Nuclear Deformities Minimally Affect Fiber‐Type‐Specific Disease Progression in Murine Models of Nuclear Envelope Myopathy

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(9)

Published: May 10, 2025

Abnormalities in nuclear morphology are specific features of the envelopathies, including Emery-Dreifuss muscular dystrophy (EDMD). The presence abnormally shaped nuclei skeletal muscles EDMD patients and murine models has been reported both vivo vitro; however, how architectural abnormalities affects disease development progression remains unclear. In this study, we analyzed slow-twitch soleus (SOL) fast-twitch extensor digitorum longus (EDL) from following model mice: emerin knockout (Emd), LmnaH222P/H222P knockin (H222P), Emd/H222P double-mutated (EH), to elucidate effects altered shapes on fiber-type-specific development. Dystrophic phenotypes were exclusively detected SOL EH mice, myonuclear shape irregularities observed only muscle but not EDL muscle. Recovery cardiotoxin (CTX) injection improved peripheral myonuclei, histology function, concomitant with an increase number size type 1 fibers regenerated mice 42 days after damage. Importantly, was relatively retained even 126 CTX injection, although dystrophic pathology gradually progressed. Taken together, our results indicate that morphological changes plays a minor role EDMD.

Language: Английский

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MicroRNA control of the myogenic cell transcriptome and proteome: the role of miR-16

AJP Cell Physiology, Journal Year: 2023, Volume and Issue: 324(5), P. C1101 - C1109

Published: March 27, 2023

MicroRNAs (miRs) control stem cell biology and fate. Ubiquitously expressed conserved miR-16 was the first miR implicated in tumorigenesis. is low muscle during developmental hypertrophy regeneration. It enriched proliferating myogenic progenitor cells but repressed differentiation. The induction of blocks myoblast differentiation myotube formation, whereas knockdown enhances these processes. Despite a central role for biology, how it mediates its potent effects incompletely defined. In this investigation, global transcriptomic proteomic analyses after C2C12 myoblasts revealed influences Eighteen hours inhibition, ribosomal protein gene expression levels were higher relative to p53 pathway-related abundance lower. At level at same time point, globally upregulated tricarboxylic acid (TCA) cycle proteins while downregulating RNA metabolism-related proteins. inhibition induced specific associated with such as ACTA2, EEF1A2, OPA1. We extend prior work hypertrophic tissue show that lower mechanically overloaded vivo. Our data collectively point aspects A deeper understanding has consequences growth, exercise-induced hypertrophy, regenerative repair injury, all which involve progenitors.

Language: Английский

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Effects of high‐resistance wheel running on hallmarks of endurance and resistance training adaptations in mice

Physiological Reports, Journal Year: 2023, Volume and Issue: 11(11)

Published: June 1, 2023

Exercise effectively promotes and preserves cardiorespiratory, neuromuscular, metabolic, cognitive functions throughout life. The molecular mechanisms underlying the beneficial adaptations to exercise training are, however, still poorly understood. To improve mechanistic study of specific adaptations, standardized, physiological, well-characterized interventions are required. Therefore, we performed a comprehensive interrogation systemic changes muscle-specific cellular voluntary low-resistance wheel running (Run) progressive high-resistance (RR) in young male mice. Following 10 weeks training, both groups showed similar improvements body composition peak oxygen uptake (V̇O2peak ), as well elevated mitochondrial proteins capillarization markers M. plantaris. Run mice clearly outperformed RR forced treadmill capacity test, while displayed increased grip strength superior mass gains soleus, associated with distinct proteomic specifying two paradigms. Thus, even though modalities induce overlapping preferably submaximal performance, is valid model training-induced plantar flexor hypertrophy.

