La salud mitocondrial es un mediador importante de la función celular en una variedad de tejidos y, como resultado, contribuye a la vitalidad de todo el cuerpo en la salud y la enfermedad.
Mitocondrias
La MITOCONDRIA es un orgánulo muy pequeño y filiforme de unos 2 a 6μM de longitud, que aparecen en todas las células de nuestro cuerpo en cantidades variables (de algunas pocas a más de mil), con excepción de los glóbulos rojos. Sus paredes cuentan con una membrana unitaria interna y otra externa. La interna presenta un marcado plegamiento y por tanto una superficie grande.
Son las centrales térmicas de las células, pues suministran la energía necesaria para todos los proceses metabólicos, en la forma de un combustible biológico universal, el adenosín trifosfato (ATP). La producción de ATP a partir de los tres nutrientes básicos: proteínas, lípidos e hidratos de carbono, tiene lugar casi exclusivamente en las mitocondrias.
El ATP es muy necesario para el cuerpo y lo utiliza para el movimiento o contracción muscular, para el transporte de sustancias a través de la membrana celular, para la síntesis de proteínas y otros componentes celulares.
Músculo esquelético
El músculo esquelético es un tejido modelo útil para el estudio de las adaptaciones mitocondriales debido a su masa y contribución al metabolismo de todo el cuerpo. La notable plasticidad de las mitocondrias les permite ajustar su volumen, estructura y capacidad en condiciones como el ejercicio, lo cual es útil o mejora la salud metabólica en personas con diversas enfermedades y/o edad avanzada.
Las mitocondrias existen dentro del músculo como un retículo funcional que se mantiene mediante procesos dinámicos de biogénesis y fusión, se equilibra mediante procesos opuestos de fisión y mitofagia (es la degradación y reciclaje selectivos de las mitocondrias).
Hasta este momento, el ejercicio físico sigue siendo el enfoque terapéutico conductual más potente para mejorar la salud mitocondrial, no solo en el músculo.
Procesos del orgánulo
La mitocondria realiza procesos de FUSIÓN (unión de la membrana externa e interna con la matriz mitocondrial para producir una mitocondria más grande) y de FISIÓN (creando pequeñas mitocondrias múltiples).
Tiene la función de RESPIRACIÓN (proceso de obtención de energía), síntesis de ATP, producción de especies reactivas de oxígeno (ROS), apertura del poro de permeabilidad de transición o producción de proteínas involucradas en la MITOFAGIA o autofagia selectiva.
La mitofagia, una forma eficiente de eliminar las mitocondrias dañadas o defectuosas mediante la autofagia, desempeña un papel fundamental en el mantenimiento de la cantidad mitocondrial y el control de calidad que permite la degradación de las mitocondrias no deseadas y, por lo tanto, rescata la homeostasis celular en respuesta al estrés.
La evidencia acumulada demuestra que la mitofagia alterada se ha asociado con muchas enfermedades neurodegenerativas, como la enfermedad de Alzheimer (AD), la enfermedad de Parkinson (EP) y la enfermedad de Huntington (HD), esclerosis lateral amiotrófica (ELA) en una variedad de pacientes y modelos de enfermedad con muerte neuronal, estrés oxidativo y alteración del metabolismo, ya sea como causa o como consecuencia.
El efecto de varias modalidades de entrenamiento físico en las mitocondrias
La ciencia reconoce que el ejercicio es un estímulo potente para inducir las distintas vías metabólicas de señalización descritas en el artículo científico, que en última instancia producen cambios fenotípicos sólidos en el medio mitocondrial y mejoran la cantidad y calidad de la red de orgánulos, lo que conduce a una mayor salud muscular.
Adaptaciones musculares al entrenamiento aeróbico
En tanto las adaptaciones a un entrenamiento tipo de resistencia son muy complejas y multifacéticas, los cambios en los músculos activos, probablemente, son fundamentales para las alteraciones metabólicas y funcionales que soportan la performance con un incremento de la resistencia, observada luego del entrenamiento. Las adaptaciones que involucran la remodelación del músculo (por ej., aumento del contenido mitocondrial y capilaridad incrementada) están influenciadas por la duración e intensidad del ejercicio diario, requieren un extenso período de entrenamiento para lograr una adaptación de estado estable y se pierden con la inactividad.
