Degenerative and regenerative features of myofibers differ among skeletal muscles in a murine model of muscular dystrophy

Ikeda, Teppei; Ichii, Osamu; Otsuka-Kanazawa, Saori; Nakamura, Teppei; Elewa, Yaser Hosny Ali; Kon, Yasuhiro

doi:10.1007/s10974-016-9452-6

Cited by 5 publications

(8 citation statements)

References 56 publications

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“…Both eMHC and tubb6 signals were markedly reduced for 71-78 and Fiona muscle extracts compared to mdx muscles. We conclude that tubb6 is elevated in regenerating muscle fibers, its staining identifies different stages of muscle regeneration that coexist in mdx muscles, and the variation in tubb6 levels is linked to the variation in regeneration between mdx animals (33,34).…”

Section: Tubb6 Expression In MDX Muscle and Other Mouse Line Muscles Is Concentrated In Fibers With Central Nuclei And Disordered Microtumentioning

confidence: 78%

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Persistent upregulation of the β-tubulin tubb6, linked to muscle regeneration, is a source of microtubule disorganization in dystrophic muscle

Randazzo

Khalique

Belanto

et al. 2018

Human Molecular Genetics

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In healthy adult skeletal muscle fibers microtubules form a three-dimensional grid-like network. In the mdx mouse, a model of Duchenne muscular dystrophy (DMD), microtubules are mostly disordered, without periodicity. These microtubule defects have been linked to the mdx mouse pathology. We now report that increased expression of the beta 6 class V β-tubulin (tubb6) contributes to the microtubule changes of mdx muscles. Wild-type muscle fibers overexpressing green f luorescent protein (GFP)-tubb6 (but not GFP-tubb5) have disorganized microtubules whereas mdx muscle fibers depleted of tubb6 (but not of tubb5) normalize their microtubules, suggesting that increasing tubb6 is toxic. However, tubb6 increases spontaneously during differentiation of mouse and human muscle cultures. Furthermore, endogenous tubb6 is not uniformly expressed in mdx muscles but is selectively increased in fiber clusters, which we identify as regenerating. Similarly, mdx-based rescued transgenic mice that retain a higher than expected tubb6 level show focal expression of tubb6 in subsets of fibers. Tubb6 is also upregulated in cardiotoxin-induced mouse muscle regeneration, in human myositis and DMD biopsies, and the tubb6 level correlates with that of embryonic myosin heavy chain, a regeneration marker. In conclusion, modulation of a β-tubulin isotype plays a role in muscle differentiation and regeneration. Increased tubb6 expression and microtubule reorganization are not pathological per se but ref lect a return to an earlier developmental stage. However, chronic elevation of tubb6, as occurs in the mdx mouse, may contribute to the repeated cycles of regeneration and to the pathology of the disease.

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Section: Tubb6 Expression In MDX Muscle and Other Mouse Line Muscles Is Concentrated In Fibers With Central Nuclei And Disordered Microtumentioning

confidence: 78%

“…7F and G) reveal that practically all tubb6-positive fibers are centrally nucleated, i.e. regenerated (33). Discrete immunoglobulin G (IgG)-positive, i.e.…”

Section: Tubb6 Expression In MDX Muscle and Other Mouse Line Muscles Is Concentrated In Fibers With Central Nuclei And Disordered Microtumentioning

confidence: 99%

Persistent upregulation of the β-tubulin tubb6, linked to muscle regeneration, is a source of microtubule disorganization in dystrophic muscle

Randazzo

Khalique

Belanto

et al. 2018

Human Molecular Genetics

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“…A robust regenerative response to pathology is observed initially in both DMD and its mouse models, as shown by the presence of many muscle fibres expressing developmental isoforms of MyHC (Dev MyHC) ( 19 , 20 , 40 ). To validate the Myogenesis score in vivo , we analysed four transcriptomic datasets comprising 61 DMD and 47 control healthy muscle biopsies ( 41–43 ).…”