Language: Английский

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Muscle fibre size and myonuclear positioning in trained and aged humans

Experimental Physiology, Journal Year: 2024, Volume and Issue: 109(4), P. 549 - 561

Published: March 10, 2024

Abstract Changes in myonuclear architecture and positioning are associated with exercise adaptations ageing. However, data on the number of myonuclei following inconsistent. Additionally, whether domains (MNDs; i.e., theoretical volume cytoplasm within which a myonucleus is responsible for transcribing DNA) altered age remains unclear. The aim this investigation was to investigate relationships between activity status positioning. Vastus lateralis muscle biopsies from younger endurance‐trained (YT) older (OT) individuals were compared age‐matched untrained counterparts (YU OU; OU samples acquired during surgical operation). Serial, optical z ‐slices throughout isolated fibres analysed give three‐dimensional coordinates fibre dimensions. mean cross‐sectional area (CSA) 33%–53% smaller other groups. nuclei relative CSA 90% greater YU fibres. scaling MND size individuals. arrangement, contrast, similar across Fibre most parameters significantly individuals, but not trained These indicate that regular endurance lifespan might better preserve maintain relationship volumes. Inactivity, however, result reduced parameters.

Language: Английский

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Ventilator‐induced diaphragm dysfunction: phenomenology and mechanism(s) of pathogenesis

The Journal of Physiology, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 31, 2024

Abstract Mechanical ventilation (MV) is used to support and pulmonary gas exchange in patients during critical illness surgery. Although MV a life‐saving intervention for respiratory failure, an unintended side‐effect of the rapid development diaphragmatic atrophy contractile dysfunction. This MV‐induced weakness labelled as ‘ventilator‐induced diaphragm dysfunction’ (VIDD). VIDD important clinical problem because risk factor failure wean from MV. Indeed, inability remove ventilator results prolonged hospitalization increased morbidity mortality. The pathogenesis has been extensively investigated, revealing that mitochondrial production reactive oxygen species within muscle fibres promotes cascade redox‐regulated signalling events leading both accelerated proteolysis depressed protein synthesis. Together, these promote review highlights changes structure/function discusses cell‐signalling mechanisms responsible VIDD. report concludes with discussion potential therapeutic opportunities prevent suggestions future research this exciting field. image

Language: Английский

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SMN Deficiency Induces an Early Non-Atrophic Myopathy with Alterations in the Contractile and Excitatory Coupling Machinery of Skeletal Myofibers in the SMN∆7 Mouse Model of Spinal Muscular Atrophy

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(22), P. 12415 - 12415

Published: Nov. 19, 2024

Spinal muscular atrophy (SMA) is caused by a deficiency of the ubiquitously expressed survival motor neuron (SMN) protein. The main pathological hallmark SMA degeneration lower neurons (MNs) with subsequent denervation and skeletal muscle. However, increasing evidence indicates that low SMN levels not only are detrimental to central nervous system (CNS) but also directly affect other peripheral tissues organs, including To better understand potential primary impact in muscle, we explored cellular, ultrastructural, molecular basis myopathy SMNΔ7 mouse model severe at an early postnatal period (P0-7) prior muscle MN loss (preneurodegenerative [PND] stage). This contrasts neurodegenerative (ND) stage (P8-14), which occur. At PND stage, found SMN∆7 mice displayed signs dysfunction overt myofiber alterations absence atrophy. We provide essential new ultrastructural data on focal segmental lesions myofibrillar contractile apparatus. These were observed association specific myonuclear domains included abnormal accumulations actin-thin myofilaments, sarcomere disruption, formation minisarcomeres. sarcoplasmic reticulum triads exhibited alterations, suggesting decoupling during excitation-contraction process. Finally, changes intermyofibrillar mitochondrial organization dynamics, indicative biogenesis overactivation, found. Overall, our results demonstrated induces loss-independent myofibers essentially contribute myopathy. strongly supports growing body indicating existence intrinsic further reinforces relevance this tissue as key therapeutic target for disease.

Language: Английский

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Myonuclear apoptosis underlies diaphragm atrophy in mechanically ventilated ICU patients

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 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.

Language: Английский

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

Biochemical Society Transactions, Journal Year: 2024, Volume and Issue: 52(6), P. 2603 - 2616

Published: Dec. 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.

Language: 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), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 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.

