El músculo, paradigma metabólico en la recuperación nutricional / Muscle, metabolic paradigm in nutritional recovery

El músculo esquelético es un tejido que representa la mayor parte de la masa corporal total y de las proteínas corporales y que desempeña diversas funciones vitales. La masa muscular es el resultado del equilibrio entre síntesis y degradación y ambos procesos son sensibles a factores como el estado nutricional, el equilibrio hormonal, la actividad física y el ejercicio, así como a la enfermedad. En diversos estados de desnutrición asociados a varias patologías infecciosas y traumáticas, así como a enfermedades crónicas, la masa muscular es afectada más o menos severamente. Asimismo, la sarcopenia es una alteración progresiva y generalizada del músculo esquelético que aparece con la edad y que se asocia con una mayor probabilidad de eventos adversos, como caídas, fracturas, incapacidad física y mortalidad. Por tanto, la recuperación de la masa y de la funcionalidad muscular es clave para mejorar los estados de desnutrición asociados a numerosas patologías. En el presente artículo se resumen las vías metabólicas y los nutrientes más utilizados por el músculo para la obtención de energía y las vías de señalización celular implicadas en la síntesis y degradación del músculo. Asimismo, se comenta la importancia de algunas mioquinas en la interacción con otros tejidos para el mantenimiento de la homeostasis corporal. Existe un gran número de reguladores positivos de la síntesis de proteína muscular. Especialmente, los aminoácidos de cadena ramificada durante la restricción energética contribuyen a la síntesis de proteína muscular, así como a la atenuación de la excreción de nitrógeno corporal y de la proteólisis muscular

Skeletal muscle is a tissue that represents the majority of total body mass and proteins in healthy humans. Muscle mass is the results of balance between synthesis and proteolysis, both processes being sensitive to a variety of factors including nutritional status, hormonal balance, physical activity and exercise, and disease. Indeed, muscle mass loss is associated with several infectious, traumatic and chronic pathologies. Likewise, sarcopenia is a progressive and generalized skeletal muscle disorder appearing with ageing associated with increased likelihood of adverse outcomes including falls, fractures, physical disability, and mortality. Hence, recovery of muscle mass and functionality is a key factor to improve undernutrition associated with many pathological conditions. The aim of the present article is to summarize the most important substrates, metabolic and cell signaling pathways involved in the synthesis, degradation and turnover in skeletal muscle. Moreover, the importance of some myokines in the interaction between skeletal muscle and other tissues, and in the maintenance of homeostasis is highlighted. A great number of positive regulators for muscle protein synthesis has been reported. Especially, during energy restriction, branched chain amino acids, e.g. leucine, contribute majorly to muscle protein synthesis as well as to attenuate nitrogen body excretion and muscle proteolysis

Effects of reactive oxygen species and interplay of antioxidants during physical exercise in skeletal muscles

A large number of researches have led to a substantial growth of knowledge about exercise and oxidative stress. Initial investigations reported that physical exercise generates free radical-mediated damages to cells; however, in recent years, studies have shown that regular exercise can upregulate endogenous antioxidants and reduce oxidative damage. Yet, strenuous exercise perturbs the antioxidant system by increasing the reactive oxygen species (ROS) content. These alterations in the cellular environment seem to occur in an exercise type-dependent manner. The source of ROS generation during exercise is debatable, but now it is well established that both contracting and relaxing skeletal muscles generate reactive oxygen species and reactive nitrogen species. In particular, exercises of higher intensity and longer duration can cause oxidative damage to lipids, proteins, and nucleotides in myocytes. In this review, we summarize the ROS effects and interplay of antioxidants in skeletal muscle during physical exercise. Additionally, we discuss how ROS-mediated signaling influences physical exercise in antioxidant system

