About

Justin R. Fallon is a Professor of Medical Science and Psychiatry and Human Behavior at Brown University. His work focuses on the intersection of basic and translational science, particularly involving a novel signaling pathway he and his team recently discovered, the MuSK-BMP pathway. This pathway has been linked to maintaining muscle and synapse integrity and is investigated for its role in regulating neural and muscle stem (satellite) cells, myofiber size, and synapse health. His research has laid the groundwork for the formation of Bolden Therapeutics, which aims to translate mechanistic insights into drug development for promoting adult hippocampal neurogenesis as a therapy for Alzheimer’s Disease, Major Depressive Disorder, and other neurological and psychiatric conditions.

Research topics

• Medicine
• Psychology
• Internal medicine
• Biology
• Neuroscience

Selected publications

• MuSK Regulates Neuromuscular Junction Nav1.4 Localization and Excitability

  Journal of Neuroscience · 2025-01-29 · 4 citations

  articleOpen accessSenior author

  The neuromuscular junction (NMJ) is the linchpin of nerve-evoked muscle contraction. Broadly, the NMJ transduces nerve action potentials into muscle fiber action potentials (MFAPs). Efficient neuromuscular transmission requires cholinergic signaling, which generates endplate potentials (EPPs), and excitation, the amplification of an EPP by postsynaptic voltage-gated sodium channels (Nav1.4) to generate the MFAP. Compared to the cholinergic component, the signaling pathways that organize Nav1.4 are poorly characterized. Muscle-specific kinase (MuSK), in addition to its Ig1 domain-dependent role as the main organizer of acetylcholine receptors (AChRs), also binds BMPs via its Ig3 domain and shapes BMP-induced signaling. Using mice lacking the MuSK Ig3 domain ("ΔIg3-MuSK"), we probed the role of this domain at the NMJ. NMJs formed in ΔIg3-MuSK animals with pre- and postsynaptic specializations aligned at all ages examined. However, the ΔIg3-MuSK postsynaptic apparatus was fragmented from an early age. Synaptic electrophysiology showed that spontaneous and nerve-evoked acetylcholine release, AChR density, and endplate currents were comparable at WT and ΔIg3-MuSK NMJs. However, single fiber electromyography revealed that nerve-evoked MFAPs in ΔIg3-MuSK muscle were abnormal, exhibiting jitter and blocking. Nerve-evoked compound muscle action potentials and muscle force were also diminished. Finally, Nav1.4 levels were reduced at ΔIg3-MuSK NMJs, but not extrasynaptically, indicating that the observed excitability defects result from impaired synaptic localization of this ion channel. We propose distinct, domain-specific roles for MuSK at the NMJ: the Ig1 domain mediates agrin-LRP4-mediated AChR localization, while the Ig3 domain maintains postsynaptic Nav1.4 density, conferring the muscle excitability required to amplify cholinergic signals and trigger action potentials.

  PublisherOA PDFDOI

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

  eLife · 2024-11-08

  preprintOpen accessSenior author

  Summary 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.

  PublisherDOI

• The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling

  Skeletal Muscle · 2024-01-03 · 17 citations

  articleOpen accessSenior author

  Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the mouse soleus, whose predominantly oxidative fiber composition is akin to that of human muscle. To investigate the role of the MuSK-BMP pathway in vivo, we generated mice lacking the BMP-binding MuSK Ig3 domain. These ∆Ig3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice, myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.

  PublisherOA PDFDOI

• Author response: MuSK-BMP signaling in adult muscle stem cells maintains quiescence and regulates myofiber size

  2024-11-08

  peer-reviewOpen accessSenior author

  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.

  PublisherDOI

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

  eLife · 2024-11-08

  preprintOpen accessSenior author

  Summary 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.

  PublisherOA PDFDOI

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

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-10-29 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Abstract 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 Statement The 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.

  PublisherOA PDFDOI

• The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt- mTOR signaling

  Research Square · 2023-02-27 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the slow soleus muscle. To investigate the role of the MuSK-BMP pathway in vivo we generated mice lacking the BMP-binding MuSK Ig3 domain. These ΔIg3-MuSKmice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.

