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Active acetylcholine receptors prevent the atrophy of skeletal muscles and favor reinnervation.

ABSTRACT: Denervation of skeletal muscles induces severe muscle atrophy, which is preceded by cellular alterations such as increased plasma membrane permeability, reduced resting membrane potential and accelerated protein catabolism. The factors that induce these changes remain unknown. Conversely, functional recovery following denervation depends on successful reinnervation. Here, we show that activation of nicotinic acetylcholine receptors (nAChRs) by quantal release of acetylcholine (ACh) from motoneurons is sufficient to prevent changes induced by denervation. Using in vitro assays, ACh and non-hydrolysable ACh analogs repressed the expression of connexin43 and connexin45 hemichannels, which promote muscle atrophy. In co-culture studies, connexin43/45 hemichannel knockout or knockdown increased innervation of muscle fibers by dorsal root ganglion neurons. Our results show that ACh released by motoneurons exerts a hitherto unknown function independent of myofiber contraction. nAChRs and connexin hemichannels are potential molecular targets for therapeutic intervention in a variety of pathological conditions with reduced synaptic neuromuscular transmission.

SUBMITTER: Cisterna BA

PROVIDER: S-EPMC7044284 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Active acetylcholine receptors prevent the atrophy of skeletal muscles and favor reinnervation.

Cisterna Bruno A BA Vargas Aníbal A AA Puebla Carlos C Fernández Paola P Escamilla Rosalba R Lagos Carlos F CF Matus María F MF Vilos Cristian C Cea Luis A LA Barnafi Esteban E Gaete Hugo H Escobar Daniel F DF Cardozo Christopher P CP Sáez Juan C JC

Nature communications 20200226 1

Denervation of skeletal muscles induces severe muscle atrophy, which is preceded by cellular alterations such as increased plasma membrane permeability, reduced resting membrane potential and accelerated protein catabolism. The factors that induce these changes remain unknown. Conversely, functional recovery following denervation depends on successful reinnervation. Here, we show that activation of nicotinic acetylcholine receptors (nAChRs) by quantal release of acetylcholine (ACh) from motoneur ...[more]

PMID: 32103010

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Project description:BackgroundSkeletal muscle mass is determined by the balance between protein synthesis and degradation. Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of protein translation and has been implicated in the control of muscle mass. Inactivation of mTORC1 by skeletal muscle-specific deletion of its obligatory component raptor results in smaller muscles and a lethal dystrophy. Moreover, raptor-deficient muscles are less oxidative through changes in the expression PGC-1?, a critical determinant of mitochondrial biogenesis. These results suggest that activation of mTORC1 might be beneficial to skeletal muscle by providing resistance to muscle atrophy and increasing oxidative function. Here, we tested this hypothesis by deletion of the mTORC1 inhibitor tuberous sclerosis complex (TSC) in muscle fibers.MethodSkeletal muscles of mice with an acute or a permanent deletion of raptor or TSC1 were examined using histological, biochemical and molecular biological methods. Response of the muscles to changes in mechanical load and nerve input was investigated by ablation of synergistic muscles or by denervation .ResultsGenetic deletion or knockdown of raptor, causing inactivation of mTORC1, was sufficient to prevent muscle growth and enhance muscle atrophy. Conversely, short-term activation of mTORC1 by knockdown of TSC induced muscle fiber hypertrophy and atrophy-resistance upon denervation, in both fast tibialis anterior (TA) and slow soleus muscles. Surprisingly, however, sustained activation of mTORC1 by genetic deletion of Tsc1 caused muscle atrophy in all but soleus muscles. In contrast, oxidative capacity was increased in all muscles examined. Consistently, TSC1-deficient soleus muscle was atrophy-resistant whereas TA underwent normal atrophy upon denervation. Moreover, upon overloading, plantaris muscle did not display enhanced hypertrophy compared to controls. Biochemical analysis indicated that the atrophy response of muscles was based on the suppressed phosphorylation of PKB/Akt via feedback inhibition by mTORC1 and subsequent increased expression of the E3 ubiquitin ligases MuRF1 and atrogin-1/MAFbx. In contrast, expression of both E3 ligases was not increased in soleus muscle suggesting the presence of compensatory mechanisms in this muscle.ConclusionsOur study shows that the mTORC1- and the PKB/Akt-FoxO pathways are tightly interconnected and differentially regulated depending on the muscle type. These results indicate that long-term activation of the mTORC1 signaling axis is not a therapeutic option to promote muscle growth because of its strong feedback induction of the E3 ubiquitin ligases involved in protein degradation.

Project description:Skeletal muscles have a highly organized hierarchical structure, whose main function is to generate forces for movement and stability. To understand the complex heterogeneous behaviors of muscles, computational modeling has advanced as a non-invasive approach to evaluate relevant mechanical quantities. Aiming to improve musculoskeletal predictions, this paper presents a framework for modeling 3D deformable muscles that includes continuum constitutive representation, parametric determination, model validation, fiber distribution estimation, and integration of multiple muscles into a system level for joint motion simulation. The passive and active muscle properties were modeled based on the strain energy approach with Hill-type hyperelastic constitutive laws. A parametric study was conducted to validate the model using experimental datasets of passive and active rabbit leg muscles. The active muscle model with calibrated material parameters was then implemented to simulate knee bending during a squat with multiple quadriceps muscles. A computational fluid dynamics (CFD) fiber simulation approach was utilized to estimate the fiber arrangements for each muscle, and a cohesive contact approach was applied to simulate the interactions among muscles. The single muscle simulation results showed that both passive and active muscle elongation responses matched the range of the testing data. The dynamic simulation of knee flexion and extension showed the predictive capability of the model for estimating the active quadriceps responses, which indicates that the presented modeling pipeline is effective and stable for simulating multiple muscle configurations. This work provided an effective framework of a 3D continuum muscle model for complex muscle behavior simulation, which will facilitate additional computational and experimental studies of skeletal muscle mechanics. This study will offer valuable insight into the future development of multiscale neuromuscular models and applications of these models to a wide variety of relevant areas such as biomechanics and clinical research.

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Active acetylcholine receptors prevent the atrophy of skeletal muscles and favor reinnervation.

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Active acetylcholine receptors prevent the atrophy of skeletal muscles and favor reinnervation.

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