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cuando se encontr&#243; que la interleucina 6 &#40;IL-6&#41; era producida por el ME como respuesta a la contracci&#243;n muscular<span class="elsevierStyleSup">7</span>&#44; se han realizado diversos estudios que han permitido descubrir nuevas miocinas y entender el papel de estas en el proceso de regulaci&#243;n fisiol&#243;gica del ejercicio f&#237;sico&#44; tanto en personas aparentemente sanas como en pacientes cr&#243;nicamente enfermos&#46;</p><p class="elsevierStylePara"> En el a&#241;o 2012 nuestro grupo de trabajo public&#243; la revisi&#243;n &#171;Papel de la producci&#243;n de miokinas a trav&#233;s del ejercicio&#187;<span class="elsevierStyleSup">8</span>&#44; donde se reunieron&#44; en su momento&#44; los hallazgos m&#225;s relevantes sobre el concepto de miocinas y su relaci&#243;n con el ejercicio&#46; Debido a los m&#250;ltiples avances respecto al tema&#44; esta revisi&#243;n pretende presentar los hallazgos m&#225;s recientes y representativos en torno a las miocinas&#44; corregir algunos conceptos y demostrar su aplicabilidad en la prescripci&#243;n del ejercicio f&#237;sico para la salud&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Metodolog&#237;a</span></p><p class="elsevierStylePara"> Se realiz&#243; una revisi&#243;n sist&#233;mica exploratoria <span class="elsevierStyleItalic">&#40;scoping review&#41;</span> dada la dificultad para ubicar estudios cl&#237;nicos controlados&#44; siguiendo las recomendaciones de estandarizaci&#243;n de revisiones PRISMA<span class="elsevierStyleSup">9</span>&#46; Se eligieron art&#237;culos originales y revisiones sistem&#225;ticas que incluyeran los t&#233;rminos de b&#250;squeda miocinas&#44; ejercicio f&#237;sico y regulaci&#243;n metab&#243;lica como objeto de estudio&#44; entre enero de 2007 y noviembre de 2017 en ingl&#233;s o en espa&#241;ol&#46;</p><p class="elsevierStylePara"> Las bases de datos utilizadas fueron&#58; Pubmed&#44; Web of Science&#44; Ovid&#44; Science Direct&#46; La cadena de b&#250;squeda utiliz&#243; los t&#233;rminos&#58; &#40;Myokines AND exercise&#41;&#44; &#40;Interleukin 6 AND exercise&#41;&#44; &#40;LIF AND exercise&#41;&#44; &#40;Interleukin 15 AND exercise&#41;&#44; &#40;BDNF AND exercise&#41;&#44; &#40;FGF21 AND exercise&#41;&#46; En total se encontraron 3&#46;671 art&#237;culos&#44; de los cuales se seleccionaron 75 art&#237;culos&#44; incluy&#233;ndose 4 art&#237;culos que por su relevancia fueron considerados en la revisi&#243;n&#46; El flujograma de la b&#250;squeda y selecci&#243;n de los art&#237;culos se encuentra en la figura 1&#46;</p><p class="elsevierStylePara"><img alt="Figura 1&#46; Diagrama de flujo de la b&#250;squeda y selecci&#243;n de art&#237;culos&#46;" src="277v53n200-90463442fig1.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Figura 1&#46; </span>Diagrama de flujo de la b&#250;squeda y selecci&#243;n de art&#237;culos&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Resultados</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">El m&#250;sculo esquel&#233;tico como &#243;rgano con propiedades endocrinas</span></p><p class="elsevierStylePara"> El ME fue considerado durante mucho tiempo como un &#243;rgano encargado &#250;nicamente de la locomoci&#243;n&#44; el almacenamiento de prote&#237;nas y la generaci&#243;n de calor&#46; Sin embargo&#44; en la actualidad se sabe que el ME tiene una alta capacidad de expresi&#243;n y represi&#243;n de genes dada por se&#241;ales intracelulares que se presentan especialmente en el ejercicio&#46; Dentro de los segundos mensajeros identificados est&#225;n el aumento del calcio intracelular&#44; la depleci&#243;n del adenosin trifosfato &#40;ATP&#41;&#44; nicotinamida adenina dinucle&#243;tido &#40;NAD&#41; y el aumento de especies reactivas de ox&#237;geno &#40;ROS&#41;&#59; adem&#225;s de se&#241;ales extracelulares como&#58; la presi&#243;n de ox&#237;geno extracelular&#44; se&#241;ales endocrinas y est&#237;mulos mec&#225;nicos&#44; entre otros<span class="elsevierStyleSup">10</span>&#46;</p><p class="elsevierStylePara"> El principal regulador de la actividad g&#233;nica&#44; en relaci&#243;n con el ejercicio&#44; est&#225; constituido por el coactivador 1&#945; del receptor activador de la proliferaci&#243;n de peroxisomas gamma &#40;PCG-1&#945;&#41;<span class="elsevierStyleSup">11</span>&#44; una prote&#237;na necesaria para la transcripci&#243;n de genes que induce&#44; entre otras funciones&#44; los procesos adaptativos del ME&#46; Algunas respuestas asociadas al PCG-1&#945; son&#58; el aumento de la expresi&#243;n de receptores de insulina&#44; la captaci&#243;n de &#225;cidos grasos y glucosa&#44; el almacenamiento de gluc&#243;geno y la biog&#233;nesis mitocondrial<span class="elsevierStyleSup">11</span>&#46;</p><p class="elsevierStylePara"> El PCG-1&#945; favorece tambi&#233;n la s&#237;ntesis de miocinas con efecto endocrino sobre el mismo ME y &#243;rganos como el tejido adiposo<span class="elsevierStyleSup">12</span>&#44; el hueso<span class="elsevierStyleSup">13</span>&#44; el cerebro<span class="elsevierStyleSup">14</span>&#44; el p&#225;ncreas<span class="elsevierStyleSup">15</span>&#44; el intestino<span class="elsevierStyleSup">16</span> y la grasa parda17&#44; entre otros&#46; El t&#233;rmino miocinas fue acu&#241;ado en 2003 por la Dra&#46; Bente Klarlund Pedersen en el centro de investigaci&#243;n muscular en Copenhague &#40;Dinamarca&#41;<span class="elsevierStyleSup">18</span>&#44; y mediante el estudio del secretoma muscular se han encontrado cientos de sustancias que se expresan en respuesta al ejercicio<span class="elsevierStyleSup">19</span>&#46; Un resumen gr&#225;fico de la producci&#243;n de miocinas por el ejercicio se encuentra en la figura 2&#46;</p><p class="elsevierStylePara"><img alt="Figura 2&#46; ATP&#58; adenos&#237;n trifosfato&#59; NAD&#58; nicotinamida adenina dinucle&#243;tido&#59; ROS&#58; especies reactivas de ox&#237;geno&#59; HIF&#58; factor inducido por hipoxia&#59; cAMP&#58; AMP c&#237;clico&#59; PCG-1&#945;&#58; coactivador 1&#945; del receptor activador de la proliferaci&#243;n de peroxisomas gamma&#59; GLUT4&#58; transportador de glucosa tipo 4&#59; IL-6&#58; interleucina 6&#59; LIF&#58; factor inhibidor de la leucemia&#59; Il-15&#58; interleucina 15&#59; BDNF&#58; factor neurotr&#243;fico derivado del cerebro&#59; FGF21&#58; factor de crecimiento fibrobl&#225;stico 21&#46;" src="277v53n200-90463442fig2.