期刊
JOURNAL OF CELL SCIENCE
卷 126, 期 23, 页码 5477-5489出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.137026
关键词
Nebulin; Nemaline myopathy; Skeletal muscle; Z-line; Sarcomere
类别
资金
- Italian Telethon Foundation [TCP07006]
- Cariplo Foundation [2007.5812]
- Italian Ministry of Education, Universities and Research [2010R8JK2X_006]
- National Institutes of Health [R01AR059334, R01HL066100, P30 AR061303, R24 HD050837]
- Department of Veterans Affairs
- Grants-in-Aid for Scientific Research [24770118, 23300144, 25670104, 25117706] Funding Source: KAKEN
- British Heart Foundation [RG/11/21/29335] Funding Source: researchfish
Nemaline myopathy (NM) is a congenital myopathy with an estimated incidence of 1: 50,000 live births. It is caused by mutations in thin filament components, including nebulin, which accounts for about 50% of the cases. The identification of NM cases with nonsense mutations resulting in loss of the extreme C-terminal SH3 domain of nebulin suggests an important role of the nebulin SH3 domain, which is further supported by the recent demonstration of its role in IGF-1-induced sarcomeric actin filament formation through targeting of N-WASP to the Z-line. To provide further insights into the functional significance of the nebulin SH3 domain in the Z-disk and to understand the mechanisms by which truncations of nebulin lead to NM, we took two approaches: (1) an affinity-based proteomic screening to identify novel interaction partners of the nebulin SH3 domain; and (2) generation and characterization of a novel knockin mouse model with a premature stop codon in the nebulin gene, eliminating its C-terminal SH3 domain (Neb Delta SH3 mouse). Surprisingly, detailed analyses of Neb Delta SH3 mice revealed no structural or histological skeletal muscle abnormalities and no changes in gene expression or localization of interaction partners of the nebulin SH3 domain, including myopalladin, palladin, zyxin and N-WASP. Also, no significant effect on peak isometric stress production, passive tensile stress or Young's modulus was found. However, Neb Delta SH3 muscle displayed a slightly altered force-frequency relationship and was significantly more susceptible to eccentric contraction-induced injury, suggesting that the nebulin SH3 domain protects against eccentric contraction-induced injury and possibly plays a role in fine-tuning the excitation-contraction coupling mechanism.
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