Pflugers Archiv : European journal of physiology最新文献

In muscle fibers, unloading and disuse cause an increase in resting calcium concentrations in the cytosol and mitochondrial matrix. S107, a stabilizer of the Ryanodine Receptor calcium channel (RyR), blocks the leakage from the sarcoplasmic reticulum and lowers mitochondrial calcium concentrations without altering cytosolic calcium levels, as demonstrated in a recent article published in Pflugers Archives (Sidorenko et al. 2025). This finding is important as it shows that, even at rest, calcium entry into the mitochondria is influenced by RyR leakage, thanks to the mitochondria unique location near the sarcoplasmic reticulum membranes. Given the role of mitochondrial function in controlling muscle fiber size, these findings may have a significant translational relevance in the treatment of disuse-induced atrophy.

During periods of muscle disuse, calcium accumulates in the myoplasm of slow-tonic muscle fibers, leading to multiple negative consequences for muscle function. Leaky ryanodine receptors (RyRs) could contribute to this excessive accumulation of calcium. We hypothesized that the administration of S-107, a stabilizer of RyRs, would reduce the accumulation of calcium in the myoplasm/mitochondria and improve rat soleus muscle function during disuse. Male Wistar rats underwent 7 days of hindlimb suspension (HS), receiving S-107 in their food daily throughout the experiment. Seven days of HS led to cytosolic and mitochondrial calcium accumulation, enhanced mitochondrial respiration, and reduced mitochondrial biogenesis in the soleus muscle. This was accompanied by reductions in the proportion of slow-type myofibres, maximal isometric force, and fatigue resistance. Administering S-107 during HS prevented the accumulation of calcium in the mitochondria and the overactivation of mitochondrial respiration. It also attenuated the decline in markers of mitochondrial biogenesis and the decrease in fatigue resistance. S-107 treatment also partially prevented the decline in the soleus muscle force production but had only a minor effect on myoplasmic calcium accumulation. Our findings suggest that the destabilization of RyRs during muscle disuse leads to an accumulation of calcium in both the mitochondria and the myoplasm, which in turn causes a decline in muscle strength and resistance to fatigue.

During pregnancy and weaning, the intestinal tract undergoes adaptations on different levels, including altered immune cell frequencies and epithelial changes. We could show in a mouse model that the overall area (crypt-villus axis length and total length) of the small intestine increased during this period of higher maternal nutrient need and that the increased area correlated with maternal weight. Quantification of cell proliferation and cell death showed an increased proliferation of epithelial cells in the lower and middle crypt. In cell culture, estriol maintained epithelial cell proliferation and progesterone-inhibited proliferation. Further, Hippo signaling is a well-known pro-proliferative pathway which integrates several upstream signals and ultimately leads to nuclear translocation of the transcription factor YAP. In the small intestine, YAP is expressed in epithelial cells, immune cells, and fibroblasts. During pregnancy and weaning, epithelial and stroma cells exhibit strong nuclear staining of YAP. Interestingly, estriol led to upregulation and increased nuclear shuttling of YAP in intestinal epithelial cell monolayers. This effect appears to be specific to the estriol treatment since the established pro-proliferative cytokine GLP-2 did not lead to increased nuclear shuttling of YAP.

Post-occlusive reactive hyperemia (PORH) is a physiological response marked by a transient increase in microvascular perfusion following ischemia. While cutaneous perfusion during PORH has been extensively characterized using optical approaches such as Doppler-based techniques, low-cost alternatives like photoplethysmography (PPG), videocapillaroscopy (VC) and near-infrared reflectance imaging (NIRI) may provide complementary insights into both microvascular and venous dynamics. However, their role in quantifying PORH remains underexplored. This study aimed to evaluate the potential of low-magnification VC and NIRI-based imaging for quantifying perfusion changes during a standardized PORH protocol in healthy subjects, using PPG as a reference. Fourteen participants (21.5 ± 4.2 years) underwent suprasystolic occlusion of a randomly selected upper limb, with simultaneous recordings using PPG and VC at the finger and NIRI at the dorsal hand veins. The protocol included a 5-min baseline, 3-min occlusion (200 mmHg), and 5-min recovery. Skin blood flow was derived from the PPG signal, a hemoglobin index (C_Hb) was extracted from VC images, and vein width was measured using NIRI. Nonparametric statistics were used for analysis. Arterial occlusion significantly reduced skin blood flow (-95.3%, p < 0.001) and C_Hb (-8.3%, p = 0.007), with milder contralateral changes. Vein width increased during occlusion (p = 0.003) and returned to baseline during recovery. VC was less sensitive than PPG but reproduced the expected hemodynamic profile. A positive correlation was found between venous dilation during recovery and the decrement velocity of microvascular perfusion during occlusion. VC and NIRI represent accessible and complementary tools for assessing vascular responses during PORH. Their combined application may enhance non-invasive vascular evaluation in both clinical and research settings.