Metabolic effects of physiological levels of caffeine in myotubes

Caffeine has been shown to stimulate multiple major regulators of cell energetics including AMP-activated protein kinase (AMPK) and Ca2+/calmodulin-dependent protein kinase II (CaMKII). Additionally, caffeine induces peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alfa) and mitochondrial biogenesis. While caffeine enhances oxidative metabolism, experimental concentrations often exceed physiologically attainable concentrations through diet. This work measured the effects of low-level caffeine on cellular metabolism and gene expression in myotubes, as well as the dependence of caffeine's effects on the nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPAR Beta/Delta). C2C12 myotubes were treated with various doses of caffeine for up to 24 h. Gene and protein expression were measured via qRT-PCR and Western blot, respectively. Cellular metabolism was determined via oxygen consumption and extracellular acidification rate. Caffeine significantly induced regulators of mitochondrial biogenesis and oxidative metabolism. Mitochondrial staining was suppressed in PPARBeta/Delta -inhibited cells which was rescued by concurrent caffeine treatment. Caffeine-treated cells also displayed elevated peak oxidative metabolism which was partially abolished following PPARβ/δ inhibition. Similar to past observations, glucose uptake and GLUT4 content were elevated in caffeine-treated cells, however, glycolytic metabolism was unaltered following caffeine treatment. Physiological levels of caffeine appear to enhance cell metabolism through mechanisms partially dependent on PPARBeta/Delta

SIRT1 overexpression in skeletal muscle in vivo induces increased insulin sensitivity and enhanced complex I but not complex II–V functions in individual subsarcolemmal and intermyofibrillar mitochondria

SIRT1 is known to improve insulin resistance (IR), but whether this effect is direct or not is still unclear, and this question has not been addressed in vivo in the skeletal muscle. Therefore, we sought to test if acute overexpression of SIRT1 in skeletal muscle of high-fat diet (HFD) rats in vivo would affect subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial complexes I–V activities and antioxidant enzymes thereby improving insulin action. In vivo electrotransfer was used to overexpress SIRT1 in the skeletal muscle of rats fed HFD for 12 weeks. Skeletal muscle insulin sensitivity and downstream effects of SIRT1 on AMPK, SIRT3, and mitochondrial biogenesis were studied. Citrate synthase (CS), complexes I–V, oxidative stress, and antioxidant levels were assessed in SS and IMF mitochondria. HFD rats showed skeletal muscle IR as well as decreasedSIRT1 and SIRT3 expressions, mitochondrial DNA (mtDNA), and mitochondrial biogenesis (p < 0.05). SS and IMF mitochondria displayed lower CS, complexes I–V, and antioxidant enzyme activities (p < 0.05). By contrast, moderate (~2.5 folds) SIRT1 overexpression attenuated HFD-induced skeletal muscle IR. This improvement was associated with increased AMPK, PGC-1alfa, SIRT3, and mtDNA expressions as well as SS and IMF mitochondrial CS and complexes I–V activities. Importantly, SIRT1 overexpression largely restored antioxidant enzyme activities and enhanced complex I but not complexes II–V functions in individual SS and IMF mitochondria. This study suggests that SIRT1 overexpression improved IR at least partly by targeting complex I functions of SS and IMF mitochondria through the activation of SIRT1 and SIRT3

Trastornos del metabolismo energético del músculo: Bases geméticas y bioquímicas de las miopatías que cursan con intolerancia al ejercicio físico / Disorders of the energetic metabolism of the muscle: Bases geméticas and biochemical of the myopathies that they deal intolerantly to the physical exercise

Las miopatías metabólicas son trastornos de la producción de energía muscular que provocan una disfunción muscular esquelética. Las miopatías relacionadas con el ejercicio comprenden un grupo de enfermedades musculares (Tabla 1y 2) con sintomatología inducida por el ejercicio muscular o situaciones de demanda energética. Las enfermedades del metabolismo energético muscular son un grupo de enfermedades heterogéneas desde el punto de vista genético, clínico y bioquímico. Esquemáticamente desde el punto de vista bioquímico pueden ser agrupadas en tres categorías, así las podemos subdividir en alteraciones del metabolismo de los hidratos de carbono, trastornos del metabolismo lipídico y alteraciones de la función mitocondrial. La genética es el área donde en los últimos años las aportaciones han sido más relevantes y numerosas, gracias a los avances proporcionados por las técnicas de genética molecular. El conocimiento, localización y clonaje de los distintos genes han facilitado enormemente el avance científico de estas enfermedades (AU)

