Erica Hurtado

Universidad Rovira i Virgili

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María A. Lanuza

Universidad Rovira i Virgili

Josep Tomàs

Universidad Rovira i Virgili

Marta Tomás

Universidad Rovira i Virgili

Neus García

Case Western Reserve University

Víctor Cilleros‐Mañé

Universidad Rovira i Virgili

Laura Nadal

Universidad Rovira i Virgili

Anna Simó

Universidad Rovira i Virgili

Laia Just‐Borràs

Universidad Rovira i Virgili

Manel M. Santafé

Universidad Rovira i Virgili

Teresa Obis

Almirall (Spain)

Cooperative Institutions

Universidad Rovira i Virgili

Institute of Predictive and Personalized Medicine of Cancer

Universitat de Barcelona

Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol

Loma Linda University

Centre National de la Recherche Scientifique

Institut d'Investigació Sanitària Pere Virgili

George Washington University

Children's National

University of Buenos Aires

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The Impact of Kinases in Amyotrophic Lateral Sclerosis at the Neuromuscular Synapse: Insights into BDNF/TrkB and PKC Signaling

Cells (2019)

María A. Lanuza Laia Just‐Borràs Erica Hurtado Víctor Cilleros‐Mañé Marta Tomás

Brain-derived neurotrophic factor (BDNF) promotes neuron survival in adulthood in the central nervous system. In the peripheral nervous system, BDNF is a contraction-inducible protein that, through its binding to tropomyosin-related kinase B receptor (TrkB), contributes to the retrograde neuroprotective control done by muscles, which is necessary for motor neuron function. BDNF/TrkB triggers downstream presynaptic pathways, involving protein kinase C, essential for synaptic function and maintenance. Undeniably, this reciprocally regulated system exemplifies the tight communication between nerve terminals and myocytes to promote synaptic function and reveals a new view about the complementary and essential role of pre and postsynaptic interplay in keeping the synapse healthy and strong. This signaling at the neuromuscular junction (NMJ) could establish new intervention targets across neuromuscular diseases characterized by deficits in presynaptic activity and muscle contractility and by the interruption of the connection between nervous and muscular tissues, such as amyotrophic lateral sclerosis (ALS). Indeed, exercise and other therapies that modulate kinases are effective at delaying ALS progression, preserving NMJs and maintaining motor function to increase the life quality of patients. Altogether, we review synaptic activity modulation of the BDNF/TrkB/PKC signaling to sustain NMJ function, its and other kinases’ disturbances in ALS and physical and molecular mechanisms to delay disease progression.

10.3390/cells8121578

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Presynaptic Membrane Receptors Modulate ACh Release, Axonal Competition and Synapse Elimination during Neuromuscular Junction Development

Frontiers in Molecular Neuroscience (2017)

Josep Tomàs Neus García María A. Lanuza Manel M. Santafé Marta Tomás

The development of the nervous system involves an initially exuberant production of neurons, which establish an excessive number of synapses, and the subsequent reduction in both neurons and synaptic contacts as maturation proceeds. Hebbian competition between axons with different activities leads to the loss of roughly half of the neurons initially produced so connectivity is refined and specificity gained. The skeletal muscle fibers in the newborn neuromuscular junction (NMJ) are polyinnervated by several motor axons but by the end of the axonal competition, two weeks later, the endplates are innervated by a single axon. This peripheral synapse has long been used as a convenient model for synapse development. In the last few years, we have studied transmitter release and the local involvement of the presynaptic muscarinic ACh autoreceptors (mAChR), adenosine autoreceptors (AR) and trophic factor receptors (TFR, for neurotrophins and trophic cytokines) during the development of NMJ and in the adult. This review brings together previously published data and proposes a molecular background for developmental axonal competition and loss. At the end of the first week postnatal, these receptors modulate transmitter release in the various nerve terminals on polyinnervated NMJ and contribute to axonal competition and synapse elimination.

10.3389/fnmol.2017.00132

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HDAC11 is a novel regulator of fatty acid oxidative metabolism in skeletal muscle

FEBS Journal (2020)

Erica Hurtado Yaiza Núñez‐Álvarez Mar Muñoz Cristina Gutiérrez‐Caballero Josefina Casas

