The nuclear envelope protein Net39 is essential for muscle nuclear integrity and chromatin organization

Ramirez-Martinez, Andres; Zhang, Yichi; Chen, Kenian; Kim, Jiwoong; Cenik, Bercin Kutluk; McAnally, John; Cai, Chunyu; Shelton, John M.; Brennan, Ana; Evers, B. Mark; Mammen, Pradeep P.A.; Xu, Lin; Bassel‐Duby, Rhonda; Liu, Ning; Olson, Eric N.

doi:10.1038/s41467-021-20987-x

Cited by 21 publications

(21 citation statements)

References 53 publications

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“…In this regard, loss of the muscle-specific NEP NET39 in mice triggers a severe phenotype only in skeletal muscles. Moreover, a direct physical interaction between LEMD2 and NET39 has been reported in C2C12 myotubes ( 42 ). In the future, further studies will be necessary to decipher whether this interaction is functionally important.…”

Section: Discussionmentioning

confidence: 97%

Loss of function of the nuclear envelope protein LEMD2 causes DNA damage–dependent cardiomyopathy

Caravia¹,

Ramirez-Martinez²,

Gan³

et al. 2022

Journal of Clinical Investigation

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Mutations in nuclear envelope proteins (NEPs) cause devastating genetic diseases, known as envelopathies, that primarily affect the heart and skeletal muscle. A mutation in the NEP LEM domain–containing protein 2 (LEMD2) causes severe cardiomyopathy in humans. However, the roles of LEMD2 in the heart and the pathological mechanisms responsible for its association with cardiac disease are unknown. We generated knockin (KI) mice carrying the human c.T38>G Lemd2 mutation, which causes a missense amino acid exchange (p.L13>R) in the LEM domain of the protein. These mice represent a preclinical model that phenocopies the human disease, as they developed severe dilated cardiomyopathy and cardiac fibrosis leading to premature death. At the cellular level, KI/KI cardiomyocytes exhibited disorganization of the transcriptionally silent heterochromatin associated with the nuclear envelope. Moreover, mice with cardiac-specific deletion of Lemd2 also died shortly after birth due to heart abnormalities. Cardiomyocytes lacking Lemd2 displayed nuclear envelope deformations and extensive DNA damage and apoptosis linked to p53 activation. Importantly, cardiomyocyte-specific Lemd2 gene therapy via adeno-associated virus rescued cardiac function in KI/KI mice. Together, our results reveal the essentiality of LEMD2 for genome stability and cardiac function and unveil its mechanistic association with human disease.

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Section: Discussionmentioning

confidence: 97%

Loss of function of the nuclear envelope protein LEMD2 causes DNA damage–dependent cardiomyopathy

Caravia¹,

Ramirez-Martinez²,

Gan³

et al. 2022

Journal of Clinical Investigation

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“…Myh4, which was down-regulated by VWR exercise and acute maximal exercise, is reportedly down-regulated in humans during aerobic and resistance exercise training 31 . Ppapdc3/Plpp7 (inactive phospholipid phosphatase 7) is a muscle-specific regulator of nuclear envelope structure enriched in fast-twitch muscles 32 and is associated with Emery-Dreifuss muscular dystrophy 3 (EDMD3) 33 . In this study, Ppapdc3 was down-regulated consistently by EPS, acute maximal exercise, and VWR exercise.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide analysis of a cellular exercise model based on electrical pulse stimulation

Lee

Kim

Shin

et al. 2022

Sci Rep

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Skeletal muscle communicates with other organs via myokines, which are secreted by muscle during exercise and exert various effects. Despite much investigation of the exercise, the underlying molecular mechanisms are still not fully understood. Here, we applied an in vitro exercise model in which cultured C2C12 myotubes were subjected to electrical pulse stimulation (EPS), which mimics contracting muscle. Based on the significantly up- and down-regulated genes in EPS, we constructed an in silico model to predict exercise responses at the transcriptional level. The in silico model revealed similarities in the transcriptomes of the EPS and exercised animals. Comparative analysis of the EPS data and exercised mouse muscle identified putative biomarkers in exercise signaling pathways and enabled to discover novel exercise-induced myokines. Biochemical analysis of selected exercise signature genes in muscle from exercised mice showed that EPS mimics in vivo exercise, at least in part, at the transcriptional level. Consequently, we provide a novel myokine, Amphiregulin (AREG), up-regulated both in vitro and in vivo, that would be a potential target for exercise mimetics.

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“…RNA sequencing was performed by the CRI Sequencing Facility at the University of Texas Southwestern Medical Center. Bioinformatics analysis was performed as previously described ( 57 ). Low-quality reads were excluded (with fewer than 30% nucleotides with Phred quality scores below 20), and the remaining reads were aligned to the mouse genome (GRCm38.mm10) with HISAT2 aligner (v2.1.0) and counted with featureCounts (v1.6.2).…”

Section: Methodsmentioning

confidence: 99%

Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome

Ramirez-Martinez¹,

Zhang²,

Boogaard³

et al. 2022

Journal of Clinical Investigation

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Skeletal muscle fibers contain hundreds of nuclei, which increase the overall transcriptional activity of the tissue and perform specialized functions. Multinucleation occurs through myoblast fusion, mediated by the muscle fusogens Myomaker ( MYMK ) and Myomixer ( MYMX ). We describe a human pedigree harboring a recessive truncating variant of the MYMX gene that eliminates an evolutionarily conserved extracellular hydrophobic domain of MYMX, thereby impairing fusogenic activity. Homozygosity of this human variant resulted in a spectrum of abnormalities that mimicked the clinical presentation of Carey-Fineman-Ziter syndrome (CFZS), caused by hypomorphic MYMK variants. Myoblasts generated from patient-derived induced pluripotent stem cells displayed defective fusion, and mice bearing the human MYMX variant died perinatally due to muscle abnormalities. In vitro assays showed that the human MYMX variant conferred minimal cell-cell fusogenicity, which could be restored with CRISPR/Cas9–mediated base editing, thus providing therapeutic potential for this disorder. Our findings identify MYMX as a recessive, monogenic human disease gene involved in CFZS, and provide new insights into the contribution of myoblast fusion to neuromuscular diseases.

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The nuclear envelope protein Net39 is essential for muscle nuclear integrity and chromatin organization

Cited by 21 publications

References 53 publications

Loss of function of the nuclear envelope protein LEMD2 causes DNA damage–dependent cardiomyopathy

Loss of function of the nuclear envelope protein LEMD2 causes DNA damage–dependent cardiomyopathy

Genome-wide analysis of a cellular exercise model based on electrical pulse stimulation

Impaired activity of the fusogenic micropeptide Myomixer causes myopathy resembling Carey-Fineman-Ziter syndrome

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