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Figura 2&#46; </span>ATP&#58; adenos&#237;n trifosfato&#59; NAD&#58; nicotinamida adenina dinucle&#243;tido&#59; ROS&#58; especies reactivas de ox&#237;geno&#59; HIF&#58; factor inducido por hipoxia&#59; cAMP&#58; AMP c&#237;clico&#59; PCG-1&#945;&#58; coactivador 1&#945; del receptor activador de la proliferaci&#243;n de peroxisomas gamma&#59; GLUT4&#58; transportador de glucosa tipo 4&#59; IL-6&#58; interleucina 6&#59; LIF&#58; factor inhibidor de la leucemia&#59; Il-15&#58; interleucina 15&#59; BDNF&#58; factor neurotr&#243;fico derivado del cerebro&#59; FGF21&#58; factor de crecimiento fibrobl&#225;stico 21&#46;</p><p class="elsevierStylePara"> A continuaci&#243;n se describen los hallazgos m&#225;s recientes en torno de las principales miocinas y su potencial aplicaci&#243;n&#44; tanto en prescripci&#243;n del ejercicio f&#237;sico para la salud&#44; como en entrenamiento deportivo&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Interleucina 6</span></p><p class="elsevierStylePara"> La IL-6 es una prote&#237;na de 212 amino&#225;cidos y un peso de ~26 kDa&#44; producida por el tejido adiposo&#44; el ME y diversas c&#233;lulas del sistema inmune<span class="elsevierStyleSup">20</span>&#46; Tiene asociaci&#243;n con el ejercicio f&#237;sico y su concentraci&#243;n plasm&#225;tica aumenta varias veces posterior a este<span class="elsevierStyleSup">21</span> como resultado de la contracci&#243;n muscular y los cambios en el comportamiento energ&#233;tico intracelular<span class="elsevierStyleSup">22</span>&#46;</p><p class="elsevierStylePara"> El receptor de membrana de la IL-6 &#40;IL-6R&#41; requiere una pareja de glucoprote&#237;nas que act&#250;an como co-receptores &#40;gp130&#41; para formar el complejo IL-6-IL6R-gp130 y ejercer su acci&#243;n intracelular&#46; Dado que pocas c&#233;lulas expresan el IL-6R&#44; a diferencia del gp130&#44; presente en pr&#225;cticamente todas las poblaciones celulares<span class="elsevierStyleSup">23</span>&#44; la IL-6 requiere un receptor soluble &#40;sIL-6R&#41;<span class="elsevierStyleSup">24</span> para unirse a todas estas&#46;</p><p class="elsevierStylePara"> Al utilizar receptores solubles la se&#241;alizaci&#243;n se denomina &#171;trans&#187;&#44; y al utilizar receptores de membrana la se&#241;alizaci&#243;n se denomina &#171;cl&#225;sica&#187;<span class="elsevierStyleSup">25</span>&#59; la se&#241;alizaci&#243;n cl&#225;sica es antiinflamatoria y la se&#241;alizaci&#243;n trans&#44; inflamatoria<span class="elsevierStyleSup">26</span>&#46;</p><p class="elsevierStylePara"> Durante el ejercicio f&#237;sico el ME produce IL-6&#44; pero no sIL-6R&#44; ya que este &#250;ltimo es producido por un clivaje enzim&#225;tico desde otras c&#233;lulas en presencia de citocinas inflamatorias como el factor de necrosis tumoral alfa &#40;TNF-&#945;&#41;<span class="elsevierStyleSup">27</span>&#46; De esta forma&#44; la IL-6 como miocina solo act&#250;a en c&#233;lulas que expresen IL-6R&#46; Al unirse a su receptor&#44; la se&#241;alizaci&#243;n intracelular involucra Janus cinasas &#40;JAK&#41;&#44; que fosforilan prote&#237;nas responsables de las se&#241;ales de transducci&#243;n y activadoras de la transcripci&#243;n &#40;STAT&#41;&#44; que en el n&#250;cleo favorecen la transcripci&#243;n de prote&#237;nas<span class="elsevierStyleSup">28</span>&#46; Las JAK tambi&#233;n fosforilan prote&#237;ncinasas activadas por AMP &#40;AMPK&#41; y fosfatidil inositol 3 cinasa &#40;PI3K&#41;<span class="elsevierStyleSup">29</span>&#44; potenciando la captaci&#243;n y la utilizaci&#243;n de sustratos energ&#233;ticos&#44; el aumento de la sensibilidad a la insulina y la oxidaci&#243;n de &#225;cidos grasos<span class="elsevierStyleSup">30</span>&#46; Adem&#225;s de esto&#44; la IL-6 participa en la hipertrofia y la miog&#233;nesis por est&#237;mulos generados sobre c&#233;lulas sat&#233;lite<span class="elsevierStyleSup">31</span>&#46;</p><p class="elsevierStylePara"> Adem&#225;s&#44; la IL-6 aumenta la lip&#243;lisis y la sensibilidad a la insulina en el tejido adiposo<span class="elsevierStyleSup">32</span>&#44; optimiza la producci&#243;n de insulina en el p&#225;ncreas<span class="elsevierStyleSup">33</span>&#44; y en el h&#237;gado incrementa la glucogen&#243;lisis y lip&#243;lisis<span class="elsevierStyleSup">34</span>&#46; Tambi&#233;n se ha encontrado que la elevaci&#243;n aguda de IL-6 en el coraz&#243;n limita las lesiones cardiacas y tiene un papel cardioprotector&#44; contrario a la elevaci&#243;n cr&#243;nica&#44; que tiene efectos delet&#233;reos<span class="elsevierStyleSup">35</span>&#46;</p><p class="elsevierStylePara"> La elevaci&#243;n aguda de la concentraci&#243;n plasm&#225;tica de IL-6 genera tambi&#233;n un efecto antiinflamatorio y regula la respuesta inflamatoria aguda&#46; Esto se presenta cuando la liberaci&#243;n de citocinas antiinflamatorias permite la IL-1 &#40;IL-1ra&#41; y la IL10<span class="elsevierStyleSup">40</span>&#44; antagonistas del receptor&#44; e inhibe la producci&#243;n de TNF-&#945;<span class="elsevierStyleSup">36</span>&#46;</p><p class="elsevierStylePara"> La creciente evidencia de los efectos ben&#233;ficos de la IL-6 contrasta con la visi&#243;n cl&#225;sica de su efecto inflamatorio&#46; Durante el ejercicio la IL-6 puede aumentar hasta 100 veces su concentraci&#243;n basal&#44; siendo un aumento agudo con vida media corta&#44; diferente a la inflamaci&#243;n&#44; donde la IL-6 aumenta en compa&#241;&#237;a de otras citocinas inflamatorias como el TNF-&#945;<span class="elsevierStyleSup">37</span> &#40;fig&#46; 3&#41;&#46;</p><p class="elsevierStylePara"><img alt="Figura 3&#46; Respuestas endocrinas y autocrinas de la interleucina 6 &#40;IL-6&#41; y el factor inhibidor de la leucemia &#40;LIF&#41;&#46; P13K&#58; fosfatidil inositol 3 cinasa&#59; AMPK&#58; prote&#237;na cinasa activada por AMP&#59; JAK&#58; cinasa JAK&#59; STAT&#58; transducci&#243;n de se&#241;ales y de los activadores de la transcripci&#243;n&#46;" src="277v53n200-90463442fig3.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Figura 3&#46; </span>Respuestas endocrinas y autocrinas de la interleucina 6 &#40;IL-6&#41; y el factor inhibidor de la leucemia &#40;LIF&#41;&#46; P13K&#58; fosfatidil inositol 3 cinasa&#59; AMPK&#58; prote&#237;na cinasa activada por AMP&#59; JAK&#58; cinasa JAK&#59; STAT&#58; transducci&#243;n de se&#241;ales y de los activadores de la transcripci&#243;n&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Factor inhibidor de la leucemia</span></p><p class="elsevierStylePara"> El factor inhibidor de la leucemia &#40;LIF&#41; es una prote&#237;na de 19&#44;7 kDa formada por 181 amino&#225;cidos asociada a la diferenciaci&#243;n de c&#233;lulas mieloides leuc&#233;micas y al est&#237;mulo para la formaci&#243;n de c&#233;lulas hematopoy&#233;ticas<span class="elsevierStyleSup">38</span>&#46; El LIF comparte el co-receptor gp130 con la IL-6&#44; por lo que tiene buena parte de los efectos inflamatorios y antiinflamatorios&#46; En relaci&#243;n con el ejercicio&#44; el LIF se asocia a hipertrofia muscular<span class="elsevierStyleSup">39</span>&#44; y por acci&#243;n paracrina sobre las c&#233;lulas sat&#233;lite&#44; a hiperplasia muscular<span class="elsevierStyleSup">40</span>&#46; Adem&#225;s&#44; se ha planteado recientemente que el LIF incrementa la captaci&#243;n de glucosa por parte del ME<span class="elsevierStyleSup">41</span> en ratones &#40;fig&#46; 3&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Interleucina 15</span></p><p class="elsevierStylePara"> La interleucina 15 &#40;IL-15&#41; es una citocina de 12&#44;9 kDa&#59; descubierta en 1994 en linfocitos T&#44; usualmente se ha relacionado con procesos inflamatorios<span class="elsevierStyleSup">42</span>&#46; Sin embargo&#44; la IL-15 tambi&#233;n es producida por el ME en respuesta al ejercicio &#40;especialmente en entrenamiento de fuerza&#41;<span class="elsevierStyleSup">43</span>&#44; encontrando receptores