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Introduction: Caffeine and the selective A2A receptor antagonist SCH58261 both have ergogenic properties, effectively reducing fatigue and enhancing exercise capacity. This study investigates in male Swiss mice the interaction between adenosine A2A receptors and dopamine D2 receptors controlling central fatigue, with a focus on the striatum where these receptors are most abundant. Methods: We employed DPCPX and SCH58261 to antagonize A1 and A2A receptors, caffeine as a non-competitive antagonist for both receptors, and haloperidol as a D2 receptor antagonist; all compounds were tested upon systemic application and caffeine and SCH58261 were also directly applied in the striatum. Behavioral assessments using the open field, grip strength, and treadmill tests allowed estimating the effect of treatments on fatigue. Results and discussion: The results suggested a complex interplay between the dopamine and adenosine systems. While systemic DPCPX had little effect on motor performance or fatigue, the application of either caffeine or SCH58261 was ergogenic, and these effects were attenuated by haloperidol. The intra-striatal administration of caffeine or SCH58261 was also ergogenic, but these effects were unaffected by haloperidol. These findings confirm a role of striatal A2A receptors in the control of central fatigue but suggest that the D2 receptor-mediated control of the ergogenic effects of caffeine and of A2A receptor antagonists might occur outside the striatum. This prompts the need of additional efforts to unveil the role of different brain regions in the control of fatigue.
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OBJECTIVE: This study aimed to investigate the effects of an 8-wk face-to-face rehabilitation program on subjects with persistent symptoms of COVID-19 compared with a remote monitoring group. DESIGN: This is clinical, nonrandomized, controlled, and open study. The face-to-face supervised rehabilitation lasted eight consecutive weeks, twice a week. The remote monitoring group received health guidance. The allocation was carried out by preference because of the emergency period without vaccination during the pandemic. Fatigue, dyspnea (Pulmonary Functional Status and Dyspnea Questionnaire), and exercise capacity (Incremental Shuttle Walk Test) were the primary outcome measures. Lung function, functional status (Post-COVID-19 Functional Status), symptoms of anxiety and depression (Hospital Anxiety and Depression Scale), attention (d2-R), memory (Rey's Auditory-Verbal Learning Test), handgrip strength, and knee extensor strength were secondary outcome measures. RESULTS: Thirty-seven subjects (24.3% hospitalized) completed the baseline and final assessment, rehabilitation ( n = 22, 40.8 [SD, 10.0] yrs, 54.5% female), or remote guidance ( n = 15, 45.4 [SD, 10.5] yrs, 40% female). Both groups showed improved fatigue and exercise capacity. Exercise rehabilitation improved dyspnea, anxiety, attention, and short-term memory. CONCLUSIONS: Rehabilitation is essential for dyspnea in subjects with persistent symptoms of COVID-19 while fatigue naturally reverses.
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COVID-19 , Enfermedad Pulmonar Obstructiva Crónica , Femenino , Humanos , Masculino , Brasil/epidemiología , COVID-19/complicaciones , Disnea/etiología , Tolerancia al Ejercicio , Fatiga/etiología , Fuerza de la Mano , Enfermedad Pulmonar Obstructiva Crónica/rehabilitación , Calidad de Vida , Adulto , Persona de Mediana EdadRESUMEN
Caffeine is one of the main ergogenic resources used in exercise and sports. Previously, we reported the ergogenic mechanism of caffeine through neuronal A2AR antagonism in the central nervous system [1]. We now demonstrate that the striatum rules the ergogenic effects of caffeine through neuroplasticity changes. Thirty-four Swiss (8-10 weeks, 47 ± 1.5 g) and twenty-four C57BL/6J (8-10 weeks, 23.9 ± 0.4 g) adult male mice were studied behaviorly and electrophysiologically using caffeine and energy metabolism was studied in SH-SY5Y cells. Systemic (15 mg/kg, i.p.) or striatal (bilateral, 15 µg) caffeine was psychostimulant in the open field (p < 0.05) and increased grip efficiency (p < 0.05). Caffeine also shifted long-term depression (LTD) to potentiation (LTP) in striatal slices and increased the mitochondrial mass (p < 0.05) and membrane potential (p < 0.05) in SH-SY5Y dopaminergic cells. Our results demonstrate the role of the striatum in the ergogenic effects of caffeine, with changes in neuroplasticity and mitochondrial metabolism.
