Melatonin, the pineal gland hormone, is produced in several extra-pineal tissues. The arylalkylamine N-acetyltransferase (AANAT) enzyme activity determines the overall rate of tissue melatonin synthesis. A decline in AANAT enzyme activity during acute amyloid-β (Aβ) neurotoxicity and reduced melatonin levels in Alzheimer's patients have been reported. These findings raise the question of whether brain melatonin synthesis is altered during cognitive decline. We investigated whether cognitive impairment induced by Aβ administration could affect the activation status of AANAT, a key hippocampal enzyme of melatonin synthesis. Male Wistar rats received intra-cerebroventricular Aβ injection. Two weeks after Aβ administration, the neuroinflammation was assessed by interleukin-1 (IL-1β) immunohistochemical staining. Hippocampal long-term potentiation (LTP) was evaluated using the technique of local field recording. The cognitive function was assessed using the Morris water maze behavioral test.The hippocampal AANAT activation status was assessed by Western blotting, and HPLC was used for melatonin level analysis. Aβ-induced spatial memory and LTP impairments were confirmed by increased escape latencies and alterations in the fEPSP slope. The Aβ provided a neuroinflammatory context, demonstrated by increased in the IL-1𝛽 staining. These alterations were accompanied by a reduction in the activation status of AANAT, as indicated by the p-AANAT/total AANAT ratio, in both the electrophysiology and behavioral experimental groups.These data suggest that the local activation status of AANAT may be contributed in the cognitive function of the hippocampus in a rodent model of cognitive decline induced by Aβ administration.

To evaluate the effects of a resistance training (RT) program applied during the development of MCT-induced pulmonary arterial hypertension (PAH) on skeletal muscle atrophy in rats. Twenty-one male Wistar rats were randomly distributed into three experimental groups (n = 7 per group): Sedentary Control (SC), Sedentary Hypertensive (SH), and Trained Hypertensive (TH). PAH was induced by a single intraperitoneal injection of monocrotaline (MCT; 60 mg/kg). Animals in the TH group underwent RT (vertical ladder; 15 climbs with 1-minute interval; 60% of the maximum load supported), 1 session/day, 5 days/week, for approximately 3 weeks. On the 24th day after injection, all animals were euthanized. Subsequently, the biceps brachii were removed, processed and destined for histological or biochemical analyses. RT increased the exercise tolerance (i.e., maximum load supported) in rats with PAH. In addition, RT prevented adverse remodeling in skeletal muscle by preserving the cross-sectional area of myocytes and attenuated total collagen deposition. Furthermore, RT reduced the gene expression of proteolytic agents (i.e., MuRF1, atrogin-1, and myostatin) and attenuated redox imbalance (i.e., CAT, NO, and CP). However, neither PAH nor RT influenced muscle hypertrophy pathways (i.e., Akt, phospo-Akt, eIF4E e phospo- eIF4E) in this model. The RT applied during the development of MCT-induced PAH protects against skeletal muscle atrophy, by mitigating adverse structural remodeling and atrophy through proteolysis modulation and attenuation of redox imbalance.

Chronic continuous hypoxia (CCH) demonstrates a pronounced protective effect in cardiac ischemia-reperfusion (IR). Opioids and opioid receptors play a significant role in this process. It has been previously shown that metabolic syndrome (MS) impairs the development of adaptive myocardial resistance to IR. The aim of this study is to identify the relationship between the cardioprotective effect of CCH and opioid peptides in circulating blood and myocardial tissue, as well as the expression of opioid receptors in the myocardium of rats with and without MS. All rats were subjected to coronary artery occlusion (45 min) and reperfusion (2 h). Some rats received high carbohydrate high fat diet for 90 days (MS) before IR. Some animals were exposed to CCH (21 days, 12% O₂) before IR. The plasma endomorphin-2, and dynorphin A levels were increased after CCH. Endomorphin-2, β-endorphin, dynorphin A (1-13), and met-enkephalin content in myocardial tissue was increased in response to CCH. In rats with MS, an increase in the plasma and myocardial opioid levels in response to CCH was reduced. A correlation was identified between plasma and myocardial tissue opioid peptide levels and the extent of myocardial injury, as well as between myocardial opioid peptide content and contractility. Furthermore, CCH and MS caused a reduction in the expression of δ- (DOR) and κ- (KOR) opioid receptors, and also an increase in µ- (MOR) opioid receptor expression. These findings suggest that a decrease in opioid peptide content could impair adaptive cardioprotection in MS.