de IL-15 &#40;IL15R&#945;&#41; en las c&#233;lulas responsables del control energ&#233;tico&#58; los rabdomiocitos&#44; los adipocitos y los hepatocitos<span class="elsevierStyleSup">44</span>&#46;</p><p class="elsevierStylePara"> La se&#241;alizaci&#243;n intracelular del IL15R&#945; tambi&#233;n se encuentra asociada al sistema JAK&#47;STAT&#44; lo cual explica la similitud que existe en las respuestas metab&#243;licas con la IL-6 y el LIF<span class="elsevierStyleSup">45</span>&#46; Una mayor expresi&#243;n de IL-15 en el ME lleva a una mayor captaci&#243;n de glucosa &#40;al parecer por la expresi&#243;n de receptores GLUT4&#41;<span class="elsevierStyleSup">46</span>&#44; mayor captaci&#243;n de &#225;cidos grasos y aumento de la expresi&#243;n de genes que favorecen los procesos oxidativos<span class="elsevierStyleSup">47</span> generando un efecto antioxidante adicional<span class="elsevierStyleSup">48</span>&#46; En un principio se expuso la IL-15 como activador de la s&#237;ntesis proteica&#59; sin embargo&#44; la evidencia reciente se ha centrado no solo en su acci&#243;n anab&#243;lica&#44; sino en su efecto a nivel de la regulaci&#243;n del metabolismo de los rabdomiocitos<span class="elsevierStyleSup">49</span>&#46;</p><p class="elsevierStylePara"> En el tejido adiposo la IL-15 favorece la lip&#243;lisis al producir una mayor actividad mitocondrial<span class="elsevierStyleSup">50</span> e inhibir la diferenciaci&#243;n de los preadipocitos<span class="elsevierStyleSup">51</span>&#46; Se da as&#237; una relaci&#243;n inversamente proporcional entre la concentraci&#243;n de IL-15 en plasma y el tejido adiposo&#44; especialmente visceral<span class="elsevierStyleSup">52</span>&#46; En la grasa parda&#44; la IL-15 aumenta la expresi&#243;n de prote&#237;nas desacopladoras&#44; el trasporte de &#225;cidos grasos y el efecto termog&#233;nico<span class="elsevierStyleSup">53</span>&#44; lo que indica que la IL-15 podr&#237;a generar cambios interesantes en la composici&#243;n corporal&#46; Sin embargo&#44; los efectos descritos anteriormente son resultados de experimentaci&#243;n en ratones&#44; y falta estudiar las respuestas fisiol&#243;gicas en humanos<span class="elsevierStyleSup">54</span>&#46;</p><p class="elsevierStylePara"> Recientemente&#44; la IL-15 ha sido descrita como un importante modulador del sistema inmune con efecto antiinflamatorio&#44; al reducir la expresi&#243;n del TNF-&#945;<span class="elsevierStyleSup">55</span>&#44; con potencial efecto ben&#233;fico en enfermedades como la obesidad y la diabetes mellitus tipo 2 &#40;DM2&#41;<span class="elsevierStyleSup">56</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Factor neurotr&#243;fico derivado del cerebro</span></p><p class="elsevierStylePara"> El factor neurotr&#243;fico derivado del cerebro &#40;BDNF&#41; es una prote&#237;na con un peso de 27 kDa&#44; producida especialmente por el sistema nervioso central&#44; con un importante papel en el desarrollo neuronal y en los procesos de memoria y aprendizaje<span class="elsevierStyleSup">57</span>&#46; Se han encontrado niveles bajos de BDNF en enfermedades neurodegenerativas y metab&#243;licas como obesidad&#44; DM2 y enfermedad cardiovascular<span class="elsevierStyleSup">58</span>&#46;</p><p class="elsevierStylePara"> El BDNF se une a un receptor quinasa B relacionado con la tropomiosina &#40;TrkB&#41;&#44; donde interacciona con diversos segundos mensajeros incluyendo el PI3K&#44; que explica en gran medida sus funciones metab&#243;licas y mitog&#233;nicas<span class="elsevierStyleSup">59</span>&#46; En la actualidad el BDNF es considerado una miocina producida durante el ejercicio f&#237;sico especialmente aer&#243;bico y en condiciones de estr&#233;s energ&#233;tico<span class="elsevierStyleSup">60&#44;61</span>&#46;</p><p class="elsevierStylePara"> Por acci&#243;n autocrina&#44; el BDNF tiene un papel importante en la regeneraci&#243;n y&#44; probablemente&#44; en la adaptaci&#243;n muscular secundaria al ejercicio<span class="elsevierStyleSup">62</span>&#46; Por acci&#243;n endocrina&#44; cambios en el BDNF plasm&#225;tico causados por el ejercicio f&#237;sico se relacionan con efectos en la corteza cerebral&#44; optimizando la ejecuci&#243;n de funciones mentales superiores&#44; especialmente en adultos mayores<span class="elsevierStyleSup">63</span>&#46; Adicionalmente&#44; el BDNF genera mayor oxidaci&#243;n de grasas&#44; disminuci&#243;n en el tama&#241;o del tejido adiposo&#44; mayor sensibilidad a la insulina y una reducci&#243;n del apetito por interacci&#243;n directa a nivel hipotal&#225;mico<span class="elsevierStyleSup">64</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Factor de crecimiento fibrobl&#225;stico 21</span></p><p class="elsevierStylePara"> El factor de crecimiento fibrobl&#225;stico 21 &#40;FGF-21&#41; pertenece a una familia de factores de crecimiento producidos por varias c&#233;lulas y con efectos fisiol&#243;gicos controvertidos<span class="elsevierStyleSup">65</span>&#46; Forma parte de una superfamilia de factores de crecimiento y su peso molecular oscila entre 17 y 26 kDa<span class="elsevierStyleSup">64</span>&#46; El FGF-21 se une a un receptor de membrana &#40;FGFR1&#41; y requiere un cofactor enzim&#225;tico denominado &#946;-Klotho&#46; El complejo FGFR1&#47;&#946;-Klotho se encuentra en el tejido adiposo y el ME&#44; y est&#225; relacionado intracelularmente con la fosforilaci&#243;n de STAT y otros reguladores de la expresi&#243;n proteica&#44; como las prote&#237;ncinasas activadas por mit&#243;genos &#40;MAPK&#41;<span class="elsevierStyleSup">66</span>&#46;</p><p class="elsevierStylePara"> El FGF-21 es producido por el ME durante el ejercicio f&#237;sico<span class="elsevierStyleSup">67</span> y lleva a una actividad metab&#243;lica muscular incrementada&#44; con mayor capacidad oxidativa de glucosa y &#225;cidos grasos<span class="elsevierStyleSup">68</span>&#44; adem&#225;s de un importante efecto antioxidante<span class="elsevierStyleSup">69</span>&#46; Sin embargo&#44; su efecto como miocina es controvertido&#44; ya que&#44; en condiciones de no ejercicio e incluso en m&#250;ltiples patolog&#237;as&#44; es posible encontrarlo aumentado&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Otras miocinas con efecto metab&#243;lico</span></p><p class="elsevierStylePara"> En la actualidad existen otras miocinas que son objeto de investigaci&#243;n por su potencial efecto metab&#243;lico&#58; la mionectina&#44; que relaciona el ejercicio con el metabolismo de &#225;cidos grasos<span class="elsevierStyleSup">70</span>&#59; la fibronectina tipo III &#40;irisina&#41;&#44; que tiene un potencial efecto en la formaci&#243;n de grasa beige a partir de grasa blanca<span class="elsevierStyleSup">71</span>&#59; el &#225;cido beta-aminoisobut&#237;rico &#40;BAIBA&#41;&#44; capaz de reducir el tejido adiposo<span class="elsevierStyleSup">72</span>&#59; la prote&#237;na secretada &#225;cida y rica en ciste&#237;na &#40;SPARC u osteonectina&#41;&#44; que tiene efecto en el metabolismo de los hidratos de carbono<span class="elsevierStyleSup">73</span>&#44; y la musclina&#44; que induce biog&#233;nesis mitocondrial<span