Lineage tracing of nuclei in skeletal myofibers uncovers distinct transcripts and interplay between myonuclear populations

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Окт. 30, 2024

Язык: Английский

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Multinucleation as a buffer against gene expression noise in syncytial myofibres

The Journal of Physiology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 25, 2025

Skeletal muscle fibres, or myofibres, are exceptional for their vast size and complex multinucleated structure. Formed by the fusion of individual myoblasts, these syncytial cells contain hundreds even thousands nuclei that collectively coordinate synthesis essential proteins, ensuring can grow, repair maintain strength (Hansson & Eftestol, 2023). With some fibres extending up to 42 cm in length achieving diameters exceeding 100 µm, myofibers possess a cellular volume approximately 4000 times greater than human oocyte et al., 2020a). This extraordinary scale, coupled with elongated, cylindrical-like morphology, raises fundamental question: Why has evolution selected multinucleation cells, what specific advantages does this structural arrangement confer? The predominant hypothesis argues facilitates expansion cytoplasmic myofibres. By adding nuclei, cell increases its DNA content, which turn provides enhanced biosynthetic regulatory capacity support high demands protein maintenance increase nuclear may drive enlargement cytoplasm, allowing myofibres achieve size. While explanation is compelling, scale functional suggest serve purposes beyond simply enabling expansion, including regulation spatial metabolic homeostasis. Importantly, not unique skeletal fibres. Comparisons other polyploid systems highlight intriguing parallels, suggesting broader significance adaptation. For instance, fungus Ashbya gossypii relies on extensive hyphal networks, require coordinated enzymatic activity across large distances (Mayer 2024). Similarly, binucleated hepatocytes sustain liver function (Darmasaputra 2024; Guidotti 2003), whereas osteoclasts efficiently secrete digestive enzymes resorb areas bone (Ono Nakashima, 2018). Additionally, maturation Drosophila oocytes supported surrounding nurse multiple copies genome. These directly transfer components, mRNA, proteins materials, during development. enables grow while circumventing limitations would likely arise from relying single set genomic such mononuclear (Spradling 2022). Together, examples illustrate how evolved as versatile strategy address challenges maintaining homeostasis functionally specialized cells. evolutionary emergence appears be convergent phenomenon, arising independently diverse taxa (Peterson Fox, 2021). convergence underscores adaptive advantages, increased scalability potential buffer stochastic fluctuations gene expression. Studying alongside uncover shared principles regulation, organization noise reduction, well lineage-specific adaptations tailored distinct biological demands. I propose only addresses logistical supporting but also serves critical mechanism mitigate fluctuations, commonly referred 'noise' Gene expression noise, variability transcription translation, results random mRNA levels (Raj van Oudenaarden, 2008; Sanchez Golding, 2013), disrupt function. In mononucleated significantly impair However, distribution transcriptional form decentralized network independent units. could averaging them out, stable consistent cell. proposed noise-buffering homeostasis, adaptation physiological stress. article will explore mathematical foundations hypothesis, examining might noise. It discuss implications biology experimental approaches investigate relationship between offering insights into aspect organization. Multinucleated like many centres volume, uniquely equipped against If each nucleus acts an unit, achieves cumulative reducing relative impact enhancing overall SNR. Therefore, distributed myonuclei suppress stabilizing manner single-nucleus cannot achieve. When small number molecules transcribed – at low rates mean level low, thus (σmRNA) becomes relatively compared mean. leads shows increases, decreases. inverse square-root dependence implies particularly prone production cause variations levels. words, distributing reduce expression, resulting more volume. Thus, decreases following 1/ N $\sqrt $ scaling. framework strengthens central opinion piece, total buffers out bursts, reliable production, contributing robustness Empirical evidence abundance, present challenge As result, genes adopt different strategies based susceptibility Comparative studies species, Saccharomyces cerevisiae, Mus musculus Homo sapiens, have shown most actually favour higher translation over (Hausser 2019). there exceptions, Escherichia coli, where encoding ribosomal exhibit both rates, rare, balance processes finely tuned gene's role sensitivity Low-abundance often tolerate because transient spikes sufficient functions, signalling Despite localized mechanisms control still presence within myofibre solution stability varying rates. One key factor half-life. Longer half-lives, assuming quality, stabilize pool available remains time without need continuous transcription. preventing rapid degradation, longer half-lives otherwise lead abundance. addition, localization plays minimizing myonuclear domains. Myonuclei strategically positioned along fibre localize mRNAs nearby regions, products translated close respective domains prevents becoming diluted degraded, occur if they were dispersed throughout concentrating discrete domains, optimize process, steady supply when needed. molecular diffusion cytoplasm introduces another layer stochasticity molecules, concentration 2020b), system. localizing effects local abundance caused diffusion, thereby likelihood degradation dilution. closer proximity transcribing myonucleus translational machinery, synthesis. it reduces risk shortages energy-efficient, solely thermal energy being effective short distances, active transport complement (Denes 2021; Pinheiro 2021), addressing demand rendering less discrete, discussed (Prasad Millay, Bagley 2023; Hansson Moreover, heterogeneity among further contributes compartmentalized (Dos Santos 2020; Kim Petrany 2020), same patterns reflecting roles regions control. genetic material donated newly fused stem existing resident divergent (Sun 2024), highlighting complexity provide organizing controlling stability, ensure efficient, robust, adaptable changing conditions. conclusion, concept offers compelling extends well-known scaling match Multinucleation help noise-reduction effect compartmentalization ensures fine-tuned regions. To test combination required. Single-nucleus imaging analysis using advanced techniques smFISH live-cell real-time influences variability. Mathematical modelling, incorporating parameters predict Genetic manipulations alter state direct stability. types, certain fungi, offer regulating exploring inter-nuclear communication synchronize computational determine whether reduction indeed driving force behind systems, significant engineering, development, disease. Please note: publisher responsible content functionality any information supplied authors. Any queries (other missing content) should directed corresponding author article. None declared. K.-A.H.: Conception design work, drafting work revising critically important intellectual final approval version published agreement accountable all aspects work. None.