Duración e Intensidad del Ejercicio
Los mecanismos mencionados responsables de inducir las adaptaciones del entrenamiento en el músculo son desconocidos. Sin embargo, es claro que los músculos deben ser reclutados durante la prueba de ejercicio con el objeto de adaptarse al programa de entrenamiento (Holloszy, 1967). Los músculos (o fibras dentro del músculo) no involucrados en la prueba de ejercicio no se adaptan. Por lo tanto, el estímulo crítico para la adaptación es algo muy específico para las fibras activas, y probablemente no sea algún factor generalizado circulante en la sangre que influye en todos los músculos. Además, para un programa de ejercicio dado, el entrenamiento debe ser ejecutado con una duración suficiente de días o semanas para permitir las adaptaciones bioquímicas específicas del músculo para alcanzar el estado estable (Figura 1). Por ejemplo, el contenido mitocondrial del músculo parece alcanzar un estado estable luego de aproximadamente 4-5 semanas de entrenamiento (Terjung, 1979).
La magnitud del incremento en el contenido mitocondrial inducido por el ejercicio también está influenciado por la duración del esfuerzo de ejercicio diario. Como se ilustra con las líneas individuales en la Figura 2, los esfuerzos de ejercicio más prolongados, generalmente producen mayores incrementos en el contenido mitocondrial. Sin embargo, la influencia de la duración del esfuerzo de ejercicio no es lineal (Dudley y cols., 1982); en tanto las sesiones de entrenamiento se tornan prolongadas de forma incrementada, el tiempo adicional de entrenamiento parece ser relativamente menos importante como señal que induce a un incremento en el contenido mitocondrial. Además, la intensidad del ejercicio interactúa con la duración del esfuerzo del ejercicio para hacer que los minutos iniciales de ejercicio sean aún más efectivos en establecer un estímulo para la adaptación. Nótese en la Figura 2 que el pico de adaptación en contenido mitocondrial parece ocurrir en duraciones más cortas de ejercicios, en tanto la intensidad de cada esfuerzo de entrenamiento se incrementa. El beneficio de sesiones de entrenamiento muy prolongadas en el aumento de la performance puede estar relacionado a adaptaciones en la función cardiovascular, en el balance de fluidos, en la disponibilidad de sustratos, u otros factores no relacionados directamente a las adaptaciones específicas del músculo.
Figura 1. Curso del tiempo de las adaptaciones de entrenamiento / desentrenamiento en el contenido mitocondrial del músculo esquelético. Nótese que aproximadamente un 50% del incremento en contenido mitocondrial fue perdido luego de una unidad de tiempo, por ej., 1 semana de desentrenamiento (a), y que toda la adaptación fue perdida luego de cinco unidades de desentrenamiento. Además, tomó cuatro unidades de trabajo, por ej., 4 semanas de reentrenamiento (b) para recuperarla adaptación perdida en la primer semana de desentrenamiento. Adaptado de Booth (1977).
Figura 2. Influencia de la duración del esfuerzo de ejercicio sobre la adaptación muscular. Desde una perspectiva práctica, uno podría asumir que el programa de ejercicio «a» fue realizado a una intensidad del 40 % del VO2 max, y «b » al 50 % del VO2 max, «c» al 70 del VO2 max, «d » al 85 % del VO2 max, y «e » al 100 % del VO2 max. Adaptado de Dudley y cols. (1982).
Al menos una parte del efecto benéfico de la intensidad de ejercicio en el incremento sobre las adaptaciones inducidas por el entrenamiento en los músculos puede atribuirse al efecto de la intensidad sobre el reclutamiento de las fibras musculares (Dudley y cols., 1982). Esto se ilustra en la Figura 3. Una vez obtenido el pico de performance (por ej., desarrollo de fuerza y/o producción de potencia) de un grupo de fibras musculares involucrado (ilustrado en la Figura 3 como las fibras altamente oxidativas), se consigue una mayor producción de potencia por el reclutamiento de fibras musculares adicionales. Esto es ilustrado por la marcada oxidación que se torna aparente en las fibras de baja oxidación, en la medida que las mismas son reclutadas para satisfacer las demandas de la prueba de ejercicio más intensa.
Entrenamiento a Corto Plazo
No toda la mejoría en la performance del ejercicio que acompaña al entrenamiento puede ser explicada por las adaptaciones bioquímicas a largo plazo. Por ejemplo, aún en los días iniciales de un programa de ejercicio, hay evidencia de una mejoría en la performance del músculo y en el metabolismo (Cadefau y cols. 1994; Green y cols. 1992), tal vez debido a que el entrenamiento breve causa un movimiento inicial en el control neuromuscular y/o cardiovascular que mejora la utilización de las fibras, el metabolismo y la distribución del flujo sanguíneo. Esto es un ejemplo de la complejidad de los cambios y la variedad de duraciones de entrenamiento requeridas para lograr adaptaciones particulares que llevan a un estado de entrenamiento óptimo. Toda la mejoría en la performance del ejercicio luego del entrenamiento no puede ser atribuida solamente a las adaptaciones musculares desarrolladas en este artículo. Otros cambios (por ej., neuromusculares, cardiovasculares y endócrinos) pueden ser instrumentos que contribuyen al incremento de la performance del ejercicio luego del entrenamiento por varias semanas o meses.