Skeletal muscle is the largest tissue in mammalian organisms and is a key determinant of basal metabolic rate and whole‐body energy metabolism. Histone deacetylase 11 (HDAC11) is the only member of the class IV subfamily of HDACs, and it is highly expressed in skeletal muscle, but its role in skeletal muscle physiology has never been investigated. Here, we describe for the first time the consequences of HDAC11 genetic deficiency in skeletal muscle, which results in the improvement of muscle function enhancing fatigue resistance and muscle strength. Loss of HDAC11 had no obvious impact on skeletal muscle structure but increased the number of oxidative myofibers by promoting a glycolytic‐to‐oxidative muscle fiber switch. Unexpectedly, HDAC11 was localized in muscle mitochondria and its deficiency enhanced mitochondrial content. In particular, we showed that HDAC11 depletion increased mitochondrial fatty acid β‐oxidation through activating the AMP‐activated protein kinase‐acetyl‐CoA carboxylase pathway and reducing acylcarnitine levels in vivo , thus providing a mechanistic explanation for the improved muscle strength and fatigue resistance. Overall, our data reveal a unique role of HDAC11 in the maintenance of muscle fiber‐type balance and the mitochondrial lipid oxidation. These findings shed light on the mechanisms governing muscle metabolism and may have implications for chronic muscle metabolic disease management.

10.1111/febs.15456

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FROM BDNF/ TRKB NEUROTROPHIC PATHWAY TO VESICULAR RELEASE AT AGED NEUROMUSCULAR JUNCTION

IBRO Neuroscience Reports (2023)

Marta Balanyà-Segura Erica Hurtado Laia Just‐Borràs А. А. Поліщук Víctor Cilleros‐Mañé

10.1016/j.ibneur.2023.08.687

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Running and Swimming Differently Adapt the BDNF/TrkB Pathway to a Slow Molecular Pattern at the NMJ

International Journal of Molecular Sciences (2021)

Laia Just‐Borràs Víctor Cilleros‐Mañé Erica Hurtado Olivier Biondi Frédéric Charbonnier

Physical exercise improves motor control and related cognitive abilities and reinforces neuroprotective mechanisms in the nervous system. As peripheral nerves interact with skeletal muscles at the neuromuscular junction, modifications of this bidirectional communication by physical activity are positive to preserve this synapse as it increases quantal content and resistance to fatigue, acetylcholine receptors expansion, and myocytes’ fast-to-slow functional transition. Here, we provide the intermediate step between physical activity and functional and morphological changes by analyzing the molecular adaptations in the skeletal muscle of the full BDNF/TrkB downstream signaling pathway, directly involved in acetylcholine release and synapse maintenance. After 45 days of training at different intensities, the BDNF/TrkB molecular phenotype of trained muscles from male B6SJLF1/J mice undergo a fast-to-slow transition without affecting motor neuron size. We provide further knowledge to understand how exercise induces muscle molecular adaptations towards a slower phenotype, resistant to prolonged trains of stimulation or activity that can be useful as therapeutic tools.

10.3390/ijms22094577

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Citations (9)

Contents Vol. 38, 2017

Developmental Neuroscience (2016)

André Obenaus Mohsen Baghchechi Amy Plaia Mary Hamer Nirmalya Ghosh

10.1159/000477423

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Adenosine Receptors in Developing and Adult Mouse Neuromuscular Junctions and Functional Links With Other Metabotropic Receptor Pathways

Frontiers in Pharmacology (2018)

Josep Tomàs Neus García María A. Lanuza Manel M. Santafé Marta Tomás

In the last few years, we have studied the presence and involvement in synaptogenesis and mature transmitter release of the adenosine autoreceptors (AR) in the mammalian neuromuscular junction (NMJ). Here, we review and bring together the previously published data to emphasize the relevance of these receptors for developmental axonal competition, synaptic loss and mature NMJ functional modulation. However, in addition to AR, activity-dependent mediators originating from any of the three cells that make the synapse (nerve, muscle and glial cells) cross the extracellular cleft to generate signals in target metabotropic receptors. Thus, the integrated interpretation of the complementary function of all these receptors is needed. We previously studied, in the NMJ, the links of AR with mAChR and the neurotrophin receptor TrkB in the control of synapse elimination and transmitter release. We conclude that AR cooperate with these receptors through synergistic and antagonistic effects in the developmental synapse elimination process. In the adult NMJ, this cooperation is manifested so as that the functional integrity of a given receptor group depends on the other receptors operating normally (i.e. the functional integrity of mAChR depends on AR operating normally). These observations underlie the relevance of AR in the NMJ function.

