MECANOTRANSDUCCION EN EL MUSCULO ESQUELETICO

FRANZ ZELADA Lic. Kinesiologa Prof. Ed. Fsica

WHAT IS MECHANOTRANSDUCTION?

Mechanotransduction is the physiological process where cells sense and respond to mechanical loads.

Mechanotransduction refers to the process by which the body converts mechanical loading into cellular responses. These cellular responses, in turn, promote structural change. A classic example of mechanotransduction in action is bone adapting to load.K M Khan, A Scott. February 2009

Bsicamente, la mecanotransduccin es el proceso de transduccin de seales celulares en respuesta a los estmulos mecnicos.

Como el msculo transduce el estrs o estmulos mecanicos del ejercicio o entrenamiento en seales moleculares y bioqumicas que permitan un fenotipo de crecimiento e hipertrofia muscular

EFECTOS DE LA CARGA MECANICAContraccin v/s Elongacin

Contraccin con Carga Alta

Elongacin Pasiva /Activa Extrema

* La Elongacin Pasiva/Activa Extrema y la Contraccin con Cargas Altas producen efectos similares: CRECIMIENTO MUSCULAR

F.Zelada

Titin and nebulin in the sarcomere and nomenclature of elastic I-band regions in the skeletal muscle titin isoforms, N2A..

Prado L G et al. J Gen Physiol 2005;126:461-480

The Rockefeller University Press

Figure 1. HCM: A disease of energy deficiency. As indicated in red, the phenotype of hypertrophic cardiomyopathy (HCM) can arise from: 1) excessive energy use (e.g., by aberrant sarcomeres); 2) inadequate energy production (e.g., from poorly functioning mitochondria), inadequate metabolic substrates, or a failure to transfer energy across cellular compartments owing to cytoarchitectural defects as exemplified by muscle LIM protein (MLP) mutations; or 3) aberrant signaling of energy deficiency (e.g., with AMP-activated protein kinase [AMPK] mutations). The final common path for these diverse defects is energy deficiency and ensuing hypertrophy. ADP = adenosine diphosphate; AMP = adenosine monophosphate; ATP = adenosine triphospate; Cr = creatine; FAM = fatty acid metabolism.

Figure 2. Major pathways activated in response to hypertrophic stimuli. Ang II indicates angiotensin II; DAG, diacylglycerol; Et, endothelin; FGF, fibroblast growth factor; G, G protein; IGF, insulin-like growth factor; IP3, inositol 1,4,5-triphosphate; MAPK, mitogen-activated protein kinase; MEK, MAP kinase kinase; NFAT, nuclear factor of activated T cells; PKC, protein kinase C; PLC, phospholipase C; RAF, mitogen-activated protein (MAP) kinase kinase kinase; RAS, monomeric GTPase

Figure 4. Model of the role of the 2 classes of histone deacetylases (HDAC) in the pathogenesis of cardiomyocyte hypertrophy.

The contractile machinery of skeletal muscle syncytial myotubes (left) and single cardiomyocytes (right) is formed from long arrays of sarcomere units, which are joined into myofibrils. The sarcomere (bottom) is constructed from interdigitating, antiparallel filaments of actin and myosin, the elastic titin filaments and the crosslinker proteins for actin -actinin, myosin and myomesin. Sarcomeres contain many other accessory components, including proteins involved in transcriptional regulation and turnover control. The transcription factor CLOCK, the transcriptional cofactors muscle LIM protein (MLP), muscle ankyrin-repeat proteins (MARPs) and LIM domain-binding protein 3 (LDB3) are found at the Z-disk and/or the I-band. Multifunctional components of the protein turnover machinery include sequestosome 1 (SQSTM1), NBR1 and the muscle-upregulated RING finger proteins (MURFs). MYOZs, myozenins.

