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INTRODUCCIÓN A LOS MOTORES MOLECULARES DE LA CONTRACCIÓN
MUSCULAR
Enrique Jaimovich
Instituto de Ciencias BiomédicasFacultad de Medicina, Universidad de Chile
Structure of the 3 muscle types. The drawings at right show these muscles in cross section. Skeletal muscle is composed of large, elongated, multinucleated fibers. Cardiac muscle is composed of irregular branched cells bound together longitudinally by intercalated disks. Smooth muscle is an agglomerate of fusiform cells. The density of the packing between the cells depends on the amount of extracellular connective tissue present.
Skeletal Muscle Cells
Skeletal muscle cells are long (up to 30 cm), possess a diameter of 10-100 µm, and are multinucleated as a result of myoblast fusion
Nuclei are found just below the sarcolemma
Each muscle fiber is inervated by a motor nerve
Muscle
Muscle fibers
Muscle fiber
MyofibrilSarcomere
Modified from McMahon, Muscles, Reflexes and LocomotionPrinceton University Press, 1984.
Cerca de la mitad de la masa corporal corresponde al músculo esquelético, con la mayoría de los músculos unidosal hueso mediante tendones; las fuerzasy movimientos que se desarrolandurante las contracciones,se transmiten al esqueleto..
Estructura jerarquizada del músculo esquelético
El movimiento de palanca desplaza el filamento de actina relativo a la cabeza demiosina (~5 nm), y, al deformar estructuras elásticas internas, produce fuerza (~5 pN).
Filamentos gruesos y delgados se interdigitan y deslizan unos respecto a otros
Para que el músculo gastrocnemio produzca ~ 45 Kg de fuerza, unos 1014 motoresdeben actuar en paralelo simultáneamente.
Cómo funciona el músculo estriado: Modelo de filamentos deslizantes
Acoplamiento mecanoquímico – conversión de energíaquímica (ATP, unas 7 kcal/mol) en fuerza/movimiento.
• ATP es termodinámicamente inestable
• Dos etapas energéticamente favorables:1. Unión de ATP a miosina2. Liberación de fosfato desde miosina
• La velocidad del ciclo depende de la actividad M·ATPasa y de la cargaexterna.
Unión débil Unión fuerte
La velocidad de acortamiento dependede la actividad ATPasa
Diferentes cadenas pesadas de miosina (MHCs) tienen actividades ATPasa distintas.
Hay al menos 7 genes separados para MHC de músculo esqueléticoordenados en serie en el cromosoma 17.
Dos genes de MHC cardíaco localizados en tandem en el cromosoma 14.
El gen MHC lento β cardíaco se expresa en forma predominanteen las fibras lentas de mamíferos
Goldspink (1999) J Anat 194:323-334.
Miosina es un motor molecular Myosin is a hexamer:2 myosin heavy chains4 myosin light chains
Estructura cristalina delfragmento S1 de miosina
Ruegg et al., (2002) News Physiol Sci 17:213-218.
NH2-terminal catalytic (motor) domain
neck region/lever arm
Cabeza de miosina: retiene todas las funciones de motor de la miosina,es decir, la abilidad de producir fuerza y movimiento.
El golpe de trabajo se produce porapertura y cierre delSitio activo, resultando en rotaciónde la región regulatoria (cuello) en torno a una bisagra (regiónconvertidora)
Cambios de menos de 1 nmen el sitio activo se amplificanmediante engranajes hastadesplazamientos de 5-10 nmen el extremo del brazo articulado
Modelo hipotético del brazomóvil
Ruegg et al., (2002) News Physiol Sci 17:213-218.
Po
wer S
troke
- fosforilación cadena regulatoria
-sarcómero largo-sarcómero corto
- pH bajo
MacIntosh (2003)
NIPS 18: 222
Sensibilidad de miofilamentos al calcio
Troponin-tropomyosin complex
Troponin is a complex formed by 3 proteins:TnT: binds strongly to tropomyosinTnC: binds Ca2+ ionsTnI: Inhibits myosin-actin interaction
The metabolic response to exercise is similar to the fasting response because similar fuels must be mobilized and generated foroxidation. For short-term exercise, lasting seconds, stored creatine phosphate and ATP provide the energy at a rate of about 50 Kcal/min. If exercise continues, the stores may be depleted. Then muscle glycogen is broken down to glucose-6-phosphate whichundergoes glycolysis, yielding energy at about 30 Kcal/min. The accumulation of lactic acid in muscle and circulation is a limitingfactor for glycolysis, not the depletion of muscle glycogen. After several minutes of exhaustive anerobic exercise, one incurs an oxygen debt of up to 12 L. From 6 to 8 L are required toresynthesize the lactic acid to glucose or oxidize it to CO2. About 2 L are required for normal replenishment of muscle ATP andcreatine phosphate. About 2 L more are needed to replenish the oxygen normally found in the lungs and body fluids bound tohemoglobin or myoglobin. If the period of exercise is less intense but of longer duration, substrates required to produce the necessary energy undergo aerobic oxidation, about 12 Kcal/min. Glucose substrates from the circulation are added to muscle glycogen and there is a manyfold increasein glucose uptake from the plasma by some groups of muscles. Glycogenolysis takes place to offset this glucose drain. As glycogenstores become exhausted by continued exercise, gluconeogenesis takes place from amino acids released by muscle proteolysis. Finally, free fatty acids are liberated from adipose tissue. In time, these free fatty acids will supply two thirds of the energy needed to maintainthe exercise. After the termination of exercise, energy is needed to rebuild the glycogen stores in the liver and muscle.