Muscle stabilizer

Nemaline myopathy is a congenital muscle disorder that is characterized by the presence of rod-like structures (nemaline bodies) within myofibers. While multiple genes have been implicated in this disease, it is not clear how these gene products contribute to muscle dysfunction. Ankit Garg and colleagues at the University of Texas Southwestern Medical Center determined that mice lacking the muscle-specific protein KLHL40 develop a severe nemaline-like myopathy that is very similar to that observed in patients with a KLHL40-deficiency. KLHL40 localized to the thin filament proteins nebulin (NEB), which has been implicated in nemaline myopathy, and leiomodin 3 (LMOD3). The interaction of KLHL40 with NEB and LMOD3 functioned to stabilize these proteins and specifically prevented ubiquitination of LMOD3. Importantly, both LMOD3 and NEB were reduced in skeletal muscle from KLHL40-deficient animals as well as patients with KLHL40-depenedent nemaline mypopathy. The accompanying image shows a sagittal section of an embryonic day 15 mouse embryo that was probed for Klhl40 mRNA with an antisense radioisotopic probe. Klhl40 (pseudocolored red) only appears in developing muscle. 

Published June 24, 2014, by Corinne Williams

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KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy
Ankit Garg, Jason O’Rourke, Chengzu Long, Jonathan Doering, Gianina Ravenscroft, Svetlana Bezprozvannaya, Benjamin R. Nelson, Nadine Beetz, Lin Li, She Chen, Nigel G. Laing, Robert W. Grange, Rhonda Bassel-Duby, Eric N. Olson
Ankit Garg, Jason O’Rourke, Chengzu Long, Jonathan Doering, Gianina Ravenscroft, Svetlana Bezprozvannaya, Benjamin R. Nelson, Nadine Beetz, Lin Li, She Chen, Nigel G. Laing, Robert W. Grange, Rhonda Bassel-Duby, Eric N. Olson
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Research Article

KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy

Abstract

Nemaline myopathy (NM) is a congenital myopathy that can result in lethal muscle dysfunction and is thought to be a disease of the sarcomere thin filament. Recently, several proteins of unknown function have been implicated in NM, but the mechanistic basis of their contribution to disease remains unresolved. Here, we demonstrated that loss of a muscle-specific protein, kelch-like family member 40 (KLHL40), results in a nemaline-like myopathy in mice that closely phenocopies muscle abnormalities observed in KLHL40-deficient patients. We determined that KLHL40 localizes to the sarcomere I band and A band and binds to nebulin (NEB), a protein frequently implicated in NM, as well as a putative thin filament protein, leiomodin 3 (LMOD3). KLHL40 belongs to the BTB-BACK-kelch (BBK) family of proteins, some of which have been shown to promote degradation of their substrates. In contrast, we found that KLHL40 promotes stability of NEB and LMOD3 and blocks LMOD3 ubiquitination. Accordingly, NEB and LMOD3 were reduced in skeletal muscle of both Klhl40–/– mice and KLHL40-deficient patients. Loss of sarcomere thin filament proteins is a frequent cause of NM; therefore, our data that KLHL40 stabilizes NEB and LMOD3 provide a potential basis for the development of NM in KLHL40-deficient patients.

Authors

Ankit Garg, Jason O’Rourke, Chengzu Long, Jonathan Doering, Gianina Ravenscroft, Svetlana Bezprozvannaya, Benjamin R. Nelson, Nadine Beetz, Lin Li, She Chen, Nigel G. Laing, Robert W. Grange, Rhonda Bassel-Duby, Eric N. Olson

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