Nebulin deficiency in adult muscle causes sarcomere defects and muscle-type-dependent changes in trophicity: Novel insights in nemaline myopathy

Frank Li, Danielle Buck, Josine De Winter, Justin Kolb, Hui Meng, Camille Birch, Rebecca Slater, Yael Natelie Escobar, John E. Smith, Lin Yang, John Konhilas, Michael W. Lawlor, Coen Ottenheijm, Hendrikus "Henk" Granzier

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Nebulin is a giant filamentous protein that is coextensive with the actin filaments of the skeletal muscle sarcomere. Nebulin mutations are the main cause of nemaline myopathy (NEM), with typical adult patients having low expression of nebulin, yet the roles of nebulin in adult muscle remain poorly understood. To establish nebulin's functional roles in adult muscle, we studied a novel conditional nebulin KO (Neb cKO) mouse model in which nebulin deletion was driven by the muscle creatine kinase (MCK) promotor. Neb cKO mice are born with high nebulin levels in their skeletal muscles, but within weeks after birth nebulin expression rapidly falls to barely detectable levels Surprisingly, a large fraction of the mice survive to adulthood with low nebulin levels (<5% of control), contain nemaline rods and undergo fiber-type switching toward oxidative types. Nebulin deficiency causes a large deficit in specific force, and mechanistic studies provide evidence that a reduced fraction of force-generating cross-bridges and shortened thin filaments contribute to the force deficit. Muscles rich in glycolytic fibers upregulate proteolysis pathways (MuRF-1, Fbxo30/MUSA1, Gadd45a) and undergo hypotrophy with smaller cross-sectional areas (CSAs), worsening their force deficit. Muscles rich in oxidative fibers do not have smaller weights and can even have hypertrophy, offsetting their specific-force deficit. These studies reveal nebulin as critically important for force development and trophicity in adult muscle. The Neb cKO phenocopies important aspects of NEM (muscle weakness, oxidative fiber-type predominance, variable trophicity effects, nemaline rods) and will be highly useful to test therapeutic approaches to ameliorate muscle weakness.

Original languageEnglish (US)
Article numberddv243
Pages (from-to)5219-5233
Number of pages15
JournalHuman Molecular Genetics
Volume24
Issue number18
DOIs
StatePublished - Apr 9 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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    Li, F., Buck, D., De Winter, J., Kolb, J., Meng, H., Birch, C., Slater, R., Escobar, Y. N., Smith, J. E., Yang, L., Konhilas, J., Lawlor, M. W., Ottenheijm, C., & Granzier, H. H. (2015). Nebulin deficiency in adult muscle causes sarcomere defects and muscle-type-dependent changes in trophicity: Novel insights in nemaline myopathy. Human Molecular Genetics, 24(18), 5219-5233. [ddv243]. https://doi.org/10.1093/hmg/ddv243