title: Nebulin deficiency in adult muscle causes sarcomere defects and muscle-type-dependent changes in trophicity: novel insights in nemaline myopathy.
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.
authors.affiliation: Department of Cellular and Molecular Medicine.
authors.forename: Frank
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Cellular and Molecular Medicine.
authors.forename: Danielle
authors.initials: D
authors.lastname: Buck
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Josine
authors.initials: J
authors.lastname: De Winter
authors.affiliation: Department of Cellular and Molecular Medicine.
authors.forename: Justin
authors.initials: J
authors.lastname: Kolb
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA and.
authors.forename: Hui
authors.initials: H
authors.lastname: Meng
authors.affiliation: Department of Physiology, University of Arizona, Tucson, AZ, USA.
authors.forename: Camille
authors.initials: C
authors.lastname: Birch
authors.affiliation: Department of Cellular and Molecular Medicine.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Slater
authors.affiliation: Department of Cellular and Molecular Medicine.
authors.forename: Yael Natelie
authors.initials: YN
authors.lastname: Escobar
authors.affiliation: Department of Cellular and Molecular Medicine.
authors.forename: John E
authors.initials: JE
authors.lastname: Smith
authors.affiliation: Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Physiology, University of Arizona, Tucson, AZ, USA.
authors.forename: John
authors.initials: J
authors.lastname: Konhilas
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, WI, USA and.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lawlor
authors.affiliation: Department of Cellular and Molecular Medicine, Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Coen
authors.initials: C
authors.lastname: Ottenheijm
authors.affiliation: Department of Cellular and Molecular Medicine, granzier@email.arizona.edu.
authors.forename: Henk L
authors.initials: HL
authors.lastname: Granzier
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics; D018908:Muscle Weakness / Q000235:genetics / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure; D017696:Myopathies, Nemaline / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012518:Sarcomeres / Q000378:metabolism* / Q000473:pathology
chemical_list: D009124:Muscle Proteins; C035620:nebulin; D009218:Myosins