class="elsevierStyleSup">74</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Discusi&#243;n</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Miocinas&#44; entrenamiento y salud</span></p><p class="elsevierStylePara"> Para garantizar un aporte continuo y suficiente de sustratos con los cuales reponer las reservas energ&#233;ticas y asegurar la reparaci&#243;n tisular&#44; el ME genera miocinas que favorecen la hidr&#243;lisis de triglic&#233;ridos en el tejido adiposo y una mayor captaci&#243;n de &#225;cidos grasos por parte del ME&#44; entre las que se encuentran la IL-6&#44; la IL-15&#44; el BDNF&#44; el FGF-21 y el BAIBA&#46; Estas&#44; a su vez&#44; generan una reducci&#243;n del tama&#241;o de los adipocitos &#40;especialmente viscerales&#41;&#44; lo que tiene un efecto interesante en relaci&#243;n con los efectos del ejercicio f&#237;sico sobre enfermedades como la obesidad<span class="elsevierStyleSup">75</span>&#46;</p><p class="elsevierStylePara"> Dado que el ME tambi&#233;n utiliza hidratos de carbono durante el ejercicio&#44; algunas miocinas &#40;IL-6&#44; LIF&#44; IL-15&#44; FGF-21&#44; FNDC5&#44; SPARC&#41; tambi&#233;n favorecen la expresi&#243;n de GLUT4 en el ME por mecanismos independientes de la insulina&#44; lo que reduce las concentraciones plasm&#225;ticas de glucosa durante el ejercicio y hasta 24 h posterior a este&#46; Estos efectos refuerzan el impacto&#44; ya bien conocido&#44; que tiene el ejercicio f&#237;sico sobre la prevenci&#243;n y el manejo de las diversas formas de diabetes mellitus<span class="elsevierStyleSup">75</span>&#46;</p><p class="elsevierStylePara"> Dado que la inflamaci&#243;n&#44; al igual que el ejercicio&#44; requiere sustratos metab&#243;licos&#44; es posible entender c&#243;mo varias de la miocinas tienen relaci&#243;n con el sistema inmune y est&#225;n involucradas en procesos inflamatorios&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Consideraciones finales</span></p><p class="elsevierStylePara"> Los hallazgos generados hasta el momento en la comprensi&#243;n de las miocinas permiten abrir un promisorio campo de investigaci&#243;n en torno de la comunicaci&#243;n qu&#237;mica entre el m&#250;sculo y otros &#243;rganos&#44; lo que permitir&#225;&#58; el desarrollo de f&#225;rmacos que act&#250;en como agonistas de los efectos ben&#233;ficos del ejercicio&#44; siendo probablemente m&#225;s importante a&#250;n la investigaci&#243;n en torno de la optimizaci&#243;n e individualizaci&#243;n de programas de entrenamiento y ejercicio f&#237;sico para la salud&#46; Un resumen general de las miocinas descritas y sus efectos en el cuerpo puede verse en la figura 4&#46;</p><p class="elsevierStylePara"><img alt="Figura 4&#46; IL-6&#58; interleucina 6&#59; LIF&#58; factor inhibidor de la leucemia&#59; Il-15&#58; interleucina 15&#59; PI3K&#58; fosfatidil inositol 3 cinasa&#59; BDNG&#58; factor neurotr&#243;fico derivado del cerebro&#59; FGF21&#58; factor de crecimiento fibrobl&#225;stico 21&#59; AMPK&#58; prote&#237;na cinasa activada per AMP&#59; STAT&#58; transducci&#243;n de se&#241;ales y de los activadores de la transcripci&#243;n&#46;" src="277v53n200-90463442fig4.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Figura 4&#46; </span>IL-6&#58; interleucina 6&#59; LIF&#58; factor inhibidor de la leucemia&#59; Il-15&#58; interleucina 15&#59; PI3K&#58; fosfatidil inositol 3 cinasa&#59; BDNG&#58; factor neurotr&#243;fico derivado del cerebro&#59; FGF21&#58; factor de crecimiento fibrobl&#225;stico 21&#59; AMPK&#58; prote&#237;na cinasa activada per AMP&#59; STAT&#58; transducci&#243;n de se&#241;ales y de los activadores de la transcripci&#243;n&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicto de intereses</span></p><p class="elsevierStylePara"> Los autores declaran que no tienen ning&#250;n conflicto de intereses&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Agradecimientos</span></p><p class="elsevierStylePara"> Al grupo de investigaci&#243;n en procesamiento de se&#241;ales biol&#243;gicas en medicina &#40;PROSEIM&#41; y a la facultad de Medicina de la Universidad de La Sabana por el apoyo en tiempo para el desarrollo de esta revisi&#243;n&#46;</p><hr></hr><p class="elsevierStylePara"> Recibido el 26 de febrero de 2018&#59;<br></br> aceptado el 4 de septiembre de 2018</p><p class="elsevierStylePara"> &#42; Autor para correspondencia&#46;<br></br><span class="elsevierStyleItalic">Correo electr&#243;nico&#58;</span><a href="mailto&#58;daniel&#46;botero&#64;unisabana&#46;edu&#46;co" class="elsevierStyleCrossRefs">daniel&#46;botero&#64;unisabana&#46;edu&#46;co</a> &#40;D&#46;A&#46; Botero-Rosas&#41;&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara"> Malos h&#225;bitos como el sedentarismo&#44; la obesidad o la sobrealimentaci&#243;n se relacionan con la evoluci&#243;n de estados pro-inflamatorios cr&#243;nicos&#44; principal factor de riesgo para el desarrollo de enfermedades cr&#243;nicas no transmisibles &#40;ECNT&#41;&#46; Sin embargo&#44; modificar &#250;nicamente el peso corporal no reduce el riesgo&#59; es necesario tambi&#233;n aumentar la masa muscular&#44; dando a entender que existe una relaci&#243;n ben&#233;fica asociada a este tejido que no est&#225; totalmente dilucidada&#46; Durante los &#250;ltimos a&#241;os las explicaciones celulares m&#225;s interesantes se han centrado en la producci&#243;n de citocinas musculares denominadas miocinas&#44; dentro de las que destacan la interleucina 6&#44; el factor inhibidor de la leucemia&#44; entre otras recientemente estudiadas como la mionectina y la musclina&#46; Debido a los m&#250;ltiples avances&#44; se realiza una revisi&#243;n que pretende presentar los hallazgos m&#225;s recientes y representativos acerca de las miocinas&#44; corregir conceptos y demostrar su aplicabilidad en la prescripci&#243;n del ejercicio f&#237;sico para la salud&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara"> Bad habits such as sedentary lifestyle&#44; obesity or overfeeding&#44; are related to the production of chronic pro-inflammatory states&#44; the main risk factor for the development of chronic noncommunicable diseases &#40;CNCD&#41;&#46; However&#44; modifying only the body weight does not reduce the risk&#44; it is necessary to increase muscle mass&#44; this implies there is a beneficial relationship associated with the muscle tissue that is not fully elucidated&#46; During the last years&#44; the most interesting cellular explanations have focused on the production of muscle cytokines called myokines&#44; among which stand out interleukin 6&#44; the inhibitory factor of leukemia&#44; with others recently studied such as mionectine and muscline&#46; Due to the multiple advances&#44; this paper intends to present the most recent and representative findings about myokines&#44; correct concepts and demonstrate their applicability in the prescription of physical exercise for health&#46;</p>"
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Miocinas y regulación metabólica, una revisión sistemática
A systematic review of “myokines and metabolic regulation”
Henry H. León-Arizaa, María P. Mendoza-Navarretea, María I. Maldonado-Arangoa, Daniel A. Botero-Rosasa
a Departamento de Morfofisiología, Facultad de Medicina, Universidad de la Sabana, Chía, Colombia.