Metabolic myopathies are disorders of muscle energy production that impair skeletal muscle function. Exercise-related myopathies are a group of muscle diseases in which symptoms a retriggered during muscle exercise or in situation of increased metabolic demands. This group of diseases is heterogeneous from a genetic, clinical and biochemical point of view. From a biochemical perspective, they can be grouped into three categories: alterations in carbohydrate and lipid metabolism, respectively, and alterations in mitochondrial function. The main advances in the understanding of these diseases come mainly from molecular biology techniques (AU)

Hepatomioneuropatía secundaria a depleción del ADN mitocondrial / Hepatomioneuropathy secondary to mitochondrial DNA depletion

Introducción. La depleción del ADN mitocondrial (ADNmt) consiste en la presencia de un menor número de copias del genoma mitocondrial, siendo sus expresiones fenotípicas muy heterogéneas. Caso clínico. Niña de 22 meses de edad que presenta hipotonía generalizada detectada a partir de los 7 meses de edad asociada a hepatoesplenomegalia con moderada elevación de la transaminasemia, sin datos de fracaso hepático funcional ni hipoglucemia hipocetótica; progresivamente se observó el desarrollo de debilidad muscular, fracaso respiratorio, hipertensión arterial, acidosis láctica y superposición de signos miopáticos y neuropáticos en los estudios neurofisiológicos periféricos. El estudio genético molecular para la atrofia muscular espinal fue normal. El examen con microscopía óptica de la biopsia muscular fue compatible con atrofia neurogénica, con presencia en el examen ultraestructural de gotas lipídicas, acúmulos mitocondriales subsarcolémicos y de gránulos de glucógeno. Los complejos de la cadena respiratoria mitocondrial (CRM) en homogenado muscular fueron normales. El estudio genético molecular a nivel muscular demostró la presencia de una depleción del ADNmt. Conclusiones. Esta observación probablemente represente una nueva expresión fenotípica de depleción del ADNmt que se puede denominar forma hepatomioneuropática. La normalidad de la CRM en músculo no excluye la depleción del ADNmt

Introduction. Mitochondrial DNA depletion (mtDNA) is an highly heterogeneous condition characterized by a decresed number of mtDNA copies. Case report. The patient is a 22-month-old girl with generalized hypotonia, marked weakness, respiratory failure, arterial hypertension, hyperlactacidemia, hepatosplenomegaly and mild hypertransaminasemia without hepatic failure neither hypoketotic hypoglycemia. Electromyographic findings were consistent with neuromyopathy and muscle biopsy suggested a neurogenic atrophy. Electron microscopy revealed lipid droplets, subsarcolemmal accumulation of mitochondrias and glycogen granules. Respiratory chain enzime activities were normal. Genetic study in muscle showed mtDNA depletion, and the diagnosis of spinal muscular atrophy caused by survival motoneuron gene deletion was excluded. Conclusions. This case might be a novel phenotype of mtDNA depletion which could be named hepatomioneuropatyc form. A normal result of respiratory chain enzimes in muscle doesn't excluded mtDNA depletion

Oftalmoplejía externa progresiva crónica: manifestaciones clínicas y electromiográficas en una serie de casos / Chronic progressive external ophthalmoplegia: clinical and electromyographic manifestations in a series of cases

Introducción. La oftalmoplejía externa progresiva crónica(CPEO) es una enfermedad mitocondrial común. Este grupode enfermedades presenta solapamiento clínico, enzimático y genéticoentre las diferentes entidades. No existe un tratamiento eficaz.La ptosis mejora con cirugía correctora de tarsorrafia comouna medida paliativa. Casos clínicos. Estudio retrospectivo en elque se busca por codificación a pacientes con ptosis u oftalmoplejíaen consultas o ingresados en neurología durante los últimos 10años. Se recogieron datos de la clínica y pruebas complementariasde estos pacientes. Se identificó a seis pacientes con CPEO; cincode ellos fueron mujeres. Sus edades estaban comprendidas entrelos 44 y los 72 años. Todos los pacientes presentaban ptosis, aunqueel 50% era asimétrica. La mitad refería disfagia leve paralíquidos. Los niveles de creatinfosfocinasa y de anticuerpos antirreceptoresde acetilcolina fueron normales. Existía un aumentodel jitter en la mitad de los pacientes y fibras rojas rasgadas en labiopsia muscular de cinco de ellos. El déficit enzimático más frecuentefue el de los complejos I y IV. No existieron formas familiares;la anomalía genética más común fue la deleción única en elácido desoxirribonucleico mitocondrial. Conclusión. El conocimientode esta entidad permite, en casos de ptosis y oftalmoplejíaque no responden a anticolinesterásicos, evitar el uso de medicacionesinmunosupresoras con efectos secundarios importantes

