Myocyte-derived Myomaker expression is required for regenerative fusion but exacerbates membrane instability in dystrophic myofibers

Petrany, Michael J.; Song, Taejeong; Sadayappan, Sakthivel; Millay, Douglas P.

doi:10.1172/jci.insight.136095

Cited by 28 publications

(32 citation statements)

References 47 publications

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“…4b,c). Overall, these observations suggest that the fusion of LPM-derived cells into the myofiber is dependent on a mechanism not involving Mymk in fibroblasts and potentially consistent with the lack of need for Mymk in myofibers for fusion 29,30 .…”

Section: Lpm-derived Fibroblasts Fuse To Growing Myofiberssupporting

confidence: 53%

Fibroblast fusion to the muscle fiber regulates myotendinous junction formation

Yaseen-Badarneh

Kraft-Sheleg

Zaffryar-Eilot

et al. 2020

Preprint

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SummaryVertebrate muscles and tendons are derived from distinct embryonic origins yet they must interact in order to facilitate muscle contraction and body movements. How robust muscle tendon junctions (MTJs) form to be able to withstand contraction forces is still not understood. Using techniques at a single cell resolution we reexamined the classical view of distinct identities for the tissues composing the musculoskeletal system. We identified fibroblasts that have switched on a myogenic program and demonstrate these dual identity cells fuse into the developing muscle fibers along the MTJs facilitating the introduction of fibroblast-specific transcripts into the elongating myofibers. We suggest this mechanism resulting in a hybrid muscle fiber, primarily along the fiber tips, enables a smooth transition from muscle fiber characteristics towards tendon features essential for forming robust MTJs. We propose that dual characteristics of junctional cells could be a common mechanism for generating stable interactions between tissues throughout the musculoskeletal system.

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Section: Lpm-derived Fibroblasts Fuse To Growing Myofiberssupporting

confidence: 53%

Fibroblast fusion to the muscle fiber regulates myotendinous junction formation

Yaseen-Badarneh

Kraft-Sheleg

Zaffryar-Eilot

et al. 2020

Preprint

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“…Furthermore, this group demonstrated the therapeutic potential of COUP-TF II antagonist by generating SC-specific COUP-TF II-deficient mdx mice, in which the progressive dystrophic symptoms were mitigated following COUP-TF II ablation. Recently, Petrany et al [39] reported that SC-specific depletion of fusogenic protein Myomaker aggravated the dystrophic pathology in the mdx mice, confirming the effects of myoblast fusion in DMD pathophysiology.…”

Section: Stem Cell-related Dmd Pathogenesismentioning

confidence: 83%

Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

Sun

Shen

Zhang

et al. 2020

Genes

109

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Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy.

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“…The cluster of RegMyon nuclei is particularly interesting as it is specific to dystrophic muscle. Among the known markers of this cluster of nuclei, we detected the embryonic and perinatal MyHC isoforms Myh3 and Myh8 and the fusogenic factor Myomaker, which is required for regenerative fusion (64). In addition, we identified putative regulators of muscle regeneration acting as transcription factors or involved in myoblast fusion.…”

Section: Discussionmentioning

confidence: 99%

Degenerative and regenerative pathways underlying Duchenne muscular dystrophy revealed by single-nucleus RNA sequencing

Chemello

Wang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

104

132

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Duchenne muscular dystrophy (DMD) is a fatal muscle disorder characterized by cycles of degeneration and regeneration of multinucleated myofibers and pathological activation of a variety of other muscle-associated cell types. The extent to which different nuclei within the shared cytoplasm of a myofiber may display transcriptional diversity and whether individual nuclei within a multinucleated myofiber might respond differentially to DMD pathogenesis is unknown. Similarly, the potential transcriptional diversity among nonmuscle cell types within dystrophic muscle has not been explored. Here, we describe the creation of a mouse model of DMD caused by deletion of exon 51 of the dystrophin gene, which represents a prevalent disease-causing mutation in humans. To understand the transcriptional abnormalities and heterogeneity associated with myofiber nuclei, as well as other mononucleated cell types that contribute to the muscle pathology associated with DMD, we performed single-nucleus transcriptomics of skeletal muscle of mice with dystrophin exon 51 deletion. Our results reveal distinctive and previously unrecognized myonuclear subtypes within dystrophic myofibers and uncover degenerative and regenerative transcriptional pathways underlying DMD pathogenesis. Our findings provide insights into the molecular underpinnings of DMD, controlled by the transcriptional activity of different types of muscle and nonmuscle nuclei.

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Myocyte-derived Myomaker expression is required for regenerative fusion but exacerbates membrane instability in dystrophic myofibers

Cited by 28 publications

References 47 publications

Fibroblast fusion to the muscle fiber regulates myotendinous junction formation

Fibroblast fusion to the muscle fiber regulates myotendinous junction formation

Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

Degenerative and regenerative pathways underlying Duchenne muscular dystrophy revealed by single-nucleus RNA sequencing

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