Acute RyR1 Ca2+ leak enhances NADH-linked mitochondrial respiratory capacity

Sustained ryanodine receptor (RyR) Ca2+ leak is associated with pathological conditions such as heart failure or skeletal muscle weakness. We report that a single session of sprint interval training (SIT), but not of moderate intensity continuous training (MICT), triggers RyR1 protein oxidation and nitrosylation leading to calstabin1 dissociation in healthy human muscle and in in vitro SIT models (simulated SIT or S-SIT). This is accompanied by decreased sarcoplasmic reticulum Ca2+ content, increased levels of mitochondrial oxidative phosphorylation proteins, supercomplex formation and enhanced NADH-linked mitochondrial respiratory capacity. Mechanistically, (S-)SIT increases mitochondrial Ca2+ uptake in mouse myotubes and muscle fibres, and decreases pyruvate dehydrogenase phosphorylation in human muscle and mouse myotubes. Countering Ca2+ leak or preventing mitochondrial Ca2+ uptake blunts S-SIT-induced adaptations, a result supported by proteomic analyses. Here we show that triggering acute transient Ca2+ leak through RyR1 in healthy muscle may contribute to the multiple health promoting benefits of exercise

Envenomations by Bothrops and Crotalus Snakes Induce the Release of Mitochondrial Alarmins

Skeletal muscle necrosis is a common manifestation of viperid snakebite envenomations. Venoms from snakes of the genus Bothrops, such as that of B. asper, induce muscle tissue damage at the site of venom injection, provoking severe local pathology which often results in permanent sequelae. In contrast, the venom of the South American rattlesnake Crotalus durissus terrificus, induces a clinical picture of systemic myotoxicity, i.e., rhabdomyolysis, together with neurotoxicity. It is known that molecules released from damaged muscle might act as ‘danger’ signals. These are known as ‘alarmins’, and contribute to the inflammatory reaction by activating the innate immune system. Here we show that the venoms of B. asper and C. d. terrificus release the mitochondrial markers mtDNA (from the matrix) and cytochrome c (Cyt c) from the intermembrane space, from ex vivo mouse tibialis anterior muscles. Cyt c was released to a similar extent by the two venoms whereas B. asper venom induced the release of higher amounts of mtDNA, thus reflecting hitherto some differences in their pathological action on muscle mitochondria. At variance, injection of these venoms in mice resulted in a different time-course of mtDNA release, with B. asper venom inducing an early onset increment in plasma levels and C. d. terrificus venom provoking a delayed release. We suggest that the release of mitochondrial ‘alarmins’ might contribute to the local and systemic inflammatory events characteristic of snakebite envenomations

Paroxysmal events during prolonged video-electroencephalography monitoring in refractory epilepsy

Introduction: Given that epileptic seizures and non-epileptic paroxysmal events have similar clinical manifestations, using specific diagnostic methods is crucial, especially in patients with drug-resistant epilepsy. Prolonged video electroencephalography monitoring during epileptic seizures reveals epileptiform discharges and has become an essential procedure for epilepsy diagnosis. The main purpose of this study is to characterise paroxysmal events and compare patterns in patients with refractory epilepsy. Methods: We conducted a retrospective analysis of medical records from 91 patients diagnosed with refractory epilepsy who underwent prolonged video electroencephalography monitoring during hospitalisation. Results: During prolonged video electroencephalography monitoring, 76.9% of the patients (n = 70) had paroxysmal events. The mean number of events was 3.4 ± 2.7; the duration of these events was highly variable. Most patients (80%) experienced seizures during wakefulness. The most common events were focal seizures with altered levels of consciousness, progressive bilateral generalised seizures and psychogenic non-epileptic seizures. Regarding all paroxysmal events, no differences were observed in the number or type of events by sex, in duration by sex or age at onset, or in the number of events by type of event. Psychogenic nonepileptic seizures were predominantly registered during wakefulness, lasted longer, started at older ages, and were more frequent in women. Conclusions: Paroxysmal events recorded during prolonged video electroencephalography monitoring in patients with refractory epilepsy show similar patterns and characteristics to those reported in other latitudes. Resumen: Introducción: La inexistencia de signos clínicos que diferencien entre crisis epilépticas y episodios paroxísticos no epilépticos hace necesario utilizar métodos diagnósticos específicos, principalmente en pacientes refractarios al tratamiento farmacológico. La monitorización prolongada con videoelectroencefalografía durante las crisis epilépticas evidencia descargas epileptiformes en el EEG ictal y constituye una prueba fundamental para su diagnóstico. La presente investigación pretende caracterizar los eventos paroxísticos y comparar los patrones encontrados en pacientes con diagnóstico de epilepsia refractaria. Métodos: Se realizó un estudio y análisis retrospectivo a partir de los registros médicos de la monitorización prolongada con video EEG de 91 pacientes diagnosticados con epilepsia refractaria durante su internamiento. Resultados: Durante el videoelectroencefalograma prolongado el 76,9% (n = 70) de los pacientes presentaron eventos paroxísticos. El número promedio de eventos fue 3,4 (± 2,7) y su duración fue muy variable. La mayoría de los pacientes (80,0%) presentó las crisis durante vigilia y los principales tipos de eventos registrados fueron: focales con alteración de la conciencia, evolutivos a crisis convulsivas bilaterales y crisis psicógenas no epilépticas. Considerando la totalidad de los eventos paroxísticos, no se objetivan diferencias en cuanto al número o tipo de eventos descritos según el sexo, la edad de inicio de la enfermedad o el sexo y la duración de los eventos, o al número de eventos según el tipo. Las crisis psicógenas no epilépticas se registran predominantemente en vigilia, presentan mayor duración, se inician más tardíamente y ocurren principalmente en mujeres. Conclusiones: Los eventos paroxísticos observados durante la monitorización prolongada con videoelectroencefalograma de pacientes internados con epilepsia refractaria muestran patrones y características similares a los descritos en otras latitudes. Keywords: Paroxysmal events, Prolonged video electroencephalography monitoring, Epilepsy monitoring unit, Refractory epilepsy, Epileptic seizures, Psychogenic non-epileptic seizures, Palabras clave: Eventos paroxísticos, Videoelectroencefalograma prolongado, Unidad de monitorización, Epilepsia refractaria, Crisis epilépticas, Crisis psicógenas no epiléptica