Synaptogenesis

10.3389/fphar.2018.00397

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Membrane Receptor-Induced Changes of the Protein Kinases A and C Activity May Play a Leading Role in Promoting Developmental Synapse Elimination at the Neuromuscular Junction

Frontiers in Molecular Neuroscience (2017)

Josep Tomàs Neus García María A. Lanuza Laura Nadal Marta Tomás

Synapses that are overproduced during histogenesis in the nervous system are eventually lost and connectivity is refined. Membrane receptor signaling leads to activity-dependent mutual influence and competition between axons directly or with the involvement of the postsynaptic cell and the associated glial cell/s. Presynaptic muscarinic acetylcholine (ACh) receptors (subtypes mAChR; M1, M2 and M4), adenosine receptors (AR; A1 and A2A) and the tropomyosin-related kinase B receptor (TrkB), among others, all cooperate in synapse elimination. Between these receptors there are several synergistic, antagonic and modulatory relations that clearly affect synapse elimination. Metabotropic receptors converge in a limited repertoire of intracellular effector kinases, particularly serine protein kinases A and C (PKA and PKC), to phosphorylate protein targets and bring about structural and functional changes leading to axon loss. In most cells A1, M1 and TrkB operate mainly by stimulating PKC whereas A2A, M2 and M4 inhibit PKA. We hypothesize that a membrane receptor-induced shifting in the protein kinases A and C activity (inhibition of PKA and/or stimulation of PKC) in some nerve endings may play an important role in promoting developmental synapse elimination at the neuromuscular junction (NMJ). This hypothesis is supported by: (i) the tonic effect (shown by using selective inhibitors) of several membrane receptors that accelerates axon loss between postnatal days P5-P9; (ii) the synergistic, antagonic and modulatory effects (shown by paired inhibition) of the receptors on axonal loss; (iii) the fact that the coupling of these receptors activates/inhibits the intracellular serine kinases; and (iv) the increase of the PKA activity, the reduction of the PKC activity or, in most cases, both situations simultaneously that presumably occurs in all the situations of singly and paired inhibition of the mAChR, AR and TrkB receptors. The use of transgenic animals and various combinations of selective and specific PKA and PKC inhibitors could help to elucidate the role of these kinases in synapse maturation.

10.3389/fnmol.2017.00255

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Muscle Contraction Regulates BDNF/TrkB Signaling to Modulate Synaptic Function through Presynaptic cPKCα and cPKCβI

Frontiers in Molecular Neuroscience (2017)

Erica Hurtado Víctor Cilleros‐Mañé Laura Nadal Anna Simó Teresa Obis

The neurotrophin Brain-derived neurotrophic factor (BDNF) acts via tropomyosin-related kinase B receptor (TrkB) to regulate synapse maintenance and function in the neuromuscular system. The potentiation of ACh release by BDNF requires TrkB phosphorylation and Protein Kinase C (PKC) activation. BDNF is secreted in an activity-dependent manner but it is not known if pre- and/or postsynaptic activities enhance BDNF expression in vivo at the neuromuscular junction (NMJ). Here, we investigated whether nerve and muscle cell activities regulate presynaptic conventional PKC (cPKCα and βI) via BDNF/TrkB signaling to modulate synaptic strength at the NMJ. To differentiate the effects of presynaptic activity from that of muscle contraction, we stimulated the phrenic nerve of rat diaphragms (1 Hz, 30 min) with or without contraction (abolished by µ-conotoxin GIIIB). Then, we performed ELISA, Western blotting, qRT-PCR, immunofluorescence and electrophysiological techniques. We found that nerve-induced muscle contraction (1) increases the levels of mature BDNF protein without affecting pro-BDNF protein or BDNF mRNA levels; (2) downregulates TrkB.T1 without affecting TrkB.FL or p75 neurotrophin receptor (p75) levels; (3) increases presynaptic cPKCα and cPKCβI protein level through TrkB signaling; and (4) enhances phosphorylation of cPKCα and cPKCβI. Furthermore, we demonstrate that cPKCβI, which is exclusively located in the motor nerve terminals, increases activity-induced acetylcholine release. Together, these results show that nerve-induced muscle contraction is a key regulator of BDNF/TrkB signaling pathway, retrogradely activating presynaptic cPKC isoforms (in particular cPKCβI) to modulate synaptic function. These results indicate that a decrease in neuromuscular activity, as occurs in several neuromuscular disorders, could affect the BDNF/TrkB/PKC pathway that links pre- and postsynaptic activity to maintain neuromuscular function.

10.3389/fnmol.2017.00147

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Citations (69)

nPKCε Mediates SNAP-25 Phosphorylation of Ser-187 in Basal Conditions and After Synaptic Activity at the Neuromuscular Junction

Molecular Neurobiology (2019)

Anna Simó Víctor Cilleros‐Mañé Laia Just‐Borràs Erica Hurtado Laura Nadal

10.1007/s12035-018-1462-5

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Citations (16)