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Estimulantes del Sistema Nervioso Central , Neuroblastoma , Sustancias para Mejorar el Rendimiento , Humanos , Masculino , Ratones , Animales , Cafeína/farmacología , Ratones Endogámicos C57BL , Estimulantes del Sistema Nervioso Central/farmacologíaRESUMEN
Coronavirus 2 is responsible for Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2), and the main sequela is persistent fatigue. Post-viral fatigue is common and affects patients with mild, asymptomatic coronavirus disease-2019 (COVID-19). However, the exact mechanisms involved in developing post-COVID-19 fatigue remain unclear. Furthermore, physical and cognitive impairments in these individuals have been widely described. Therefore, this review aims to summarize and propose tools from a multifaceted perspective to assess COVID-19 infection. Herein, we point out the instruments that can be used to assess fatigue in long-term COVID-19: fatigue in a subjective manner or fatigability in an objective manner. For physical and mental fatigue, structured questionnaires were used to assess perceived symptoms, and physical and cognitive performance assessment tests were used to measure fatigability using reduced performance.
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COVID-19 , Fatiga , Humanos , Cognición , COVID-19/complicaciones , COVID-19/diagnóstico , Síndrome de Fatiga Crónica/diagnóstico , Síndrome de Fatiga Crónica/etiología , Síndrome de Fatiga Crónica/fisiopatología , SARS-CoV-2 , Evaluación de Síntomas , Fatiga/diagnóstico , Fatiga/etiología , Fatiga/fisiopatología , Fatiga Mental/diagnóstico , Fatiga Mental/etiología , Fatiga Mental/fisiopatología , Encuestas y Cuestionarios , Pruebas Neuropsicológicas , Síndrome Post Agudo de COVID-19RESUMEN
Ecto-5'-nucleotidase or CD73 is the main source of extracellular adenosine involved in the activation of adenosine A2A receptors, responsible for the ergogenic effects of caffeine. We now investigated the role of CD73 in exercise by comparing female wild-type (WT) and CD73 knockout (KO) mice in a treadmill-graded test to evaluate running power, oxygen uptake (VÌO2), and respiratory exchange ratio (RER) - the gold standards characterizing physical performance. Spontaneous locomotion in the open field and submaximal running power and VÌO2 in the treadmill were similar between CD73-KO and WT mice; VÌO2max also demonstrated equivalent aerobic power, but CD73-KO mice displayed a 43.7 ± 4.2% larger critical power (large effect size, P < 0.05) and 3.8 ± 0.4% increase of maximum RER (small effect size, P < 0.05). Thus, KO of CD73 was ergogenic; i.e., it increased physical performance.
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5'-Nucleotidasa/deficiencia , 5'-Nucleotidasa/genética , Prueba de Esfuerzo/métodos , Eliminación de Gen , Condicionamiento Físico Animal/métodos , Condicionamiento Físico Animal/fisiología , Animales , Femenino , Ratones , Ratones NoqueadosRESUMEN
Caffeine is one of the most used ergogenic aid for physical exercise and sports. However, its mechanism of action is still controversial. The adenosinergic hypothesis is promising due to the pharmacology of caffeine, a nonselective antagonist of adenosine A1 and A2A receptors. We now investigated A2AR as a possible ergogenic mechanism through pharmacological and genetic inactivation. Forty-two adult females (20.0 ± 0.2 g) and 40 male mice (23.9 ± 0.4 g) from a global and forebrain A2AR knockout (KO) colony ran an incremental exercise test with indirect calorimetry (VÌO2 and RER). We administered caffeine (15 mg/kg, i.p., nonselective) and SCH 58261 (1 mg/kg, i.p., selective A2AR antagonist) 15 min before the open field and exercise tests. We also evaluated the estrous cycle and infrared temperature immediately at the end of the exercise test. Caffeine and SCH 58621 were psychostimulant. Moreover, Caffeine and SCH 58621 were ergogenic, that is, they increased VÌO2max, running power, and critical power, showing that A2AR antagonism is ergogenic. Furthermore, the ergogenic effects of caffeine were abrogated in global and forebrain A2AR KO mice, showing that the antagonism of A2AR in forebrain neurons is responsible for the ergogenic action of caffeine. Furthermore, caffeine modified the exercising metabolism in an A2AR-dependent manner, and A2AR was paramount for exercise thermoregulation.
