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Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy
Yichi Zhang, … , Ning Liu, Eric N. Olson
Yichi Zhang, … , Ning Liu, Eric N. Olson
Published July 3, 2023
Citation Information: J Clin Invest. 2023;133(13):e163333. https://doi.org/10.1172/JCI163333.
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Research Article Muscle biology Article has an altmetric score of 7

Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy

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Abstract

Mutations in genes encoding nuclear envelope proteins lead to diseases known as nuclear envelopathies, characterized by skeletal muscle and heart abnormalities, such as Emery-Dreifuss muscular dystrophy (EDMD). The tissue-specific role of the nuclear envelope in the etiology of these diseases has not been extensively explored. We previously showed that global deletion of the muscle-specific nuclear envelope protein NET39 in mice leads to neonatal lethality due to skeletal muscle dysfunction. To study the potential role of the Net39 gene in adulthood, we generated a muscle-specific conditional knockout (cKO) of Net39 in mice. cKO mice recapitulated key skeletal muscle features of EDMD, including muscle wasting, impaired muscle contractility, abnormal myonuclear morphology, and DNA damage. The loss of Net39 rendered myoblasts hypersensitive to mechanical stretch, resulting in stretch-induced DNA damage. Net39 was downregulated in a mouse model of congenital myopathy, and restoration of Net39 expression through AAV gene delivery extended life span and ameliorated muscle abnormalities. These findings establish NET39 as a direct contributor to the pathogenesis of EDMD that acts by protecting against mechanical stress and DNA damage.

Authors

Yichi Zhang, Andres Ramirez-Martinez, Kenian Chen, John R. McAnally, Chunyu Cai, Mateusz Z. Durbacz, Francesco Chemello, Zhaoning Wang, Lin Xu, Rhonda Bassel-Duby, Ning Liu, Eric N. Olson

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Figure 7

DNA damage and MEF2C induction in human EDMD.

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DNA damage and MEF2C induction in human EDMD.
(A) Immunostaining for MYH...
(A) Immunostaining for MYH7 (red) and WGA (green) in healthy Ctrl and EDMD patient muscle biopsies (left). White arrowheads indicate atrophic myofibers. Scale bar: 50 μm. Quantification of percentage of atrophic myofibers out of the total number of myofibers (right). **P < 0.01. Approximately 60–100 myofibers per sample. (B) Immunostaining for γH2A.X (red), WGA (white), and DAPI (blue) in Ctrl and EDMD muscle biopsies. Scale bar: 50 μm (left). Quantification of γH2A.X-positive nuclei (right). ****P < 0.0001. Approximately 50–100 nuclei analyzed per sample. (C) Immunostaining for γH2A.X (red), MYH7 (green), WGA (white), and DAPI (blue) in EDMD muscle biopsies (left). γH2A.X is mostly detected in small angular myofibers that are also MYH7 positive. White arrowheads indicate γH2A.X-positive nuclei. An atrophic myofiber with γH2A.X-positive nuclei (red box) is enlarged (middle). Quantification of γH2A.X-positive fibers that are also atrophic among all atrophic myofibers in Ctrl and EDMD muscle (right). ***P < 0.001. Scale bars: 50 μm. Approximately 60–100 myofibers analyzed per sample. (D) Upstream regulator analysis of TFs for the most upregulated genes from a published human EDMD patient microarray (34, 35). (E) Immunostaining of MEF2C (green), WGA (white), and DAPI (red) in Ctrl and EDMD muscle biopsies. White arrowheads indicate MEF2C-positive nuclei in EDMD. Scale bar: 10 μm. Quantification of MEF2C-positive nuclei (right). *P < 0.05. Approximately 50–100 nuclei analyzed per sample. Unpaired, 2-tailed Student’s t test was performed for A, B, C, and E. n = 3 human samples were analyzed for A, B, C, and E. Data are represented as mean ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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