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    "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Introducci&#243;n</span></p><p class="elsevierStylePara"> Los cambios en el estilo de vida durante los &#250;ltimos a&#241;os involucran ampliamente el sedentarismo&#44; la sobrealimentaci&#243;n&#44; la obesidad y la exposici&#243;n continua a sustancias t&#243;xicas&#46; Estos cambios se asocian al desarrollo de estados proinflamatorios cr&#243;nicos&#44; constituyendo el principal factor de riesgo para el desarrollo de enfermedades cr&#243;nicas no transmisibles &#40;ECNT&#41;<span class="elsevierStyleSup">1</span>&#46; Este estado pro-inflamatorio se acompa&#241;a de citocinas producidas principalmente por el sistema inmune&#44; el tejido adiposo o c&#233;lulas del sistema inmune asociadas al tejido adiposo &#40;especialmente macr&#243;fagos&#41;&#59; estas citocinas se conocen en la actualidad como adipocinas y sus receptores se expresan en m&#250;ltiples &#243;rganos&#44; contribuyendo al desarrollo de las ECNT<span class="elsevierStyleSup">2</span>&#46;</p><p class="elsevierStylePara"> Adem&#225;s de la amplia evidencia que relaciona la presencia de adipocinas con las ECNT&#44; en la actualidad es claro que una reducci&#243;n de la calidad y la cantidad de masa muscular esquel&#233;tica es tambi&#233;n un factor de riesgo en el desarrollo de ECNT<span class="elsevierStyleSup">3</span>&#46; Por tanto&#44; para mantener la salud no solo se debe pensar en tener un peso adecuado&#44; sino que es necesario mejorar la masa muscular<span class="elsevierStyleSup">4</span>&#46;</p><p class="elsevierStylePara"> En las &#250;ltimas d&#233;cadas&#44; m&#250;ltiples investigaciones han estudiado la relaci&#243;n que existe entre las respuestas ben&#233;ficas sist&#233;micas y la contracci&#243;n muscular generada por el ejercicio&#59; se sabe que el m&#250;sculo esquel&#233;tico &#40;ME&#41; genera respuestas hipoglucemiantes y antioxidantes<span class="elsevierStyleSup">5</span>&#59; sin embargo&#44; las explicaciones celulares m&#225;s interesantes se han enfocado en la producci&#243;n de citocinas musculares con acci&#243;n tanto endocrina como autoparacrina denominadas miocinas<span class="elsevierStyleSup">6</span>&#46;</p><p class="elsevierStylePara"> Desde el a&#241;o 2000&#44; cuando se encontr&#243; que la interleucina 6 &#40;IL-6&#41; era producida por el ME como respuesta a la contracci&#243;n muscular<span class="elsevierStyleSup">7</span>&#44; se han realizado diversos estudios que han permitido descubrir nuevas miocinas y entender el papel de estas en el proceso de regulaci&#243;n fisiol&#243;gica del ejercicio f&#237;sico&#44; tanto en personas aparentemente sanas como en pacientes cr&#243;nicamente enfermos&#46;</p><p class="elsevierStylePara"> En el a&#241;o 2012 nuestro grupo de trabajo public&#243; la revisi&#243;n &#171;Papel de la producci&#243;n de miokinas a trav&#233;s del ejercicio&#187;<span class="elsevierStyleSup">8</span>&#44; donde se reunieron&#44; en su momento&#44; los hallazgos m&#225;s relevantes sobre el concepto de miocinas y su relaci&#243;n con el ejercicio&#46; Debido a los m&#250;ltiples avances respecto al tema&#44; esta revisi&#243;n pretende presentar los hallazgos m&#225;s recientes y representativos en torno a las miocinas&#44; corregir algunos conceptos y demostrar su aplicabilidad en la prescripci&#243;n del ejercicio f&#237;sico para la salud&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Metodolog&#237;a</span></p><p class="elsevierStylePara"> Se realiz&#243; una revisi&#243;n sist&#233;mica exploratoria <span class="elsevierStyleItalic">&#40;scoping review&#41;</span> dada la dificultad para ubicar estudios cl&#237;nicos controlados&#44; siguiendo las recomendaciones de estandarizaci&#243;n de revisiones PRISMA<span class="elsevierStyleSup">9</span>&#46; Se eligieron art&#237;culos originales y revisiones sistem&#225;ticas que incluyeran los t&#233;rminos de b&#250;squeda miocinas&#44; ejercicio f&#237;sico y regulaci&#243;n metab&#243;lica como objeto de estudio&#44; entre enero de 2007 y noviembre de 2017 en ingl&#233;s o en espa&#241;ol&#46;</p><p class="elsevierStylePara"> Las bases de datos utilizadas fueron&#58; Pubmed&#44; Web of Science&#44; Ovid&#44; Science Direct&#46; La cadena de b&#250;squeda utiliz&#243; los t&#233;rminos&#58; &#40;Myokines AND exercise&#41;&#44; &#40;Interleukin 6 AND exercise&#41;&#44; &#40;LIF AND exercise&#41;&#44; &#40;Interleukin 15 AND exercise&#41;&#44; &#40;BDNF AND exercise&#41;&#44; &#40;FGF21 AND exercise&#41;&#46; En total se encontraron 3&#46;671 art&#237;culos&#44; de los cuales se seleccionaron 75 art&#237;culos&#44; incluy&#233;ndose 4 art&#237;culos que por su relevancia fueron considerados en la revisi&#243;n&#46; El flujograma de la b&#250;squeda y selecci&#243;n de los art&#237;culos se encuentra en la figura 1&#46;</p><p class="elsevierStylePara"><img alt="Figura 1&#46; Diagrama de flujo de la b&#250;squeda y selecci&#243;n de art&#237;culos&#46;" src="277v53n200-90463442fig1.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Figura 1&#46; </span>Diagrama de flujo de la b&#250;squeda y selecci&#243;n de art&#237;culos&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Resultados</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">El m&#250;sculo esquel&#233;tico como &#243;rgano con propiedades endocrinas</span></p><p class="elsevierStylePara"> El ME fue considerado durante mucho tiempo como un &#243;rgano encargado &#250;nicamente de la locomoci&#243;n&#44; el almacenamiento de prote&#237;nas y la generaci&#243;n de calor&#46; Sin embargo&#44; en la actualidad se sabe que el ME tiene una alta capacidad de expresi&#243;n y represi&#243;n de genes dada por se&#241;ales intracelulares que se presentan especialmente en el ejercicio&#46; Dentro de los segundos mensajeros identificados est&#225;n el aumento del calcio intracelular&#44; la depleci&#243;n del adenosin trifosfato &#40;ATP&#41;&#44; nicotinamida adenina dinucle&#243;tido &#40;NAD&#41; y el aumento de especies reactivas de ox&#237;geno &#40;ROS&#41;&#59; adem&#225;s de se&#241;ales extracelulares como&#58; la presi&#243;n de ox&#237;geno extracelular&#44; se&#241;ales endocrinas y est&#237;mulos mec&#225;nicos&#44; entre otros<span class="elsevierStyleSup">10</span>&#46;</p><p class="elsevierStylePara"> El principal regulador de la actividad g&#233;nica&#44; en relaci&#243;n con el ejercicio&#44; est&#225; constituido por el coactivador 1&#945; del receptor activador de la proliferaci&#243;n de peroxisomas gamma &#40;PCG-1&#945;&#41;<span class="elsevierStyleSup">11</span>&#44; una prote&#237;na necesaria para la transcripci&#243;n de genes que induce&#44; entre otras funciones&#44; los procesos adaptativos del ME&#46; Algunas respuestas asociadas al PCG-1&#945; son&#58; el aumento de la expresi&#243;n de receptores de insulina&#44; la captaci&#243;n de &#225;cidos grasos y glucosa&#44; el almacenamiento de gluc&#243;geno y la biog&#233;nesis mitocondrial<span class="elsevierStyleSup">11</span>&#46;</p><p class="elsevierStylePara"> El PCG-1&#945; favorece tambi&#233;n la s&#237;ntesis de miocinas con efecto endocrino sobre el mismo ME y &#243;rganos como el tejido adiposo<span class="elsevierStyleSup">12</span>&#44; el hueso<span class="elsevierStyleSup">13</span>&#44; el cerebro<span class="elsevierStyleSup">14</span>&#44; el p&#225;ncreas<span class="elsevierStyleSup">15</span>&#44; el intestino<span class="elsevierStyleSup">16</span> y la grasa parda17&#44; entre otros&#46; El t&#233;rmino miocinas fue acu&#241;ado en 2003 por la Dra&#46; Bente Klarlund Pedersen en el centro de investigaci&#243;n muscular en Copenhague &#40;Dinamarca&#41;<span class="elsevierStyleSup">18</span>&#44; y mediante el estudio del secretoma muscular se han encontrado cientos de sustancias que se expresan en respuesta al ejercicio<span class="elsevierStyleSup">19</span>&#46; Un resumen gr&#225;fico de la producci&#243;n de miocinas por el ejercicio se encuentra en la figura 2&#46;</p><p class="elsevierStylePara"><img alt="Figura 2&#46; ATP&#58; adenos&#237;n trifosfato&#59; NAD&#58; nicotinamida adenina dinucle&#243;tido&#59; ROS&#58; especies reactivas de ox&#237;geno&#59; HIF&#58; factor inducido por hipoxia&#59; cAMP&#58; AMP c&#237;clico&#59; PCG-1&#945;&#58; coactivador 1&#945; del receptor activador de la proliferaci&#243;n de peroxisomas gamma&#59; GLUT4&#58; transportador de glucosa tipo 4&#59; IL-6&#58; interleucina 6&#59; LIF&#58; factor inhibidor de la leucemia&#59; Il-15&#58; interleucina 15&#59; BDNF&#58; factor neurotr&#243;fico derivado del cerebro&#59; FGF21&#58; factor de crecimiento fibrobl&#225;stico 21&#46;" src="277v53n200-90463442fig2.