Section: Resultsmentioning

confidence: 99%

Skeletal muscle regeneration in facioscapulohumeral muscular dystrophy is correlated with pathological severity

Banerji

Henderson

Tawil

et al. 2020

Human Molecular Genetics

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Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant myopathy, characterised by slowly progressive skeletal muscle weakness and wasting. While a regenerative response is often provoked in many muscular dystrophies, little is known about whether a regenerative response is regularly elicited in FSHD muscle. For comparison, we also examined the similarly slowly progressing Myotonic Dystrophy type 2 (DM2). To investigate regeneration at the transcriptomic level, we first used the 200 human gene Hallmark Myogenesis list. This Myogenesis biomarker was elevated in FSHD and control healthy myotubes compared to their myoblast counterparts, so is higher in myogenic differentiation. The Myogenesis biomarker was also elevated in muscle biopsies from most independent FSHD, DM2 or Duchenne muscular dystrophy (DMD) studies compared to control biopsies, and on meta-analysis for each condition. The Myogenesis biomarker was also a robust binary discriminator of FSHD, DM2 and DMD from controls. We also analysed muscle regeneration at the protein level by immunolabelling muscle biopsies for Developmental Myosin Heavy Chain. Such immunolabelling revealed one or more regenerating myofibres in 76% of FSHD muscle biopsies from quadriceps and 91% from tibialis anterior. The mean proportion of regenerating myofibres per quadriceps biopsy was 0.48%, significantly less that the 1.72% in the tibialis anterior. All DM2 muscle biopsies contained regenerating myofibres, with a mean of 1.24% per biopsy. Muscle regeneration in FSHD was correlated with the pathological hallmarks of fibre size variation, central nucleation, fibrosis and necrosis/regeneration/inflammation. In summary, the regenerative response in FSHD muscle biopsies correlates with the severity of pathology.

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“…Hematoxylin presents a deep blue-purple color and stains nucleic acids, whereas eosin is pink and stains proteins. Although unspecific, this common staining can allow the visualization of both central nuclei and basophilic small fibers, readily identifying regenerating myofibers [83].…”

Section: The Role Of Satellite Cellsmentioning

confidence: 99%

“…Cells 2020, 9, x FOR PEER REVIEW 8 of 28 this common staining can allow the visualization of both central nuclei and basophilic small fibers, readily identifying regenerating myofibers [83]. The downmodulation of proliferative genes ratifies the exit of satellite cells from the cell cycle.…”

Section: The Role Of Satellite Cellsmentioning

confidence: 99%

Mechanisms Regulating Muscle Regeneration: Insights into the Interrelated and Time-Dependent Phases of Tissue Healing

Forcina

Cosentino

Musarò

2020

Cells

123

105

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Despite a massive body of knowledge which has been produced related to the mechanisms guiding muscle regeneration, great interest still moves the scientific community toward the study of different aspects of skeletal muscle homeostasis, plasticity, and regeneration. Indeed, the lack of effective therapies for several physiopathologic conditions suggests that a comprehensive knowledge of the different aspects of cellular behavior and molecular pathways, regulating each regenerative stage, has to be still devised. Hence, it is important to perform even more focused studies, taking the advantage of robust markers, reliable techniques, and reproducible protocols. Here, we provide an overview about the general aspects of muscle regeneration and discuss the different approaches to study the interrelated and time-dependent phases of muscle healing.

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Degenerative and regenerative features of myofibers differ among skeletal muscles in a murine model of muscular dystrophy

Cited by 5 publications

References 56 publications

Persistent upregulation of the β-tubulin tubb6, linked to muscle regeneration, is a source of microtubule disorganization in dystrophic muscle

Persistent upregulation of the β-tubulin tubb6, linked to muscle regeneration, is a source of microtubule disorganization in dystrophic muscle

Skeletal muscle regeneration in facioscapulohumeral muscular dystrophy is correlated with pathological severity

Mechanisms Regulating Muscle Regeneration: Insights into the Interrelated and Time-Dependent Phases of Tissue Healing

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