Cardiovascular function depends on an adequate vascular tone facilitating appropriate blood flow to individual tissues according to their needs. The tone results from the interplay between vasodilatation and vasoconstriction. Its rapid and efficient regulation is secured by many interconnected physiological mechanisms, both at the level of the vascular smooth muscle and the endothelium. The purpose of this review is to provide an update of the current knowledge on the mechanisms of physiological vasodilatation. First, two principal intracellular signaling pathways linked to the activation of protein kinases PKA and PKG are introduced. Subsequently, the role of endothelium-derived relaxing factors together with the endothelium-dependent hyperpolarization is discussed. The roles of ion channels and gap junctions in the communication between endothelium and vascular smooth muscle cells are particularly discussed. Finally, principal vasodilatory stimuli (mechanical, thermal, chemical) and their mechanisms of action are briefly introduced.

Voltage-gated Na⁺ channels (VGSCs) are recognized for their roles in cancer biology, particularly in promoting tumor aggressiveness. However, their presence and functional significance in early-stage breast cancer remain poorly understood. This study investigates the physiological role of VGSCs in breast cancer progression, focusing on their contribution to metastatic potential and their promise as novel therapeutic targets. To address these issues, we examined VGSCs expression and electrophysiological properties in two primary breast tumor cell lines, MACL-1 and MGSO-3, using patch-clamp whole-cell recordings. Both exhibited fast inward currents, peaking near 0 mV, which were abolished by extracellular Na⁺ removal, confirming that inward current was due to the presence of VGSCs. Pharmacological inhibition with tetrodotoxin (TTX, 100 nM) showed that MACL-1 cells exclusively express TTX-sensitive VGSCs, while MGSO-3 cells express both TTX-sensitive and -resistant VGSCs. In contrast, non-tumoral MCF-10A breast cells, although they express VGSCs, showed no detectable inward Na⁺ current. Despite having similar Na⁺ current activation properties, the Na⁺ current in MGSO-3 cells exhibited slower inactivation kinetics compared to MACL-1 cells, suggesting functional heterogeneity. However, neither TTX nor anemone toxin (ATX) influenced proliferation or migration, challenging the established link between VGSCs and tumor aggressiveness in early-stage breast cancer. Immunocytochemistry revealed the presence of Nav1.5 (a TTX-resistant VGSC isoform), Nav1.6, and Nav1.7 (TTX-sensitive VGSCs isoforms) in both non-tumoral and tumoral cells, with these isoforms localized to different intracellular compartments, raising questions about their regulatory roles.

Tissue perfusion is acutely regulated by the changes in the vascular tone resulting in vasodilatation or vasoconstriction (there are also long-term changes in tissue perfusion, effectively accomplished by vascular remodeling). Even though vasodilatation predominates under physiological conditions, vasoconstriction represents an essential part of normal vascular physiology. The process of vasoconstriction is very complex, being influenced by many mediators, some of which are produced by the adjacent endothelial cells. The purpose of this review is to provide an overview of the machinery of vasoconstriction addressing the main components. First, the role of calcium is discussed including its intracellular and extracellular sources, its principal function in smooth muscle contraction machinery and mechanisms counteracting its effects. Subsequently, protein kinase C is included with its activation, effects and feedback. The role of RhoA/ROCK system is addressed in a similar way. The next section deals with the role of vascular endothelium-derived contracting factors and their effects on the adjacent smooth muscle cells. Finally, principal mechanisms of action of vasoconstrictive stimuli and myogenic tone are concisely discussed.