Eventos paroxísticos durante la monitorización prolongada con videoelectroencefalografía en epilepsia refractaria

Resumen: Introducción: La inexistencia de signos clínicos que diferencien entre crisis epilépticas y episodios paroxísticos no epilépticos hace necesario utilizar métodos diagnósticos específicos, principalmente en pacientes refractarios al tratamiento farmacológico. La monitorización prolongada con videoelectroencefalografía durante las crisis epilépticas evidencia descargas epileptiformes en el EEG ictal y constituye una prueba fundamental para su diagnóstico. La presente investigación pretende caracterizar los eventos paroxísticos y comparar los patrones encontrados en pacientes con diagnóstico de epilepsia refractaria. Métodos: Se realizó un estudio y análisis retrospectivo a partir de los registros médicos de la monitorización prolongada con video EEG de 91 pacientes diagnosticados con epilepsia refractaria durante su internamiento. Resultados: Durante el videoelectroencefalograma prolongado el 76,9% (n = 70) de los pacientes presentaron eventos paroxísticos. El número promedio de eventos fue 3,4 (± 2,7) y su duración fue muy variable. La mayoría de los pacientes (80,0%) presentó las crisis durante vigilia y los principales tipos de eventos registrados fueron: focales con alteración de la conciencia, evolutivos a crisis convulsivas bilaterales y crisis psicógenas no epilépticas. Considerando la totalidad de los eventos paroxísticos, no se objetivan diferencias en cuanto al número o tipo de eventos descritos según el sexo, la edad de inicio de la enfermedad o el sexo y la duración de los eventos, o al número de eventos según el tipo. Las crisis psicógenas no epilépticas se registran predominantemente en vigilia, presentan mayor duración, se inician más tardíamente y ocurren principalmente en mujeres. Conclusiones: Los eventos paroxísticos observados durante la monitorización prolongada con videoelectroencefalograma de pacientes internados con epilepsia refractaria muestran patrones y características similares a los descritos en otras latitudes. Abstract: Introduction: Given that epileptic seizures and non-epileptic paroxysmal events have similar clinical manifestations, using specific diagnostic methods is crucial, especially in patients with drug-resistant epilepsy. Prolonged video electroencephalography monitoring during epileptic seizures reveals epileptiform discharges and has become an essential procedure for epilepsy diagnosis. The main purpose of this study is to characterise paroxysmal events and compare patterns in patients with refractory epilepsy. Methods: We conducted a retrospective analysis of medical records from 91 patients diagnosed with refractory epilepsy who underwent prolonged video electroencephalography monitoring during hospitalisation. Results: During prolonged video electroencephalography monitoring, 76.9% of the patients (n = 70) had paroxysmal events. The mean number of events was 3.4 ± 2.7; the duration of these events was highly variable. Most patients (80%) experienced seizures during wakefulness. The most common events were focal seizures with altered levels of consciousness, progressive bilateral generalized seizures and psychogenic non-epileptic seizures. Regarding all paroxysmal events, no differences were observed in the number or type of events by sex, in duration by sex or age at onset, or in the number of events by type of event. Psychogenic nonepileptic seizures were predominantly registered during wakefulness, lasted longer, started at older ages, and were more frequent in women. Conclusions: Paroxysmal events recorded during prolonged video electroencephalography monitoring in patients with refractory epilepsy show similar patterns and characteristics to those reported in other latitudes. Palabras clave: Eventos paroxísticos, Videoelectroencefalograma prolongado, Unidad de monitorización, Epilepsia refractaria, Crisis epilépticas, Crisis psicógenas no epilépticas, Keywords: Paroxysmal events, Prolonged video electroencephalography monitoring, Epilepsy monitoring unit, Refractory epilepsy, Epileptic seizures, Psychogenic non-epileptic seizure

Acute RyR1 Ca²⁺ leak enhances NADH-linked mitochondrial respiratory capacity.

Sustained ryanodine receptor (RyR) Ca <sup>2+</sup> leak is associated with pathological conditions such as heart failure or skeletal muscle weakness. We report that a single session of sprint interval training (SIT), but not of moderate intensity continuous training (MICT), triggers RyR1 protein oxidation and nitrosylation leading to calstabin1 dissociation in healthy human muscle and in in vitro SIT models (simulated SIT or S-SIT). This is accompanied by decreased sarcoplasmic reticulum Ca <sup>2+</sup> content, increased levels of mitochondrial oxidative phosphorylation proteins, supercomplex formation and enhanced NADH-linked mitochondrial respiratory capacity. Mechanistically, (S-)SIT increases mitochondrial Ca <sup>2+</sup> uptake in mouse myotubes and muscle fibres, and decreases pyruvate dehydrogenase phosphorylation in human muscle and mouse myotubes. Countering Ca <sup>2+</sup> leak or preventing mitochondrial Ca <sup>2+</sup> uptake blunts S-SIT-induced adaptations, a result supported by proteomic analyses. Here we show that triggering acute transient Ca <sup>2+</sup> leak through RyR1 in healthy muscle may contribute to the multiple health promoting benefits of exercise