Язык: Английский

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Skeletal muscle effects of antisense oligonucleotides targeting glycogen synthase 1 in a mouse model of Pompe disease

Clinical and Translational Medicine, Год журнала: 2025, Номер 15(4)

Опубликована: Апрель 1, 2025

Abstract Pompe disease (PD) is a progressive myopathy caused by the aberrant accumulation of glycogen in skeletal and cardiac muscle resulting from deficiency enzyme acid alpha‐glucosidase (GAA). Administration recombinant human GAA as replacement therapy (ERT) works well alleviating manifestations PD but loses sustained benefit ameliorating pathology. The limited efficacy ERT partially attributable to its inability curb new produced synthase 1 (GYS1). Substrate reduction therapies aimed at knocking down GYS1 expression represent promising avenue improve myopathy. However, finding specific inhibitors for challenging given presence highly homologous GYS2 liver. Antisense oligonucleotides (ASOs) are chemically modified oligomers that hybridise their complementary target RNA induce degradation with exquisite specificity. In present study, we show ASO‐mediated Gys1 knockdown Gaa −/− mouse model led robust muscle. addition, combining ASO slightly further reduced content muscle, eliminated autophagic buildup lysosomal dysfunction, improved motor function mice. Our results provide strong foundation validation use ASO, alone or combination ERT, PD. We propose early administration may be key preventative treatment options Key points oligonucleotide (ASO) achieves reduces Combination improves performance compared disease.

Язык: Английский

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Functional specialisation and coordination of myonuclei

Biological reviews/Biological reviews of the Cambridge Philosophical Society, Год журнала: 2024, Номер 99(4), С. 1164 - 1195

Опубликована: Март 13, 2024

ABSTRACT Myofibres serve as the functional unit for locomotion, with sarcomere fundamental subunit. Running entire length of this structure are hundreds myonuclei, located at periphery myofibre, juxtaposed to plasma membrane. Myonuclear specialisation and clustering centre ends fibre known be essential muscle contraction, yet molecular basis regionalisation has remained unclear. While ‘myonuclear domain hypothesis’ helped explain how myonuclei can independently govern large cytoplasmic territories, novel technologies have provided granularity on diverse transcriptional programs running simultaneously within syncytia added a new perspective communicate. Building upon this, we explore critical cellular sources heterogeneity myofibres, discussing impact intrinsic extrinsic factors myonuclear programs. This knowledge provides insights understanding development, repair, disease, but also opens avenues development precise therapeutic approaches.