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Figura 2&#46; </span>ATP&#58; adenos&#237;n trifosfato&#59; NAD&#58; nicotinamida adenina dinucle&#243;tido&#59; ROS&#58; especies reactivas de ox&#237;geno&#59; HIF&#58; factor inducido por hipoxia&#59; cAMP&#58; AMP c&#237;clico&#59; PCG-1&#945;&#58; coactivador 1&#945; del receptor activador de la proliferaci&#243;n de peroxisomas gamma&#59; GLUT4&#58; transportador de glucosa tipo 4&#59; IL-6&#58; interleucina 6&#59; LIF&#58; factor inhibidor de la leucemia&#59; Il-15&#58; interleucina 15&#59; BDNF&#58; factor neurotr&#243;fico derivado del cerebro&#59; FGF21&#58; factor de crecimiento fibrobl&#225;stico 21&#46;</p><p class="elsevierStylePara"> A continuaci&#243;n se describen los hallazgos m&#225;s recientes en torno de las principales miocinas y su potencial aplicaci&#243;n&#44; tanto en prescripci&#243;n del ejercicio f&#237;sico para la salud&#44; como en entrenamiento deportivo&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Interleucina 6</span></p><p class="elsevierStylePara"> La IL-6 es una prote&#237;na de 212 amino&#225;cidos y un peso de ~26 kDa&#44; producida por el tejido adiposo&#44; el ME y diversas c&#233;lulas del sistema inmune<span class="elsevierStyleSup">20</span>&#46; Tiene asociaci&#243;n con el ejercicio f&#237;sico y su concentraci&#243;n plasm&#225;tica aumenta varias veces posterior a este<span class="elsevierStyleSup">21</span> como resultado de la contracci&#243;n muscular y los cambios en el comportamiento energ&#233;tico intracelular<span class="elsevierStyleSup">22</span>&#46;</p><p class="elsevierStylePara"> El receptor de membrana de la IL-6 &#40;IL-6R&#41; requiere una pareja de glucoprote&#237;nas que act&#250;an como co-receptores &#40;gp130&#41; para formar el complejo IL-6-IL6R-gp130 y ejercer su acci&#243;n intracelular&#46; Dado que pocas c&#233;lulas expresan el IL-6R&#44; a diferencia del gp130&#44; presente en pr&#225;cticamente todas las poblaciones celulares<span class="elsevierStyleSup">23</span>&#44; la IL-6 requiere un receptor soluble &#40;sIL-6R&#41;<span class="elsevierStyleSup">24</span> para unirse a todas estas&#46;</p><p class="elsevierStylePara"> Al utilizar receptores solubles la se&#241;alizaci&#243;n se denomina &#171;trans&#187;&#44; y al utilizar receptores de membrana la se&#241;alizaci&#243;n se denomina &#171;cl&#225;sica&#187;<span class="elsevierStyleSup">25</span>&#59; la se&#241;alizaci&#243;n cl&#225;sica es antiinflamatoria y la se&#241;alizaci&#243;n trans&#44; inflamatoria<span class="elsevierStyleSup">26</span>&#46;</p><p class="elsevierStylePara"> Durante el ejercicio f&#237;sico el ME produce IL-6&#44; pero no sIL-6R&#44; ya que este &#250;ltimo es producido por un clivaje enzim&#225;tico desde otras c&#233;lulas en presencia de citocinas inflamatorias como el factor de necrosis tumoral alfa &#40;TNF-&#945;&#41;<span class="elsevierStyleSup">27</span>&#46; De esta forma&#44; la IL-6 como miocina solo act&#250;a en c&#233;lulas que expresen IL-6R&#46; Al unirse a su receptor&#44; la se&#241;alizaci&#243;n intracelular involucra Janus cinasas &#40;JAK&#41;&#44; que fosforilan prote&#237;nas responsables de las se&#241;ales de transducci&#243;n y activadoras de la transcripci&#243;n &#40;STAT&#41;&#44; que en el n&#250;cleo favorecen la transcripci&#243;n de prote&#237;nas<span class="elsevierStyleSup">28</span>&#46; Las JAK tambi&#233;n fosforilan prote&#237;ncinasas activadas por AMP &#40;AMPK&#41; y fosfatidil inositol 3 cinasa &#40;PI3K&#41;<span class="elsevierStyleSup">29</span>&#44; potenciando la captaci&#243;n y la utilizaci&#243;n de sustratos energ&#233;ticos&#44; el aumento de la sensibilidad a la insulina y la oxidaci&#243;n de &#225;cidos grasos<span class="elsevierStyleSup">30</span>&#46; Adem&#225;s de esto&#44; la IL-6 participa en la hipertrofia y la miog&#233;nesis por est&#237;mulos generados sobre c&#233;lulas sat&#233;lite<span class="elsevierStyleSup">31</span>&#46;</p><p class="elsevierStylePara"> Adem&#225;s&#44; la IL-6 aumenta la lip&#243;lisis y la sensibilidad a la insulina en el tejido adiposo<span class="elsevierStyleSup">32</span>&#44; optimiza la producci&#243;n de insulina en el p&#225;ncreas<span class="elsevierStyleSup">33</span>&#44; y en el h&#237;gado incrementa la glucogen&#243;lisis y lip&#243;lisis<span class="elsevierStyleSup">34</span>&#46; Tambi&#233;n se ha encontrado que la elevaci&#243;n aguda de IL-6 en el coraz&#243;n limita las lesiones cardiacas y tiene un papel cardioprotector&#44; contrario a la elevaci&#243;n cr&#243;nica&#44; que tiene efectos delet&#233;reos<span class="elsevierStyleSup">35</span>&#46;</p><p class="elsevierStylePara"> La elevaci&#243;n aguda de la concentraci&#243;n plasm&#225;tica de IL-6 genera tambi&#233;n un efecto antiinflamatorio y regula la respuesta inflamatoria aguda&#46; Esto se presenta cuando la liberaci&#243;n de citocinas antiinflamatorias permite la IL-1 &#40;IL-1ra&#41; y la IL10<span class="elsevierStyleSup">40</span>&#44; antagonistas del receptor&#44; e inhibe la producci&#243;n de TNF-&#945;<span class="elsevierStyleSup">36</span>&#46;</p><p class="elsevierStylePara"> La creciente evidencia de los efectos ben&#233;ficos de la IL-6 contrasta con la visi&#243;n cl&#225;sica de su efecto inflamatorio&#46; Durante el ejercicio la IL-6 puede aumentar hasta 100 veces su concentraci&#243;n basal&#44; siendo un aumento agudo con vida media corta&#44; diferente a la inflamaci&#243;n&#44; donde la IL-6 aumenta en compa&#241;&#237;a de otras citocinas inflamatorias como el TNF-&#945;<span class="elsevierStyleSup">37</span> &#40;fig&#46; 3&#41;&#46;</p><p class="elsevierStylePara"><img alt="Figura 3&#46; Respuestas endocrinas y autocrinas de la interleucina 6 &#40;IL-6&#41; y el factor inhibidor de la leucemia &#40;LIF&#41;&#46; P13K&#58; fosfatidil inositol 3 cinasa&#59; AMPK&#58; prote&#237;na cinasa activada por AMP&#59; JAK&#58; cinasa JAK&#59; STAT&#58; transducci&#243;n de se&#241;ales y de los activadores de la transcripci&#243;n&#46;" src="277v53n200-90463442fig3.