Introduction. Chronic progressive external ophthalmoplegia (CPEO) is a common mitochondrial disease. Thedifferent conditions in this group of diseases overlap clinically, enzymatically and genetically. There is no effective treatment.Ptosis improves with corrective surgery involving tarsorrhaphy as a palliative measure. Case reports. Code numbers wereexamined in a retrospective study conducted in order to search for patients with ptosis or ophthalmoplegia who had eithervisited or been admitted to the neurology department over the last 10 years. Data concerning these patients' clinical featuresand results of complementary tests were collected. Six patients with CPEO were identified, five of whom were females. Agesranged from 44 to 72 years. All the patients had ptosis, although 50% were asymmetric. Half of them reported mild dysphagiawhile swallowing liquids. Levels of creatine phosphokinase and acetylcholine antireceptor antibodies were normal. Half thepatients showed increased jitter and a muscle biopsy revealed that five of them had ragged red fibres. The most frequentenzyme deficit was complex I and IV deficiency. There were no familial forms; the most common genetic anomaly was singledeletion in the mitochondrial deoxyribonucleic acid. Conclusions. In cases of ptosis and ophthalmoplegia that do not respondto anticholinesterases, knowledge of this condition makes it possible to avoid the use of immunosuppressant drugs, which haveimportant side effects

Oftalmoplejía crónica progresiva externa familiar de origen mitocondrial / Familiar chronic progressive external ophthalmoplegia of mitochondrial origin

Introducción. El síndrome de oftalmoplejía crónica progresiva externa (CPEO) es una enfermedad mitocondrial caracterizada por ptosis palpebral bilateral y parálisis de la musculatura oculomotora, que se ha asociado a la presencia de grandes deleciones, únicas o múltiples, en el ADN mitocondrial (ADNmt) del tejido muscular. Caso clínico. Presentamos un caso familiar de CPEO de herencia materna que comenzó desde el nacimiento, tanto en la madre como en el hijo, y que se desarrolló progresivamente sin afectación multisistémica. Ninguno de los afectados presenta fibras rojas rasgadas en el músculo esquelético. El análisis genético mostró la presencia de una deleción única de 4.977 pares de bases, comprendida entre los nucleótidos 8.482 y 13.460, flanqueada por una repetición directa en el ADNmt del hijo. Conclusiones. A pesar del bajo porcentaje de moléculas de ADNmt con la deleción en el músculo ocular de esta paciente (15 por ciento), se sugiere que dicha deleción es la causa molecular de su presentación fenotípica. Éste es uno de los pocos casos de CPEO de herencia materna (AU)

Introduction. The syndrome of chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease characterized by ptosis and ophthalmoplegia that has been associated to the presence of large deletion, single or multiple, in the mitochondrial DNA of skeletal muscle. Case report. We report a familiar case of chronic progressive external ophthalmoplegia of maternal inheritance that began at birth, and developed with slow progression but with no multisistemic involvement. Non of the affected individuals had ragged-red fibers in skeletal muscle. Genetic analysis of mitochondrial DNA revealed the presence of a single deletion of 4,977 bp that encompasses the nucleotide positions 8,482 to 13,460, flanked by a direct repeat sequence. Conclusions. The amount of deleted mitochondrial DNA (15%) in this patient’s muscle suggests, even if the percentage of the mutation is low, that this deletion is the molecular cause of the phenotypic presentation of this patient. This is one of the few cases described in the literature of CPEO maternally inherited (AU)

Participación mitocondrial en la lipodistrofia asociada al tratamiento antirretroviral de gran actividad de pacientes infectados por el virus de la inmunodeficiencia humana / Mitochondrial involvement in antiretroviral therapy-related lipodystrophy of HIV-infected patients

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Utilización del cuestionario PRIME-MD® para la detección de trastornos mentales en mujeres inmigrantes iberoamericanas e hispanohablantes / Utilization of the questionnaire PrimeMD for the detection of mental disorders among Latin American and Spanish native speaker immigrant women

No disponible