Disruption of both nesprin 1 and desmin results in nuclear anchorage defects and fibrosis in skeletal muscle

Mark A. Chapman, Jianlin Zhang, Indroneal Banerjee, Ling T. Guo, Zhiwei Zhang, G. Diane Shelton, Kunfu Ouyang, Richard L. Lieber, Ju Chen*

*Corresponding author for this work

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Proper localization and anchorage of nuclei within skeletal muscle is critical for cellular function. Alterations in nuclear anchoring proteins modify a number of cellular functions including mechanotransduction, nuclear localization, chromatin positioning/compaction and overall organ function. In skeletal muscle, nesprin 1 and desmin are thought to link the nucleus to the cytoskeletal network. Thus, we hypothesize that both of these factors play a key role in skeletal muscle function. To examine this question, we utilized global ablation murine models of nesprin 1, desmin or both nesprin 1 and desmin. Herein, we have created the nesprindesmindouble- knockout(DKO)mouse, eliminatingamajor fractionof nuclear-cytoskeletal connectionsandenabling understanding of the importance of nuclear anchorage in skeletal muscle. Globally,DKOmice are marked by decreased lifespan, body weight and muscle strength. With regard to skeletal muscle, DKO myonuclear anchorage was dramatically decreased compared with wild-type, nesprin 12/2 and desmin2/2 mice. Additionally, nuclear-cytoskeletal strain transmission was decreased in DKO skeletal muscle. Finally, loss of nuclear anchorage inDKOmice coincided with a fibrotic response as indicated by increased collagen and extracellular matrix deposition and increased passive mechanical properties of muscle bundles. Overall, our data demonstrate that nesprin 1 and desmin serve redundant roles in nuclear anchorage and that the loss of nuclear anchorage in skeletal muscle results in a pathological response characterized by increased tissue fibrosis and mechanical stiffness.

Original languageEnglish (US)
Pages (from-to)5879-5892
Number of pages14
JournalHuman molecular genetics
Volume23
Issue number22
DOIs
StatePublished - Nov 15 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Chapman, M. A., Zhang, J., Banerjee, I., Guo, L. T., Zhang, Z., Shelton, G. D., Ouyang, K., Lieber, R. L., & Chen, J. (2014). Disruption of both nesprin 1 and desmin results in nuclear anchorage defects and fibrosis in skeletal muscle. Human molecular genetics, 23(22), 5879-5892. https://doi.org/10.1093/hmg/ddu310