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Abstract-We sought to understand the effect of a transient exposure of cardiac myocytes to H 2 O 2 at a concentration that did not induce apoptosis. Myocytes were exposed to 30 mol/L H 2 O 2 for 5 minutes followed by 10 U/mL catalase for 5 minutes to degrade the H 2 O 2 . Cellular superoxide was measured using dihydroethidium. Transient exposure to H 2 O 2 caused a 66.4% increase in dihydroethidium signal compared with controls exposed to only catalase, without activation of caspase 3 or evidence of necrosis. The increase in dihydroethidium signal was attenuated by the mitochondrial inhibitors myxothiazol or carbonyl cyanide p-(trifluoromethoxy)phenyl-hydrazone and when calcium uptake by the mitochondria was inhibited with Ru360. We investigated the L-type Ca 2ϩ channel (I Ca-L ) as a source of calcium influx. Nisoldipine, an inhibitor of I Ca-L , attenuated the increase in superoxide. Basal channel activity increased from 5.4 to 8.9 pA/pF. Diastolic calcium was significantly increased in quiescent and contracting myocytes after H 2 O 2 . The response of I Ca-L to ␤-adrenergic receptor stimulation was used as a functional reporter because decreasing intracellular H 2 O 2 alters the sensitivity of I Ca-L to isoproterenol. H 2 O 2 increased the K 0.5 required for activation of I Ca-L by isoproterenol from 5.8 to 27.8 nmol/L. This effect and the increase in basal current density persisted for several hours after H 2 O 2 . We propose that extracellular H 2 O 2 is associated with an increase in superoxide from the mitochondria caused by an increase in Ca R eactive oxygen species (ROS) can act as signaling molecules able to stimulate and modulate a variety of biochemical and genetic systems, including the regulation of signal transduction pathways, gene expression, proliferation, and cell death by apoptosis. 1 The regulation of signaling pathways by hydrogen peroxide (H 2 O 2 ) and superoxide has been linked to the development of various cardiovascular diseases including ischemic heart disease, hypertension, cardiomyopathies, cardiac hypertrophy, and congestive heart failure. [2][3][4] Mitochondria play an integral role in cellular metabolism and oxidative phosphorylation but are also a source of superoxide and an important determinant of the fate of a cell. Increased ROS production by mitochondria has been reported after exposing mitochondria to ROS in cardiac myocytes. 5,6 The synchronized release of ROS by the mitochondria has been shown to induce oscillations in action-potential duration and life-threatening postischemic arrhythmias. 5,7,8 A persistent increase in intracellular ROS is associated with pathological remodeling and myocardial dysfunction. 2,4,9 It has been suggested that increases in mitochondriaderived ROS are attributable to a direct effect of ROS on mitochondrial function. 5,6 Another possible explanation for increased production of ROS by the mitochondria is enhanced Ca 2ϩ uptake attributable to altered L-type Ca 2ϩ channel (I Ca-L ) function. It is reasonable to postulate an involvement of the ch...

Thus, in addition to the known effects on cortical excitability and synaptic plasticity, our data demonstrate that LI-rMS can change the survival and structural complexity of neurons. These findings provide a cellular and molecular framework for understanding what low intensity magnetic stimulation may contribute to human rTMS outcomes.

The molecular roles of the dually targeted ElaC domain protein 2 (ELAC2) during nuclear and mitochondrial RNA processing have not been distinguished. We generated conditional knockout mice of ELAC2 to identify that it is essential for life and its activity is non-redundant. Heart and skeletal muscle-specific loss of ELAC2 causes dilated cardiomyopathy and premature death at 4 weeks. Transcriptome-wide analyses of total RNAs, small RNAs, mitochondrial RNAs, and miRNAs identified the molecular targets of ELAC2 We show that ELAC2 is required for processing of tRNAs and for the balanced maintenance of C/D box snoRNAs, miRNAs, and a new class of tRNA fragments. We identify that correct biogenesis of regulatory non-coding RNAs is essential for both cytoplasmic and mitochondrial protein synthesis and the assembly of mitochondrial ribosomes and cytoplasmic polysomes. We show that nuclear tRNA processing is required for the balanced production of snoRNAs and miRNAs for gene expression and that 3' tRNA processing is an essential step in the production of all mature mitochondrial RNAs and the majority of nuclear tRNAs.