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Antagonistas del Receptor de Adenosina A2 , Cafeína/farmacología , Estimulantes del Sistema Nervioso Central , Sustancias para Mejorar el Rendimiento , Condicionamiento Físico Animal/fisiología , Receptor de Adenosina A2A/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Regulación de la Temperatura Corporal/efectos de los fármacos , Regulación de la Temperatura Corporal/fisiología , Cafeína/administración & dosificación , Ciclo Estral/efectos de los fármacos , Femenino , Masculino , Ratones , Ratones Noqueados , Neuronas/fisiología , Prosencéfalo/citología , Prosencéfalo/metabolismo , Pirimidinas/farmacología , Triazoles/farmacologíaAsunto(s)
Tolerancia al Ejercicio , Ejercicio Físico , Terapia por Ejercicio , Femenino , Humanos , Masculino , Caracteres SexualesRESUMEN
Upper limb nerve injuries are common, and their treatment poses a challenge for physicians and surgeons. Experimental models help in minimum exploration of the functional characteristics of peripheral nerve injuries of forelimbs. This study was conducted to characterize the functional recovery (1, 3, 7, 10, 14, and 21 days) after median and ulnar nerve crush in mice and analyze the histological and biochemical markers of nerve regeneration (after 21 days). Sensory-functional impairments appeared after 1 day. The peripheral nerve morphology, the nerve structure, and the density of myelin proteins [myelin protein zero (P0) and peripheral myelin protein 22 (PMP22)] were analyzed after 21 days. Cold allodynia and fine motor coordination recovery occurred on the 10th day, and grip strength recovery was observed on the 14th day after injury. After 21 days, there was partial myelin sheath recovery. PMP22 recovery was complete, whereas P0 recovery was not. Results suggest that there is complete functional recovery even with partial remyelination of median and ulnar nerves in mice.
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Nervio Mediano/fisiopatología , Recuperación de la Función , Remielinización , Nervio Cubital/fisiopatología , Animales , Masculino , Nervio Mediano/lesiones , Nervio Mediano/metabolismo , Ratones , Proteína P0 de la Mielina/metabolismo , Proteínas de la Mielina/metabolismo , Compresión Nerviosa , Nervio Cubital/lesiones , Nervio Cubital/metabolismoRESUMEN
Exercise physiology is different in males and females. Females are poorly studied due to the complexity of the estrous cycle and this bias has created an exercise sex gap. Here, we evaluated the impact of sexual dimorphism and of the estrous cycle on muscle strength and running power of C57BL/6 mice. Like men, male mice were stronger and more powerful than females. Exercise-induced increase of O2 consumption ([Formula: see text]O2) and CO2 production ([Formula: see text]CO2) were equal between sexes, indicating that running economy was higher in males. Thermoregulation was also more efficient in males. In females, proestrus increased exercise [Formula: see text]O2 and [Formula: see text]CO2 at low running speeds (30-35% female [Formula: see text]O2max) and estrus worsened thermoregulation. These differences translated into different absolute and relative workloads on the treadmill, even at equal submaximal [Formula: see text]O2 and belt speeds. In summary, our results demonstrate the better muscle strength, running power and economy, and exercise-induced thermoregulation of males compared to females. Proestrus and estrus still undermined the running economy and exercise-induced thermoregulation of females, respectively. These results demonstrate an important exercise sex gap in mice.