Figura 3. Influencia de la intensidad del esfuerzo del ejercicio sobre las adaptaciones inducidas por el entrenamiento, en el contenido mitocondrial del músculo. En la medida que los esfuerzos de ejercicio se tornan más intensos, más fibras de baja oxidación (Tipo IIb) son reclutadas y se adaptan al entrenamiento. Adaptado de Dudley y cols. (1982).
Desentrenamiento
Al tiempo que las adaptaciones significativas son inducidas por la actividad física, éstas se pierden gradualmente en personas que se tornan inactivas. El alcance y curso del tiempo de regresión no son conocidos para muchas variables, y probablemente estén relacionados al proceso exacto bajo consideración. Por ej., como se ilustra en la Figura 1, aproximadamente un 50% del contenido mitocondrial del músculo inducido por el entrenamiento puede ser perdido en una semana de desentrenamiento (Henriksson y Reitman, 1977; Terjung, 1979). Un retorno al entrenamiento hace recobrar las adaptaciones musculares; sin embargo, el tiempo requerido para reestablecer la condición entrenada de estado estable puede tomar más tiempo que el intervalo de desentrenamiento (Booth, 1977). Por ejemplo, en la Figura 1 se compara el tiempo relativamente largo (identificado como «b») necesario para recuperarse del tiempo breve de desentrenamiento que causó la declinación en el contenido mitocondrial.
Tipos de fibras reclutadas
Terjung y sus colegas ilustraron la importante interacción entre la intensidad y la duración para determinar el grado de adaptación mitocondrial en cada tipo de fibra (Dudley et al . 1982 ). Las fibras de tipo I, en particular, se reclutan más fácilmente a intensidades de ejercicio tan bajas como el 40 % o menos. A medida que la carga de trabajo aumenta y supera el 40 % de , se reclutan fibras de tipo IIa, y solo después de que la intensidad del ejercicio supera aproximadamente el 75 % de las fibras de tipo IIx se activan
Basado en este principio, que las unidades motoras deben ser reclutadas para adaptarse, los enfoques de entrenamiento han evolucionado desde el ejercicio tradicional de resistencia de larga distancia a modalidades alternativas que ahorran tiempo, como el entrenamiento de intervalos de velocidad (SIT), el entrenamiento de intervalos de alta intensidad ( HIIT) e incluso ejercicios de resistencia, que pueden conducir a diversas adaptaciones mitocondriales en el músculo.
Entrenamiento de Fuerza y Resistencia
El ejercicio de fuerza se asocia típicamente con la hipertrofia muscular y la mejora de la capacidad de generación de fuerza, a diferencia de la resistencia a la fatiga y la mejora del metabolismo de la energía aeróbica (Baar, 2006 ). También el ejercicio de resistencia de carga baja y alta de una sola serie puede estimular la biogénesis mitocondrial del músculo humano.
El hallazgo importante y novedoso en un estudio (2007 ) , , , y ( es que el entrenamiento con ejercicios de resistencia revierte muchos aspectos de la firma transcriptómica del envejecimiento. Esto implica que una mejora funcional en el envejecimiento muscular debido al ejercicio de resistencia se asocia con una mejora global del envejecimiento, en particular para las transcripciones relacionadas con la función mitocondrial.
Figura. Los cambios en la expresión génica asociados con el envejecimiento se revierten a niveles juveniles después de 6 meses de entrenamiento físico.
De los 596 genes asociados con la edad en individuos fisiológicamente normales, 179 de estos se asociaron de manera estadísticamente significativa con una respuesta al ejercicio en un FDR del 5%. una. Gene Index representa los 179 genes asociados con la edad y el ejercicio. La expresión de estos genes se ha normalizado en relación con los valores jóvenes (la expresión joven está representada por la línea oscura dibujada a lo largo del gráfico en 1). La expresión relativa promedio de cada gen dentro de los 14 individuos mayores se puede ver en relación con los individuos más jóvenes. Los genes que se regulan a la baja con la edad muestran una marcada reversión a niveles juveniles con el ejercicio, y los genes que se regulan al alza con la edad también muestran la misma tendencia a volver a los niveles juveniles en asociación con el ejercicio. b. Pruebas de permutación de genes asociados con el ejercicio y la edad, para determinar reversiones estadísticamente significativas con el ejercicio. El eje x (log2 ) representa la proporción de expresión génica posterior al ejercicio de sujetos mayores en comparación con individuos jóvenes, siendo 0 equivalente a la expresión génica «joven». Esto dio como resultado un valor de p <0,02. La conclusión es que las proporciones de log 2 están mucho más cerca de 0 (la expresión es la misma en el ejercicio viejo y en el joven) de lo que cabría esperar por casualidad (extracción aleatoria de los 596 genes relacionados con la edad).