  PublisherOA PDFDOI

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

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-05-18 · 4 citations

  preprintOpen accessSenior authorCorresponding

  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. Highlights: MuSK, in its role as a BMP co-receptor, regulates adult muscle stem cell quiescenceThe MuSK-BMP pathway acts cell autonomouslyIncreased muscle size and function with preservation of myonuclear density and stemness in mice with attenuated MuSK-BMP signaling.

  PublisherOA PDFDOI

• Up-regulation of cholesterol synthesis pathways and limited neurodegeneration in a knock-in <i>Sod1</i> mutant mouse model of ALS

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-05-05 · 6 citations

  preprintOpen access

  ABSTRACT Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder affecting brain and spinal cord motor neurons. Mutations in the copper/zinc superoxide dismutase gene ( SOD1 ) are associated with ∼20% of inherited and 1-2% of sporadic ALS cases. Much has been learned from mice expressing transgenic copies of mutant SOD1, which typically involve high-level transgene expression, thereby differing from ALS patients expressing one mutant gene copy. To generate a model that more closely represents patient gene expression, we created a knock-in point mutation (G85R, a human ALS-causing mutation) in the endogenous mouse Sod1 gene, leading to mutant SOD1 G85R protein expression. Heterozygous Sod1 G85R mutant mice resemble wild type, whereas homozygous mutants have reduced body weight and lifespan, a mild neurodegenerative phenotype, and express very low mutant SOD1 protein levels with no detectable SOD1 activity. Homozygous mutants exhibit partial neuromuscular junction denervation at 3-4 months of age. Spinal cord motor neuron transcriptome analyses of homozygous Sod1 G85R mice revealed up-regulation of cholesterol synthesis pathway genes compared to wild type. Transcriptome and phenotypic features of these mice are similar to Sod1 knock-out mice, suggesting the Sod1 G85R phenotype is largely driven by loss of SOD1 function. By contrast, cholesterol synthesis genes are down-regulated in severely affected human TgSOD1 G93A transgenic mice at 4 months. Our analyses implicate dysregulation of cholesterol or related lipid pathway genes in ALS pathogenesis. The Sod1 G85R knock-in mouse is a useful ALS model to examine the importance of SOD1 activity in control of cholesterol homeostasis and motor neuron survival. SIGNIFICANCE STATEMENT Amyotrophic lateral sclerosis is a devastating disease involving the progressive loss of motor neurons and motor function for which there is currently no cure. Understanding biological mechanisms leading to motor neuron death is critical for developing new treatments. Using a new knock-in mutant mouse model carrying a Sod1 mutation that causes ALS in patients, and in the mouse, causes a limited neurodegenerative phenotype similar to Sod1 loss-of-function, we show that cholesterol synthesis pathway genes are up-regulated in mutant motor neurons, whereas the same genes are down-regulated in transgenic SOD1 mice with a severe phenotype. Our data implicate dysregulation of cholesterol or other related lipid genes in ALS pathogenesis and provide new insights that could contribute to strategies for disease intervention.

  PublisherOA PDFDOI

• The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling

  bioRxiv (Cold Spring Harbor Laboratory) · 2022-11-05 · 1 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the slow soleus muscle. To investigate the role of the MuSK-BMP pathway in vivo we generated mice lacking the BMP-binding MuSK Ig3 domain. These ΔIg3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01MH053571

  NIH · $637k · 1999

• NIH Grant U01NS064295

  NIH · $10.7M · 2018

• NIH Grant P01NS039321

  NIH · $7.8M · 2005

• NIH Grant R01HD023924

  NIH · $4.6M · 2007

• Interdisciplinary Predoctoral Neuroscience Training Program in the Neuroscience Graduate Program.

  NIH · $7.8M · 1999–2026

Frequent coauthors

• Edward G. Stopa

  Brown University

  35 shared

• Michael S. Rafii

  LMU Klinikum

  32 shared

• David G. Wells

  31 shared

• Michael R. Akins

  Drexel University

  30 shared

• David J. Glass

  30 shared

• Tyler M. Berzin

  Harvard University

  29 shared

• Emily E. Stackpole

  University of Massachusetts Chan Medical School

  24 shared

• John E. Donahue

  Rhode Island Hospital

  23 shared

Labs

• Justin Fallon's LabPI

  N/A