Current knowledge on store-operated Ca²⁺ entry (SOCE) regarding its localization, kinetics, and regulation is mostly derived from studies performed in non-excitable cells. After a long time of relative disinterest in skeletal muscle SOCE, this mechanism is now recognized as an essential contributor to muscle physiology, as highlighted by the muscle pathologies that are associated with mutations in the SOCE molecules STIM1 and Orai1. This review mainly focuses on the peculiar aspects of skeletal muscle SOCE that differentiate it from its counterpart found in non-excitable cells. This includes questions about SOCE localization and the movement of respective proteins in the highly organized skeletal muscle fibers, as well as the diversity of expressed STIM isoforms and their differential expression between muscle fiber types. The emerging evidence of a phasic SOCE, which is activated during EC coupling, and its physiological implication is described as well. The specific issues related to the use of SOCE modulators in skeletal muscles are discussed. This review highlights the complexity of SOCE activation and its regulation in skeletal muscle, with an emphasis on the most recent findings and the aim to reach a current picture of this mesmerizing phenomenon.

Alterations in cardiac impulse conduction may exert both beneficial and detrimental effects. The assessment of ventricular conduction properties is of paramount importance both in clinical and in experimental settings. Currently the duration of the QRS complex is regarded as hallmark of in-vivo assessment of global ventricular conduction time. In addition, the amplitude of the QRS complex has been suggested to reflect ventricular con-duction time in man and in rats. Here, for the first time, we systematically investigated the relationship between QRS duration ("QRS") and QRS amplitude ("RS-height"; RSh) in the murine ECG obtained during anesthesia. In mice harbouring a homozygous knockout of the transmembrane protein podoplanin (PDPN-/-; n = 10) we found both a shorter QRS and a greater RSh than in wild-type animals (n = 13). In both genotypes cumulative i.p. administration of 5 mg/kg and 10 mg/kg of the Na channel blocker flecainide resulted in dose-dependent QRS increase and RSh decrease, whereby the drug-induced changes in RSh were greater than in QRS. In both ge-notypes the flecainide-induced changes in QRS and in RSh were significantly correlated with each other (R =-0.56, P = 0.004). Whereas dispersion of QRS and RSh was similar between genotypes, dispersion of the ratio QRS/RSh was significantly smaller in PDPN-/-than in wild-types. We conclude that in the murine ECG QRS is inversely related to RSh.We suggest that both parameters should be considered in the analysis of ventricular conduction time in the murine ECG.

Aim: This study investigates the activation and regulation of phasic store‐operated calcium entry (pSOCE) in fast‐ and slow‐twitch skeletal muscle fibers. Specifically, we aimed to enhance the sensitivity of pSOCE detection in slow‐twitch fibers by optimizing ionic conditions and to compare the physiological relevance of pSOCE between fiber types.Methods: We employed mechanically skinned fast‐twitch extensor digitorum longus (EDL) muscle fibers loaded with spectrally distinct Ca²⁺‐sensitive dyes to simultaneously measure action potential‐induced sarcoplasmic reticulum Ca²⁺ release and t‐tubular system Ca²⁺ dynamics with millisecond resolution. Experimental conditions were optimized by reducing cytosolic Mg²⁺ and EGTA buffering to enhance Ca²⁺ release in slow‐twitch soleus fibers. Confocal microscopy was used to track t‐tubular system Ca²⁺ depletion and reuptake during electric field stimulation.Results: Skinned soleus fibers exhibited ~8‐fold lower Ca²⁺ release per action potential compared to EDL fibers, yet pSOCE amplitudes were comparable. Reducing Mg²⁺ and EGTA levels increased Ca²⁺ release and left pSOCE kinetics in EDL fibers unaltered, but enabled pSOCE measurements in soleus fibers. While pSOCE in EDL fibers followed a linear dependence on the ambient Ca²⁺ concentration in the t‐tubular system, such a relationship was violated in soleus fibers.Conclusion: These findings reveal a novel, fiber‐type‐specific difference in pSOCE regulation. When compared to EDL fibers, soleus fibers exhibited a higher sensitivity to SOCE activation despite releasing less Ca²⁺ from the sarcoplasmic reticulum upon an action potential. These differences may allow soleus fibers to sustain Ca²⁺ homeostasis more effectively, be more resilient against disruptions in Ca²⁺ handling, and entail protection against disease states.

The endocannabinoid system (ECS) is known to regulate crucial bodily functions, including healthy muscle activity. However, its precise roles in normal skeletal muscle function and the development of muscle disorders remain unclear. Previously, we developed a tamoxifen-inducible, skeletal muscle-specific CB₁ receptor knockdown (skmCB1-KD) mouse model using the Cre/LoxP system. In this study, we aimed to clarify the mechanisms behind the observed reduction in muscle force generation in these mice. To investigate this, we analyzed calcium dynamics following electrical stimulation-induced muscle fatigue, assessed store-operated calcium entry (SOCE), and performed functional analysis of mitochondrial respiration. Our findings suggest that the reduced muscle performance observed in vivo likely arises from interconnected alterations in ATP production by mitochondria. Moreover, in skmCB1-KD mice, we detected a significant decrease in a component of the respiratory chain (complex IV) and a slowed dissipation of mitochondrial membrane potential upon the addition of an un-coupler (FCCP).

T-type Ca channels are strongly expressed and important in the developing heart. In the adult heart, these channels play a significant role in pacemaker tissues, but there is uncertainty about their presence and physiological relevance in the working myocardium. Here, we show that the T-type Ca channel isoforms Cav3.1 and Cav3.2 are expressed at a protein level in ventricular cardiomyocytes from healthy adult C57/BL6 mice. Myocytes isolated from adult wild-type and Cav3.2 KO mice showed considerable whole cell T-type Ca currents under beta-adrenergic stimulation with isoprenaline. We further show that the detectability of basal T-type Ca currents in murine wild-type cardiomyocytes depends on the applied experimental conditions. Together, these findings reveal the presence of functional T-type Ca channels in the membrane of ventricular myocytes. In addition, electrically evoked Ca release from the sarcoplasmic reticulum was significantly impaired in Cav3.2 KO compared to wild-type cardiomyocytes. Our work implies a physiological role of T-type Ca channels in the healthy adult murine ventricular working myocardium.

The endocannabinoid system (ECS) regulates and controls many of our most critical bodily functions including healthy muscles however, its potential role(s) in physiological skeletal muscle function and its disorders are unclear. Earlier using the Cre/LoxP system we generated and characterized a tamoxifen-inducible skel-etal muscle-specific CB1R knockdown (skmCB1-KD) mouse model. Here, we sought to elucidate the mechanisms underlying reduced muscle force generation. To address this, we measured calcium movements following electrical stimula-tion-induced muscle fatigue, evaluated store-operated calcium entry (SOCE), and conducted functional analysis of respiring mitochondria. Based on our measure-ments, it is likely that the reduced muscle performance recorded in vivo may oc-cur due to complementary changes in ATP production by mitochondria. Further-more, in skmCB1-KD mice, we observed a significant decrease in one component of the respiratory chain and a delayed mitochondrial membrane potential dissipa-tion upon the application of an un-coupler.