¿Se mantiene la salud mitocondrial con la edad?
Una característica distintiva del envejecimiento es la pérdida progresiva de masa muscular, denominada sarcopenia, que se desarrolla a partir de cambios estructurales y moleculares que ocurren dentro del tejido y tiene amplias implicaciones en la movilidad, el riesgo de caídas y la aparición de diabetes tipo 2 y obesidad.
El proceso natural de envejecimiento junto con el sedentarismo prolongado promueve el deterioro de la integridad mitocondrial, lo que contribuye aún más a la naturaleza progresiva de la sarcopenia. El músculo envejecido puede exhibir tanto mitocondrias fragmentadas como orgánulos atípicamente agrandados.
El ejercicio regular va a mejorar al menos una parte de la disminución de la salud de los orgánulos con la edad. Sin embargo, esto se logra con una sensibilidad reducida al estímulo del ejercicio, ya que la activación de la quinasa de señalización se atenúa en el músculo con la edad, al igual que la capacidad de eliminar las mitocondrias disfuncionales a través de la mitofagia inducida por el ejercicio (Ljubicic & Hood, 2009 ; Chen et al .2018a ).
Por lo tanto, el ejercicio sigue siendo una estrategia confiable y no farmacológica para el mantenimiento de la salud metabólica en las últimas etapas de la vida.
La salud mitocondrial y el cerebro
Los efectos del ejercicio sobre la salud mitocondrial en otros tejidos se han estudiado escasamente, pero el reconocimiento de que el músculo secreta mioquinas, o exerquinas, durante el ejercicio, sugiere que los beneficios del ejercicio para la salud pueden incluir beneficios mediados por la actividad muscular en otros tejidos, como el cerebro.
El cerebro consume alrededor del 20% del consumo total de oxígeno del cuerpo y depende casi por completo de la producción de energía mitocondrial, ya que las neuronas tienen una actividad glucolítica (la glucólisis es la ruta metabólica encargada de oxidar la glucosa con la finalidad de obtener energía para la célula) limitada.
El ejercicio se ha asociado durante mucho tiempo con el bienestar de la salud neuronal, y se prescribe de forma rutinaria como estrategia terapéutica y preventiva en pacientes con demencia. El ejercicio también altera la estructura cerebral en pacientes con enfermedades neurodegenerativas, mediando aumentos en la angiogénesis, neurogénesis del hipocampo, plasticidad sináptica y disminuciones en la atrofia cerebral relacionada con la edad (Bernardo et al . 2016 ).
Conclusión
El papel de las mitocondrias en la contribución a la salud y la vitalidad en general está cada vez más enfocado, como lo demuestra el creciente volumen de investigación mitocondrial que se lleva a cabo dentro de la comunidad científica médica. De hecho, estos orgánulos están en el nexo de una variedad de vías de señalización y procesos biológicos que impactan en la salud celular, más allá de la provisión de ATP. El músculo esquelético es de gran interés porque comprende una gran proporción de la masa corporal, es altamente metabólico y su contenido mitocondrial es maleable a los estímulos externos. Por lo tanto, el músculo representa un tejido ideal para el estudio de las mitocondrias en la salud y la enfermedad.
Desde una perspectiva aplicada, mientras que el entrenamiento con ejercicios de resistencia ha sido apreciado durante mucho tiempo para mejorar la capacidad aeróbica del músculo esquelético a través de un mayor control de calidad, contenido y función mitocondrial, las modalidades alternativas de entrenamiento con ejercicios están ganando terreno como intervenciones viables capaces de inducir mejoras similares en las mitocondrias, mientras condensan un carga de trabajo similar en un período más corto y, por lo tanto, lograr un nivel de eficiencia de tiempo por turno de ejercicio. El trabajo adicional que explora diferentes programas de capacitación que mejoran la eficiencia del estímulo y fomentan un aumento en la adopción pública también presenta un área de estudio atractiva.
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