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Hum Mol Genet. 2014 Nov 15;23(22):5879-92. doi: 10.1093/hmg/ddu310. Epub 2014 Jun 18.

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

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Department of Bioengineering and.
Department of Medicine.
Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Department of Cardiothoracic Surgery, The Second Xiangya Hospital of Central South University, No. 139 Renmin Road, Changsha, Hunan 410011, P.R. China and.
Department of Medicine, School of Chemical Biology and Biotechnology, Peking University, Shenzhen 518055, P.R. China.
Department of Bioengineering and Department of Orthopaedic Surgery, University of California San Diego, and Department of Veteran's Affairs, 9500 Gilman Drive, La Jolla, CA 92093-0863, USA.
Department of Medicine,


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 nesprin-desmin double-knockout (DKO) mouse, eliminating a major fraction of nuclear-cytoskeletal connections and enabling understanding of the importance of nuclear anchorage in skeletal muscle. Globally, DKO mice 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 1(-/-) and desmin(-/-) mice. Additionally, nuclear-cytoskeletal strain transmission was decreased in DKO skeletal muscle. Finally, loss of nuclear anchorage in DKO mice 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.

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