Schematic of the components of cardiac myocyte structure. The sarcomere, comprised of interdigitating thick and thin filaments, is the fundamental structural and functional unit of cardiac muscle. Sarcomeres are linked by a complex network of cytoskeletal proteins with the sarcolemma, extracellular matrix, and nucleus. The intermyofibrillar cytoskeleton is comprised of desmin intermediate filaments, actin-containing microfilaments, and microtubules. The subsarcolemmal cytoskeleton is comprised of costameres, sites of interconnection between the various pathways linking sarcomeres to sarcolemmal transmembrane proteins. Muscle contraction is an energy-requiring process that utilizes ATP supplied by mitochondria. The intracellular free Ca2+ concentration ([Ca2+]i) critically regulates muscle contraction and relaxation. Muscle contraction is initiated by an increase in [Ca2+]i. This results from depolarization-induced influx of a small amount of Ca2+via voltage-gated dihydropyridine receptors (DHPR) in t tubules, which in turn triggers the release of a large quantum of Ca2+ from the sarcoplasmic reticulum (SR), a process called Ca2+-induced Ca2+release. Muscle relaxation is initiated by the uptake of cytosolic Ca2+into the SR via the high energy-dependent pump, the SR Ca2+-ATPase (SERCA2a) and by extrusion through the sarcolemmal Na+/Ca2+exchanger. Pathophysiological mechanisms that have been implicated in hypertrophic and dilated cardiomyopathies include the following: defective force generation, due to mutations in sarcomeric protein genes; defective force transmission, due to mutations in cytoskeletal protein genes; myocardial energy deficits, due to mutations in ATP regulatory protein genes; and abnormal Ca2+ homeostasis, due to altered availability of Ca2+ and altered myofibrillar Ca2+ sensitivity. RyR, ryanodine receptor.

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Hoshijima M Am J Physiol Heart Circ Physiol 2006;290:H1313-H1325

2006 by American Physiological Society

Fig. 3. Z disk/I band titin associated signal cascades. Several nodal molecules of transmembrane signaling have been mapped on Z disks and I band titin. Mitogen-activated protein (MAP) kinase cascade interact with I-band titin through ERK2-FHL2 association. Calcium signal activates calcineurin (Cn) and subsequently nuclear factor of activated T cells (NFAT). The interaction of Cn with two distinctive Z disk proteins has been revealed (MYZO2 and MLP/CRP3). A subset of PKC isotypes localize at Z disk or its vicinity and PDZ-3LIM proteins (enigma, enigma homolog, and LIM domain-binding factor 3) may be critical for their sequestration

Fig. 4. Sarcomere protein turnover and Z disk/M-band-associated ubiquitin (Ub) ligase complexes. Ubiqutination-dependent protein turnover may critically regulate turnover of cardiac proteins. Selective localizations of E3 ubiquitin ligase complex components have been identified: MURFs at Mband titin and atrogin-1 at Z disks. In addition to their direct interaction with sarocomere proteins, M-band MURF may regulate the SRF transcriptional factor, and atrogin-1 binds and induces degradation of Cn at Z disk. Collectively, sarcomere-associated ubiquitine ligase components may serve as critical regulators of both cardiac protein synthesis and degradation.

Fig. 5. Sarcolemmal actin assembly and nuclear signaling. Recent studies have revealed that cytoplasmic actin assembly/disassembly may regulate transcriptional factors. The rho GTPase is a nodal molecule of this pathway and has been linked to various sarcolemmal activators (G protein coupling receptors, GPCR; tyrosine-kinase receptors, TyR; adhesion plaque complexes; and the caveolae-like structure). Cytoplasmic actin assembly has been found to regulate SRF transcriptional activities through G-actin association with megakaryotic acute leukemia (MAL)/myocardin-related transcriptional factors (MRTF) proteins. STARS (striated muscle activator of rho signaling) also regulates actin disassembly.

SIGNALLING RESISTANCE EXERCISE

IGF-1 or insulin

PI3K PDK1 PKB mTOR

4E-BP1 P S6 P P eIF4E

p70S6k

P

Translation activation

Ribosome Skeletal muscle fibre

(3) Autocrine, paracrine IGFs

(4) Systemic IGFs (5)

IGF-1/MGF binding to receptor

(2) IGF-1 precursor splicing into IGF-1, MGF

PI3K (6) PDK1 PKB

(1) Stretch, other signals

(7) High energy turnover , hypoxia

AMPK

mTOR raptor

(8) Amino acids

4E-BP1 P S6 P

p70S6k (10)Translation

IGF promoter Nucleus

(9) eIF3 of ribosomal and proteins P eIF4E translation Ribosome Peptide/protein activation Skeletal muscle fibre

Mechanotransducction of Muscle Hypertrofy

J Appl.. Physiol 2004, Tidball

SIGNALLING ENDURANCE EXERCISE AND RESISTANCE EXERCISE

Sport. Med. 2007, Coffey

Adaptaciones Fisiolgicas

Gracias...

Adaptaciones Celulares Moleculares