Language: Английский

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Automated in‐depth fiber and nuclei typing in cross‐sectional muscle images can pave the way to a better understanding of skeletal muscle diseases

Acta Physiologica, Journal Year: 2023, Volume and Issue: 239(1)

Published: Aug. 8, 2023

In this issue of Acta Physiologica, Lundquist et al.1 present a new platform for automated image data analysis skeletal muscle samples. Immunohistochemical can be used to visualize the fiber type composition different muscles and their sex-specific adaptations with age, which are individually influenced by genetic predisposition, physical exercise, nutrition, stress, environmental factors (Figure 1). Because correlation structure physiology, assessment also provide an important contribution evaluation diseased tissue. Over past 5 years various software have been developed that allow immunohistochemical cross-sectional images. Manual limits quantitative result in terms representativeness, since only small number samples investigated due time required, objectivity, is highly dependent on qualifications evaluator. future, automation will crucial compare results animal models as well human biopsies from research institutions clinical centers. If quality sample preparation microscopy ensured, it would possible build global databases could used, example, improve therapy rare diseases—a worthwhile goal. Some available routines images were programmed directly MatLab (e.g., MyoView2) or performed paid Imaris3). However, two open source processing packages mainly community analyze data. One these Fiji/ImageJ, was based JAVA employee NIH constantly being expanded large team. Of hundreds plug-ins now written user community, Myosight,4 MuscleJ,5 Myosoft,6 MyoVision,7 QauntiMus8 one more macro9 CellProfiler created at Broad Institute MIT Harvard permanently improved there project team Cimini Lab. The software, Python, thus free, open-source into anyone write own algorithms module. So far, Muscle2view10 has evaluate CellProfiler. al. introduce FiNuTyper (Fiber Nucleus Typer) module1 2). question arises, novel possibilities opens cross-section compared already packages. Fiber identification, typing size determination all mentioned modules. By integrating Cellpose,11 algorithm Python machine object recognition, authors able accuracy detection algorithms. Furthermore, first tool automatic groupings defined collections same This parameter seems play role especially slow-twitch fibers. Here, increase such may marker reinnervated fibers reflect activity-related plasticity. Whereas differentiation slow- fast-twitch previously using antibodies detect distribution myosin heavy chains (MyHC), take approach.1 aimed simultaneously perform differential nucleotyping, not via contractile protein labeling. entire family Ca2+-ATPases, three work sarcoplasmic reticulum Ca2+ pumps (SERCA).12 SERCA1 expressed muscle.12 SERCA2 found fast- slow-twitch, smooth, cardiac non-muscle cells.12 SERCA3, other hand, solely nuclear envelope, physically separates nucleoplasm cytoplasm, interrupted complex branched network invaginations, nucleoplasmic reticulum. Among many functions, structures control selective bidirectional transport ions. under SERCA, shown cardiomyocytes.13 Disruption signaling appears trigger development hypertrophy heart failure early stage.13 With selection appropriate SERCA detailed comparison established MyHC1 MyHC2A immunohistochemistry, convince sensitive specific 2 1. demonstrate methodological approach both healthy pathological nuclei isoforms advantage exclusively myonuclei detected distinguished mononuclei blood vessel cells, fibroblasts satellite cells. Since cells resource growth per myofiber allows statements about condition atrophy),14 method clearly superior its informative value staining DAPI. incorporating another deep learning algorithm, nucleAIzer,15 itself FiNuTyper1 further improved. within plays essential supply regulation,16 but mechanisms motility, increase, degradation poorly understood date.16 nucleotyping specify health status addition typing, search subject some time. pericentriolar material 1 post-mitotic myonuclei.14 presented provides advantages over A assignment tissue section. initial promising patients amyotrophic lateral sclerosis inclusion body myositis FiNuTyper.1 As Lloyd al.17 conclude review just published process change triggered endogenous factors, characterizes manifestation variety neuromuscular diseases. Slow- show susceptibility stressors1, 17 Due acquisition data, unfortunately often inadequately. makes characterization disease patterns difficult. Considering fact, make significant here. broader application whether meets expectations needs improvement. Simone Baltrusch: Conceptualization; writing – original draft. None. Research lab supported DFG (GRK 2676) Deutsche Diabetes Gesellschaft. author no conflicts interest disclose.

Language: Английский

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