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Figura 3&#46; </span>Respuestas endocrinas y autocrinas de la interleucina 6 &#40;IL-6&#41; y el factor inhibidor de la leucemia &#40;LIF&#41;&#46; P13K&#58; fosfatidil inositol 3 cinasa&#59; AMPK&#58; prote&#237;na cinasa activada por AMP&#59; JAK&#58; cinasa JAK&#59; STAT&#58; transducci&#243;n de se&#241;ales y de los activadores de la transcripci&#243;n&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Factor inhibidor de la leucemia</span></p><p class="elsevierStylePara"> El factor inhibidor de la leucemia &#40;LIF&#41; es una prote&#237;na de 19&#44;7 kDa formada por 181 amino&#225;cidos asociada a la diferenciaci&#243;n de c&#233;lulas mieloides leuc&#233;micas y al est&#237;mulo para la formaci&#243;n de c&#233;lulas hematopoy&#233;ticas<span class="elsevierStyleSup">38</span>&#46; El LIF comparte el co-receptor gp130 con la IL-6&#44; por lo que tiene buena parte de los efectos inflamatorios y antiinflamatorios&#46; En relaci&#243;n con el ejercicio&#44; el LIF se asocia a hipertrofia muscular<span class="elsevierStyleSup">39</span>&#44; y por acci&#243;n paracrina sobre las c&#233;lulas sat&#233;lite&#44; a hiperplasia muscular<span class="elsevierStyleSup">40</span>&#46; Adem&#225;s&#44; se ha planteado recientemente que el LIF incrementa la captaci&#243;n de glucosa por parte del ME<span class="elsevierStyleSup">41</span> en ratones &#40;fig&#46; 3&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Interleucina 15</span></p><p class="elsevierStylePara"> La interleucina 15 &#40;IL-15&#41; es una citocina de 12&#44;9 kDa&#59; descubierta en 1994 en linfocitos T&#44; usualmente se ha relacionado con procesos inflamatorios<span class="elsevierStyleSup">42</span>&#46; Sin embargo&#44; la IL-15 tambi&#233;n es producida por el ME en respuesta al ejercicio &#40;especialmente en entrenamiento de fuerza&#41;<span class="elsevierStyleSup">43</span>&#44; encontrando receptores de IL-15 &#40;IL15R&#945;&#41; en las c&#233;lulas responsables del control energ&#233;tico&#58; los rabdomiocitos&#44; los adipocitos y los hepatocitos<span class="elsevierStyleSup">44</span>&#46;</p><p class="elsevierStylePara"> La se&#241;alizaci&#243;n intracelular del IL15R&#945; tambi&#233;n se encuentra asociada al sistema JAK&#47;STAT&#44; lo cual explica la similitud que existe en las respuestas metab&#243;licas con la IL-6 y el LIF<span class="elsevierStyleSup">45</span>&#46; Una mayor expresi&#243;n de IL-15 en el ME lleva a una mayor captaci&#243;n de glucosa &#40;al parecer por la expresi&#243;n de receptores GLUT4&#41;<span class="elsevierStyleSup">46</span>&#44; mayor captaci&#243;n de &#225;cidos grasos y aumento de la expresi&#243;n de genes que favorecen los procesos oxidativos<span class="elsevierStyleSup">47</span> generando un efecto antioxidante adicional<span class="elsevierStyleSup">48</span>&#46; En un principio se expuso la IL-15 como activador de la s&#237;ntesis proteica&#59; sin embargo&#44; la evidencia reciente se ha centrado no solo en su acci&#243;n anab&#243;lica&#44; sino en su efecto a nivel de la regulaci&#243;n del metabolismo de los rabdomiocitos<span class="elsevierStyleSup">49</span>&#46;</p><p class="elsevierStylePara"> En el tejido adiposo la IL-15 favorece la lip&#243;lisis al producir una mayor actividad mitocondrial<span class="elsevierStyleSup">50</span> e inhibir la diferenciaci&#243;n de los preadipocitos<span class="elsevierStyleSup">51</span>&#46; Se da as&#237; una relaci&#243;n inversamente proporcional entre la concentraci&#243;n de IL-15 en plasma y el tejido adiposo&#44; especialmente visceral<span class="elsevierStyleSup">52</span>&#46; En la grasa parda&#44; la IL-15 aumenta la expresi&#243;n de prote&#237;nas desacopladoras&#44; el trasporte de &#225;cidos grasos y el efecto termog&#233;nico<span class="elsevierStyleSup">53</span>&#44; lo que indica que la IL-15 podr&#237;a generar cambios interesantes en la composici&#243;n corporal&#46; Sin embargo&#44; los efectos descritos anteriormente son resultados de experimentaci&#243;n en ratones&#44; y falta estudiar las respuestas fisiol&#243;gicas en humanos<span class="elsevierStyleSup">54</span>&#46;</p><p class="elsevierStylePara"> Recientemente&#44; la IL-15 ha sido descrita como un importante modulador del sistema inmune con efecto antiinflamatorio&#44; al reducir la expresi&#243;n del TNF-&#945;<span class="elsevierStyleSup">55</span>&#44; con potencial efecto ben&#233;fico en enfermedades como la obesidad y la diabetes mellitus tipo 2 &#40;DM2&#41;<span class="elsevierStyleSup">56</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Factor neurotr&#243;fico derivado del cerebro</span></p><p class="elsevierStylePara"> El factor neurotr&#243;fico derivado del cerebro &#40;BDNF&#41; es una prote&#237;na con un peso de 27 kDa&#44; producida especialmente por el sistema nervioso central&#44; con un importante papel en el desarrollo neuronal y en los procesos de memoria y aprendizaje<span class="elsevierStyleSup">57</span>&#46; Se han encontrado niveles bajos de BDNF en enfermedades neurodegenerativas y metab&#243;licas como obesidad&#44; DM2 y enfermedad cardiovascular<span class="elsevierStyleSup">58</span>&#46;</p><p class="elsevierStylePara"> El BDNF se une a un receptor quinasa B relacionado con la tropomiosina &#40;TrkB&#41;&#44; donde interacciona con diversos segundos mensajeros incluyendo el PI3K&#44; que explica en gran medida sus funciones metab&#243;licas y mitog&#233;nicas<span class="elsevierStyleSup">59</span>&#46; En la actualidad el BDNF es considerado una miocina producida durante el ejercicio f&#237;sico especialmente aer&#243;bico y en condiciones de estr&#233;s energ&#233;tico<span class="elsevierStyleSup">60&#44;61</span>&#46;</p><p class="elsevierStylePara"> Por acci&#243;n autocrina&#44; el BDNF tiene un papel importante en la regeneraci&#243;n y&#44; probablemente&#44; en la adaptaci&#243;n muscular secundaria al ejercicio<span class="elsevierStyleSup">62</span>&#46; Por acci&#243;n endocrina&#44; cambios en el BDNF plasm&#225;tico causados por el ejercicio f&#237;sico se relacionan con efectos en la corteza cerebral&#44; optimizando la ejecuci&#243;n de funciones mentales superiores&#44; especialmente en adultos mayores<span class="elsevierStyleSup">63</span>&#46; Adicionalmente&#44; el BDNF genera mayor oxidaci&#243;n de grasas&#44; disminuci&#243;n en el tama&#241;o del tejido adiposo&#44; mayor sensibilidad a la insulina y una reducci&#243;n del apetito por interacci&#243;n directa a nivel hipotal&#225;mico<span class="elsevierStyleSup">64</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Factor de crecimiento fibrobl&#225;stico 21</span></p><p class="elsevierStylePara"> El factor de crecimiento fibrobl&#225;stico 21 &#40;FGF-21&#41; pertenece a una familia de factores de crecimiento producidos por varias c&#233;lulas y con efectos fisiol&#243;gicos controvertidos<span class="elsevierStyleSup">65</span>&#46; Forma parte de una superfamilia de factores de crecimiento y su peso molecular oscila entre 17 y 26 kDa<span class="elsevierStyleSup">64</span>&#46; El FGF-21 se une a un receptor de membrana &#40;FGFR1&#41; y requiere un cofactor enzim&#225;tico denominado &#946;-Klotho&#46; El complejo FGFR1&#47;&#946;-Klotho se encuentra en el tejido adiposo y el ME&#44; y est&#225; relacionado intracelularmente con la fosforilaci&#243;n de STAT y otros reguladores de la expresi&#243;n proteica&#44; como las prote&#237;ncinasas activadas por mit&#243;genos &#40;MAPK&#41;<span class="elsevierStyleSup">66</span>&#46;</p><p class="elsevierStylePara"> El FGF-21 es producido por el ME durante el ejercicio f&#237;sico<span class="elsevierStyleSup">67</span> y lleva a una actividad metab&#243;lica muscular incrementada&#44; con mayor capacidad oxidativa de glucosa y &#225;cidos grasos<span class="elsevierStyleSup">68</span>&#44; adem&#225;s de un importante efecto antioxidante<span class="elsevierStyleSup">69</span>&#46; Sin embargo&#44; su efecto como miocina es controvertido&#44; ya que&#44; en condiciones de no ejercicio e incluso en m&#250;ltiples patolog&#237;as&#44; es posible encontrarlo aumentado&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Otras miocinas con efecto metab&#243;lico</span></p><p class="elsevierStylePara"> En la actualidad existen otras miocinas que son objeto de investigaci&#243;n por su potencial efecto metab&#243;lico&#58; la mionectina&#44; que