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Ciclo Estral/fisiología , Fuerza Muscular/fisiología , Músculo Esquelético/metabolismo , Condicionamiento Físico Animal/fisiología , Animales , Dióxido de Carbono/metabolismo , Femenino , Frecuencia Cardíaca/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Consumo de Oxígeno/fisiología , Carrera/fisiología , Factores SexualesRESUMEN
Exercise increases both the consumption of oxygen and the production of reactive species in biological tissues, and this is counterbalanced by antioxidant adaptations to regular physical training. When the intensity of exercise fluctuates between mild and moderate, it improves the status of reduction-oxidation balance in the brain and induces neuroplasticity. However, intense exercise can oxidize the brain and impair neurological function. The effect of the frequency of exercise, which is an important factor in physical training, is still unknown. The effect of periodic exercise on biomarkers of oxidative stress in the hippocampus of mice was evaluated in this study. Mice were made to run on a treadmill for 8 weeks, two, three, or five times per week, and their hippocampi and quadriceps femoris muscles were then dissected. Biomarkers of oxidative damage were negatively correlated with the frequency of exercise and mitochondrial muscular activity, while the sulfhydryl contents were positively correlated with exercise frequency. A logistic analysis revealed a dose-dependent effect of exercise on these biomarkers. In summary, these results suggested that manipulating the frequency of physical exercise could induce antioxidant-related adaptations in the hippocampi of adult mice.
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Antioxidantes/metabolismo , Hipocampo/metabolismo , Condicionamiento Físico Animal/fisiología , Animales , Ácido Láctico/sangre , Masculino , Ratones , Estrés Oxidativo/fisiología , Condicionamiento Físico Animal/métodos , Distribución Aleatoria , Factores de TiempoRESUMEN
BACKGROUND: This study was conducted to test whether the IBB Forelimb Scale (Irvine et al., 2010) which was originally developed for rats with spinal cord injury, is also capable of measuring the functional performance of Swiss mice with lesions of the median and ulnar nerves inflicted via crushing with standardized strength. NEW METHOD: This test was performed at days 1, 3, 7, 10, 14 and 21 after surgery and each animal gives a score of 9, where 0 represented the worst functionality and 9 represented the habitual behavior. RESULTS: The control animals usually exhibited movements in the task that were scored as 9 during the experimental period. The lesion group began with a score of 2 on the 1st and 3rd post-operative days. On the 7th and 10th postoperative days, respectively, they scored 7, and on the 14th post-operative day, they achieved a score of 8. Only on the 21st post-operative day, did they exhibit habitual skillful behaviors. COMPARISON WITH EXISTING METHOD(S): IBB Forelimb Scale is effective for determining how the animals perform the movements in detail, which is not readily revealed by other methods. Furthermore, this test show similar recovery periods with grasping test, staircase test and seems to be more sensitive than paw print analysis for this type of lesion. CONCLUSIONS: Our data demonstrate that IBB scale was capable of measuring gradual improvements in motor forelimb functions in this model and may be a new and effective assessment tool for peripheral nerve injury.
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Evaluación de la Discapacidad , Miembro Anterior , Nervio Mediano/lesiones , Traumatismos de los Nervios Periféricos/diagnóstico , Recuperación de la Función , Nervio Cubital/lesiones , Animales , Fenómenos Biomecánicos , Diagnóstico Diferencial , Modelos Animales de Enfermedad , Miembro Anterior/fisiopatología , Masculino , Ratones , Destreza Motora/fisiología , Traumatismos de los Nervios Periféricos/fisiopatología , Distribución Aleatoria , Índice de Severidad de la Enfermedad , Análisis y Desempeño de Tareas , Factores de TiempoRESUMEN
Physical exercise and smoking are environmental factors that generally cause opposite health-promoting adaptations. Both physical exercise and smoking converge on mitochondrial adaptations in various tissues, including the pro-oxidant nervous system. Here, we analyzed the impact of cigarette smoking on exercise-induced brain mitochondrial adaptations in the hippocampus and pre-frontal cortex of adult mice. The animals were exposed to chronic cigarette smoke followed by 8 weeks of moderate-intensity physical exercise that increased mitochondrial activity in the hippocampus and pre-frontal cortex in the non-smoker mice. However, mice previously exposed to cigarette smoke did not present these exercise-induced mitochondrial adaptations. Our results suggest that smoking can inhibit some brain health-promoting changes induced by physical exercise.