Store-operated Ca2+ entry (SOCE), a ubiquitous mechanism that allows recovery of Ca2+ ions from the extracellular space, has been proposed to limit fatigue during repetitive skeletal muscle activity. However, the subcellular location for SOCE in muscle fibers has not been unequivocally identified. Here we show that exercise drives a significant remodeling of the sarcotubular system to form previously unidentified junctions between the sarcoplasmic reticulum (SR) and transverse-tubules (TTs). We also demonstrate that these new SR-TT junctions contain the molecular machinery that mediate SOCE: stromal interaction molecule-1 (STIM1), which functions as the SR Ca2+ sensor, and Orai1, the Ca2+-permeable channel in the TT. In addition, EDL muscles isolated from exercised mice exhibit an increased capability of maintaining contractile force during repetitive stimulation in the presence of 2.5 mM extracellular Ca2+, compared to muscles from control mice. This functional difference is significantly reduced by either replacement of extracellular Ca2+ with Mg2+ or the addition of SOCE inhibitors (BTP-2 and 2-APB). We propose that the new SR-TT junctions formed during exercise, and that contain STIM1 and Orai1, function as Ca2+ Entry Units (CEUs), structures that provide a pathway to rapidly recover Ca2+ ions from the extracellular space during repetitive muscle activity.

Exercise promotes the formation of intracellular junctions in skeletal muscle between stacks of sarcoplasmic reticulum (SR) cisternae and extensions of transverse-tubules (TT) that increase co-localization of proteins required for store-operated Ca2+ entry (SOCE). Here, we report that SOCE, peak Ca2+ transient amplitude and muscle force production during repetitive stimulation are increased after exercise in parallel with the time course of TT association with SR-stacks. Unexpectedly, exercise also activated constitutive Ca2+ entry coincident with a modest decrease in total releasable Ca2+ store content. Importantly, this decrease in releasable Ca2+ store content observed after exercise was reversed by repetitive high-frequency stimulation, consistent with enhanced SOCE. The functional benefits of exercise on SOCE, constitutive Ca2+ entry and muscle force production were lost in mice with muscle-specific loss of Orai1 function. These results indicate that TT association with SR-stacks enhances Orai1-dependent SOCE to optimize Ca2+ dynamics and muscle contractile function during acute exercise.

Abstract-Physiological hypertrophy represents the adaptive changes of the heart required for supporting the increased hemodynamic load in regularly trained healthy subjects. Mechanisms responsible for the athlete's hypertrophy still remain unknown. In 15 trained competitive soccer players and in 15 healthy men not engaged in sporting activities (sedentary control subjects) of equivalent age, we investigated the relationship among cardiac growth factor formation, cardiac sympathetic activity, and left ventricular morphology and function. Cardiac formation of insulin-like growth factor (IGF)-I, endothelin (ET)-1, big ET-1, and angiotensin (Ang) II was investigated at rest by measuring artery-coronary sinus concentration gradients. Cardiac sympathetic activity was studied by [ 3 H]norepinephrine (NE) kinetics. Cardiac IGF-I, but not ET-1, big ET-1, and Ang II, formation was higher in athletes than in control subjects (PϽ0.01). NE levels in arterial and peripheral venous blood did not differ between groups. In contrast, coronary sinus NE concentration was higher in athletes than in control subjects (PϽ0.01). Cardiac, but not total systemic, NE spillover was also increased in athletes (PϽ0.01), whereas cardiac [ 3 H]NE reuptake and clearance were not different. Echocardiographic modifications indicated a volume overload-induced hypertrophy associated with increased myocardial contractility. Multivariate stepwise analysis selected left ventricular mass index as the most predictive independent variable for cardiac IGF-I formation and velocity of circumferential fiber shortening for cardiac NE spillover. In conclusion, increased cardiac IGF-I formation and enhanced sympathetic activity selectively confined to the heart appear to be responsible for the physiological hypertrophy in athletes performing predominantly isotonic exercise. Key Words: insulin-like growth factor-I Ⅲ norepinephrine Ⅲ sympathetic nervous system Ⅲ exercise Ⅲ hypertrophy, left ventricular T he heart sustains an increased hemodynamic load by adjusting its mass independently of whether the enhanced workload is due to physiological activity or to pathological alterations in the cardiovascular system. There is much evidence that the development of myocardial hypertrophy results from the interaction of mechanical forces (the increased workload) and cardiac growth factors. The hemodynamic overload leads to myocardial cellular stretch and strain that in turn induce gene expression of cardiac growth factors. 1,2 In regularly trained healthy subjects, both isotonic and isometric exercise cause cardiac changes resulting in modifications of the ventricular chambers and in a notable enhancement of heart performance. These modifications, called physiological hypertrophy or athlete's hypertrophy, are required for sustaining the tremendous increase in cardiac output during exercise. Cardiac growth factors involved in the development of physiological hypertrophy in humans are still unknown, and their knowledge might also be relevant for better understanding the mech...

Right ventricular pacing worsens LV function in patients with and without LV dysfunction unless the RV pacing site is optimized. Left ventricular and BiV pacing preserve LV function in patients with EF >40% and improve function in patients with EF <40% despite no clinical indication for BiV pacing.