MuSK-BMP signaling in adult muscle stem cells maintains quiescence and regulates myofiber size

Madigan, Laura A.; Jaime, Diego; Fallon, Justin R.

doi:10.1101/2023.05.17.541238

Cited by 4 publications

(1 citation statement)

References 90 publications

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“…Cells derived from these mice exhibit attenuated BMP-induced Smad1/5/8 phosphorylation and reduced levels of MuSK-dependent BMP-induced transcripts (Jaime et al, 2022, 2023). We have also used this model to show that the MuSK-BMP pathway acts in a cell autonomous manner in muscle stem (satellite) cells to regulate their quiescence and activation (Madigan et al, 2023), and that MuSK localized extrasynaptically in slow muscle is important for maintaining slow (but not fast) myofiber size via the Akt-mTOR pathway (Jaime et al, 2022, 2023). However, the function of the MuSK-BMP pathway at the NMJ is unknown.…”

Section: Introductionmentioning

confidence: 99%

The MuSK-BMP pathway regulates synaptic Nav1.4 localization and muscle excitability

Fish,

Ewing,

Jaime

et al. 2023

Preprint

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The neuromuscular junction (NMJ) is the linchpin of nerve-evoked muscle contraction. Broadly considered, the function of the NMJ is to transduce a nerve action potential into a muscle fiber action potential (MFAP). Efficient information transfer requires both cholinergic signaling, responsible for the generation of endplate potentials (EPPs), and excitation, the activation of postsynaptic voltage-gated sodium channels (Nav1.4) to trigger MFAPs. In contrast to the cholinergic apparatus, the signaling pathways that organize Nav1.4 and muscle fiber excitability are poorly characterized. Muscle-specific kinase (MuSK), in addition to its Ig1 domain-dependent role as an agrin-LRP4 receptor, is also a BMP co-receptor that binds BMPs via its Ig3 domain and shapes BMP-induced signaling and transcriptional output. Here we probed the function of the MuSK-BMP pathway at the NMJ using mice lacking the MuSK Ig3 domain (‘ΔIg3-MuSK’). Synapses formed normally in ΔIg3-MuSK animals, but the postsynaptic apparatus was fragmented from the first weeks of life. Anatomical denervation was not observed at any age examined. Moreover, spontaneous and nerve-evoked acetylcholine release, AChR density, and endplate currents were comparable to WT. However, trains of nerve-evoked MFAPs in ΔIg3-MuSK muscle were abnormal as revealed by increased jitter and blocking in single fiber electromyography. Further, nerve-evoked compound muscle action potentials (CMAPs), as well as twitch and tetanic muscle torque force production, were also diminished. Finally, Nav1.4 levels were reduced at ΔIg3-MuSK synapses but not at the extrajunctional sarcolemma, indicating that the observed excitability defects are the result of impaired localization of this voltage-gated ion channel at the NMJ. We propose that MuSK plays two distinct roles at the NMJ: as an agrin-LRP4 receptor necessary for establishing and maintaining cholinergic signaling, and as a BMP co-receptor required for maintaining proper Nav1.4 density, nerve-evoked muscle excitability and force production. The MuSK-BMP pathway thus emerges as a target for modulating excitability and functional innervation, which are defective in conditions such as congenital myasthenic syndromes and aging.Significance StatementThe neuromuscular junction (NMJ) is required for nerve-evoked muscle contraction and movement, and its function is compromised during aging and disease. Although the mechanisms underlying neurotransmitter release and cholinergic response at this synapse have been studied extensively, the machinery necessary for nerve-evoked muscle excitation are incompletely characterized. We show that MuSK (Muscle-specific kinase), in its role as a BMP co-receptor, regulates NMJ structure as well as the localization of the voltage-gated sodium channels necessary for full nerve-evoked muscle fiber excitation and force production. This novel function of MuSK is structurally and mechanistically distinct from its role in organizing cholinergic machinery. The MuSK-BMP pathway thus presents a new opportunity to understand mechanisms that may preserve or enhance neuromuscular excitability in the face of aging and disease.