Язык: Английский

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Myonuclear apoptosis underlies diaphragm atrophy in mechanically ventilated ICU patients

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 24, 2024

Abstract Rationale Mechanical ventilation plays an important role in critical illness-associated diaphragm weakness. Weakness contributes to difficult weaning and is associated with increased morbidity mortality. Diaphragm weakness caused by a combination of atrophy dysfunction myofibers, which are large syncytial cells maintained population myonuclei. Each myonucleus provides gene transcripts finite fiber volume, termed the myonuclear domain. Changes number myofibers undergoing has not been investigated mechanically ventilated ICU patients. Myonuclear determinant transcriptional capacity, therefore for muscle regeneration after atrophy. Objectives Our objective was investigate if how changes patients whether myofiber Methods We used transcriptomics, immunohistochemistry, confocal microscopy study alterations quadriceps biopsies from Results domain were reduced Intrinsic apoptotic pathway activation identified as mechanism underlying removal Total activity decreased loss. Furthermore, stem cell Conclusion loss due intrinsic potential This novel insights Targeted therapies may limit development improve outcome.

Язык: Английский

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The expanding roles of myonuclei in adult skeletal muscle health and function

Biochemical Society Transactions, Год журнала: 2024, Номер 52(6), С. 2603 - 2616

Опубликована: Дек. 19, 2024

Skeletal muscle cells (myofibers) require multiple nuclei to support a cytoplasmic volume that is larger than other mononuclear cell types. It dogmatic mammalian resident myonuclei rely on stem (specifically satellite cells) for adding new DNA fibers facilitate expansion occurs during growth. In this review, we discuss the relationship between size and supporting genetic material. We present evidence may undergo synthesis as strategy increase material in myofibers independent from cells. then describe details of our experiments demonstrated can replicate vivo. Finally, findings context expanding knowledge about myonuclear heterogeneity, mobility shape. also address why replication potentially important provide future directions remaining unknowns. Myonuclear replication, coupled with discoveries transcription, morphology, behavior response stress, opportunities leverage previously unappreciated skeletal biological processes therapeutic targets mass, function, plasticity.

Язык: Английский

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Lineage tracing of newly accrued nuclei in skeletal myofibers uncovers distinct transcripts and interplay between nuclear populations

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Авг. 25, 2023

Multinucleated skeletal muscle cells have an obligatory need to acquire additional nuclei through fusion with activated stem when responding both developmental and adaptive growth stimuli. A fundamental question in biology has been the reason underlying this for new syncytial that already harbor hundreds of nuclei. To begin answer long-standing question, we utilized nuclear RNA-sequencing approaches developed a lineage tracing strategy capable defining transcriptional state recently fused distinguishing from pre-existing Our findings reveal presence conserved markers newly during development after hypertrophic stimulus adult. However, also exhibit divergent gene expression is determined by myogenic environment which they fuse. Moreover, accrual required resident adult myofibers mount normal response load-inducing stimulus. We propose model mutual regulation control adaptations, where myonuclear populations influence each other maintain optimal functional growth.

Язык: Английский

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Effect of Sijunzi Decoction on the Myonuclear Domain of Rat Soleus in Spleen Qi Deficiency

Chinese Medicine, Год журнала: 2023, Номер 14(04), С. 276 - 285

Опубликована: Янв. 1, 2023

Objective: To study the mechanism of Sijunzi decoction treating limb weakness in spleen Qi deficiency (SQD) based on myonuclear domain (MND) theory. Methods: 40 male Sprague-Dawley rats were randomly divided into normal group, SQD model group (model group), SQD+ still water (SW group) and (CM 10 each group; Grip-Strength Meter was used to measure grip strength; transmission electron microscope employed observe ultrastructural changes myofibers, Image Pro 6.0 numbers, cross-section area (CSA) then their ratios (the MND sizes) calculated, immunofluorescence assay chosen test expressions paired box gene 7 (Pax7) myogenic differentiation antigen (MyoD). Results: Compared with those strength decreased, sarcomeres abnormal, all CSA sizes reduced, but Pax7+ cell numbers increased, significantly, SW groups; groups, basically normal, number both greater, MyoD+ CM group. Conclusion: might increase by activating MSCs treat SQD.

Язык: Английский

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