relaciona el ejercicio con el metabolismo de &#225;cidos grasos<span class="elsevierStyleSup">70</span>&#59; la fibronectina tipo III &#40;irisina&#41;&#44; que tiene un potencial efecto en la formaci&#243;n de grasa beige a partir de grasa blanca<span class="elsevierStyleSup">71</span>&#59; el &#225;cido beta-aminoisobut&#237;rico &#40;BAIBA&#41;&#44; capaz de reducir el tejido adiposo<span class="elsevierStyleSup">72</span>&#59; la prote&#237;na secretada &#225;cida y rica en ciste&#237;na &#40;SPARC u osteonectina&#41;&#44; que tiene efecto en el metabolismo de los hidratos de carbono<span class="elsevierStyleSup">73</span>&#44; y la musclina&#44; que induce biog&#233;nesis mitocondrial<span class="elsevierStyleSup">74</span>&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Discusi&#243;n</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Miocinas&#44; entrenamiento y salud</span></p><p class="elsevierStylePara"> Para garantizar un aporte continuo y suficiente de sustratos con los cuales reponer las reservas energ&#233;ticas y asegurar la reparaci&#243;n tisular&#44; el ME genera miocinas que favorecen la hidr&#243;lisis de triglic&#233;ridos en el tejido adiposo y una mayor captaci&#243;n de &#225;cidos grasos por parte del ME&#44; entre las que se encuentran la IL-6&#44; la IL-15&#44; el BDNF&#44; el FGF-21 y el BAIBA&#46; Estas&#44; a su vez&#44; generan una reducci&#243;n del tama&#241;o de los adipocitos &#40;especialmente viscerales&#41;&#44; lo que tiene un efecto interesante en relaci&#243;n con los efectos del ejercicio f&#237;sico sobre enfermedades como la obesidad<span class="elsevierStyleSup">75</span>&#46;</p><p class="elsevierStylePara"> Dado que el ME tambi&#233;n utiliza hidratos de carbono durante el ejercicio&#44; algunas miocinas &#40;IL-6&#44; LIF&#44; IL-15&#44; FGF-21&#44; FNDC5&#44; SPARC&#41; tambi&#233;n favorecen la expresi&#243;n de GLUT4 en el ME por mecanismos independientes de la insulina&#44; lo que reduce las concentraciones plasm&#225;ticas de glucosa durante el ejercicio y hasta 24 h posterior a este&#46; Estos efectos refuerzan el impacto&#44; ya bien conocido&#44; que tiene el ejercicio f&#237;sico sobre la prevenci&#243;n y el manejo de las diversas formas de diabetes mellitus<span class="elsevierStyleSup">75</span>&#46;</p><p class="elsevierStylePara"> Dado que la inflamaci&#243;n&#44; al igual que el ejercicio&#44; requiere sustratos metab&#243;licos&#44; es posible entender c&#243;mo varias de la miocinas tienen relaci&#243;n con el sistema inmune y est&#225;n involucradas en procesos inflamatorios&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Consideraciones finales</span></p><p class="elsevierStylePara"> Los hallazgos generados hasta el momento en la comprensi&#243;n de las miocinas permiten abrir un promisorio campo de investigaci&#243;n en torno de la comunicaci&#243;n qu&#237;mica entre el m&#250;sculo y otros &#243;rganos&#44; lo que permitir&#225;&#58; el desarrollo de f&#225;rmacos que act&#250;en como agonistas de los efectos ben&#233;ficos del ejercicio&#44; siendo probablemente m&#225;s importante a&#250;n la investigaci&#243;n en torno de la optimizaci&#243;n e individualizaci&#243;n de programas de entrenamiento y ejercicio f&#237;sico para la salud&#46; Un resumen general de las miocinas descritas y sus efectos en el cuerpo puede verse en la figura 4&#46;</p><p class="elsevierStylePara"><img alt="Figura 4&#46; IL-6&#58; interleucina 6&#59; LIF&#58; factor inhibidor de la leucemia&#59; Il-15&#58; interleucina 15&#59; PI3K&#58; fosfatidil inositol 3 cinasa&#59; BDNG&#58; factor neurotr&#243;fico derivado del cerebro&#59; FGF21&#58; factor de crecimiento fibrobl&#225;stico 21&#59; AMPK&#58; prote&#237;na cinasa activada per AMP&#59; STAT&#58; transducci&#243;n de se&#241;ales y de los activadores de la transcripci&#243;n&#46;" src="277v53n200-90463442fig4.jpg"></img></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Figura 4&#46; </span>IL-6&#58; interleucina 6&#59; LIF&#58; factor inhibidor de la leucemia&#59; Il-15&#58; interleucina 15&#59; PI3K&#58; fosfatidil inositol 3 cinasa&#59; BDNG&#58; factor neurotr&#243;fico derivado del cerebro&#59; FGF21&#58; factor de crecimiento fibrobl&#225;stico 21&#59; AMPK&#58; prote&#237;na cinasa activada per AMP&#59; STAT&#58; transducci&#243;n de se&#241;ales y de los activadores de la transcripci&#243;n&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicto de intereses</span></p><p class="elsevierStylePara"> Los autores declaran que no tienen ning&#250;n conflicto de intereses&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Agradecimientos</span></p><p class="elsevierStylePara"> Al grupo de investigaci&#243;n en procesamiento de se&#241;ales biol&#243;gicas en medicina &#40;PROSEIM&#41; y a la facultad de Medicina de la Universidad de La Sabana por el apoyo en tiempo para el desarrollo de esta revisi&#243;n&#46;</p><hr></hr><p class="elsevierStylePara"> Recibido el 26 de febrero de 2018&#59;<br></br> aceptado el 4 de septiembre de 2018</p><p class="elsevierStylePara"> &#42; Autor para correspondencia&#46;<br></br><span class="elsevierStyleItalic">Correo electr&#243;nico&#58;</span><a href="mailto&#58;daniel&#46;botero&#64;unisabana&#46;edu&#46;co" class="elsevierStyleCrossRefs">daniel&#46;botero&#64;unisabana&#46;edu&#46;co</a> &#40;D&#46;A&#46; Botero-Rosas&#41;&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara"> Malos h&#225;bitos como el sedentarismo&#44; la obesidad o la sobrealimentaci&#243;n se relacionan con la evoluci&#243;n de estados pro-inflamatorios cr&#243;nicos&#44; principal factor de riesgo para el desarrollo de enfermedades cr&#243;nicas no transmisibles &#40;ECNT&#41;&#46; Sin embargo&#44; modificar &#250;nicamente el peso corporal no reduce el riesgo&#59; es necesario tambi&#233;n aumentar la masa muscular&#44; dando a entender que existe una relaci&#243;n ben&#233;fica asociada a este tejido que no est&#225; totalmente dilucidada&#46; Durante los &#250;ltimos a&#241;os las explicaciones celulares m&#225;s interesantes se han centrado en la producci&#243;n de citocinas musculares denominadas miocinas&#44; dentro de las que destacan la interleucina 6&#44; el factor inhibidor de la leucemia&#44; entre otras recientemente estudiadas como la mionectina y la musclina&#46; Debido a los m&#250;ltiples avances&#44; se realiza una revisi&#243;n que pretende presentar los hallazgos m&#225;s recientes y representativos acerca de las miocinas&#44; corregir conceptos y demostrar su aplicabilidad en la prescripci&#243;n del ejercicio f&#237;sico para la salud&#46;</p>"
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        "resumen" => "<p class="elsevierStylePara"> Bad habits such as sedentary lifestyle&#44; obesity or overfeeding&#44; are related to the production of chronic pro-inflammatory states&#44; the main risk factor for the development of chronic noncommunicable diseases &#40;CNCD&#41;&#46; However&#44; modifying only the body weight does not reduce the risk&#44; it is necessary to increase muscle mass&#44; this implies there is a beneficial relationship associated with the muscle tissue that is not fully elucidated&#46; During the last years&#44; the most interesting cellular explanations have focused on the production of muscle cytokines called myokines&#44; among which stand out interleukin 6&#44; the inhibitory factor of leukemia&#44; with others recently studied such as mionectine and muscline&#46; Due to the multiple advances&#44; this paper intends to present the most recent and representative findings about myokines&#44; correct concepts and demonstrate their applicability in the prescription of physical exercise for health&#46;</p>"
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