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Section: Introductionmentioning

confidence: 99%

The MuSK-BMP pathway regulates synaptic Nav1.4 localization and muscle excitability

Fish,

Ewing,

Jaime

et al. 2023

Preprint

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MuSK-BMP signaling in adult muscle stem cells maintains quiescence and regulates myofiber size

Madigan¹,

Jaime²,

Fallon

2023

Preprint

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A central question in the biology of adult stem cells is elucidating the signaling pathways regulating their dynamics and function in diverse physiological and age-related contexts. Adult muscle stem cells (Satellite Cells; SCs) are generally quiescent but can activate and contribute to muscle homeostasis and repair. Here we tested the role of the MuSK-BMP pathway in regulating adult SC quiescence and myofiber size. We attenuated MuSK-BMP signaling by deletion of the BMP-binding MuSK Ig3 domain ('delta-Ig3MuSK') and studied the fast TA and EDL muscles. In germ line mutants at 3 months of age SC and myonuclei numbers as well as myofiber size were comparable in delta-Ig3MuSK and WT animals. However, in 5-month-old delta-Ig3MuSK animals SC density was decreased while myofiber size, myonuclear number and grip strength were increased - indicating that SCs had activated and productively fused into the myofibers over this interval. Notably, myonuclear domain size was conserved. Following injury, the mutant muscle fully regenerated with restoration of myofiber size and SC pool to WT levels, indicating that delta-Ig3MuSK SCs maintain full stem cell function. Conditional expression of delta-Ig3MuSK in adult SCs showed that the MuSK-BMP pathway regulates quiescence and myofiber size in a cell autonomous fashion. Transcriptomic analysis revealed that SCs from uninjured delta-Ig3MuSK mice exhibit signatures of activation, including elevated Notch and epigenetic signaling. We conclude that the MuSK-BMP pathway regulates SC quiescence and myofiber size in a cell autonomous, age-dependent manner. Targeting MuSK-BMP signaling in muscle stem cells thus emerges a therapeutic strategy for promoting muscle growth and function in the settings of injury, disease, and aging.

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MuSK-BMP signaling in adult muscle stem cells maintains quiescence and regulates myofiber size

Madigan,

Jaime,

Chen

et al. 2024

Preprint

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A central question in adult stem cell biology is elucidating the signaling pathways regulating their dynamics and function in diverse physiological and age-related contexts. Muscle stem cells in adults (Satellite Cells; SCs) are generally quiescent but can activate and contribute to muscle repair and growth. Here we tested the role of the MuSK-BMP pathway in regulating adult SC quiescence by deletion of the BMP-binding MuSK Ig3 domain (‘ΔIg3-MuSK’). At 3 months of age SC and myonuclei numbers and myofiber size were comparable to WT. However, at 5 months of age SC density was decreased while myofiber size, myonuclear number and grip strength were increased - indicating that SCs had activated and productively fused into the myofibers over this interval. Transcriptomic analysis showed that SCs from uninjured ΔIg3-MuSK mice exhibit signatures of activation. Regeneration experiments showed that ΔIg3-MuSK SCs maintain full stem cell function. Expression of ΔIg3-MuSK in adult SCs was sufficient to break quiescence and increase myofiber size. We conclude that the MuSK-BMP pathway regulates SC quiescence and myofiber size in a cell autonomous, age-dependent manner. Targeting MuSK-BMP signaling in muscle stem cells thus emerges a therapeutic strategy for promoting muscle growth and function in the settings of injury, disease, and aging.

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MuSK-BMP signaling in adult muscle stem cells maintains quiescence and regulates myofiber size

Cited by 4 publications

References 90 publications

The MuSK-BMP pathway regulates synaptic Nav1.4 localization and muscle excitability

The MuSK-BMP pathway regulates synaptic Nav1.4 localization and muscle excitability

MuSK-BMP signaling in adult muscle stem cells maintains quiescence and regulates myofiber size

MuSK-BMP signaling in adult muscle stem cells maintains quiescence and regulates myofiber size

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