Nebulin deficiency in adult muscle causes sarcomere defects and muscle-type-dependent changes in trophicity: novel insights in nemaline myopathy. Hum Mol Genet 2015 Sep 15;24(18):5219-33
Date
07/01/2015Pubmed ID
26123491Pubmed Central ID
PMC4550825DOI
10.1093/hmg/ddv243Scopus ID
2-s2.0-84940663695 (requires institutional sign-in at Scopus site) 49 CitationsAbstract
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.
Author List
Li F, Buck D, De Winter J, Kolb J, Meng H, Birch C, Slater R, Escobar YN, Smith JE 3rd, Yang L, Konhilas J, Lawlor MW, Ottenheijm C, Granzier HLAuthor
Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsDisease Models, Animal
Gene Expression
Gene Expression Profiling
Mice
Mice, Knockout
Muscle Contraction
Muscle Fibers, Skeletal
Muscle Proteins
Muscle Weakness
Muscle, Skeletal
Myopathies, Nemaline
Myosins
Phenotype
Sarcomeres
