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Cullin-3–dependent deregulation of ACTN1 represents a pathogenic mechanism in nemaline myopathy
Jordan Blondelle, … , Jeffrey D. Singer, Stephan Lange
Jordan Blondelle, … , Jeffrey D. Singer, Stephan Lange
Published April 16, 2019
Citation Information: JCI Insight. 2019;4(10):e125665. https://doi.org/10.1172/jci.insight.125665.
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Research Article Muscle biology

Cullin-3–dependent deregulation of ACTN1 represents a pathogenic mechanism in nemaline myopathy

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Abstract

Nemaline myopathy is a congenital neuromuscular disorder characterized by muscle weakness, fiber atrophy, and presence of nemaline bodies within myofibers. However, understanding of the underlying pathomechanisms is lacking. Recently, mutations in KBTBD13, KLHL40, and KLHL41, three substrate adaptors for the E3 ubiquitin ligase Cullin-3, have been associated with early-onset nemaline myopathies. We hypothesized that deregulation of Cullin-3 and its muscle protein substrates may be responsible for disease development. Using Cullin-3–knockout mice, we identified accumulation of non-muscle α-actinins (ACTN1 and ACTN4) in muscles of these mice, which we also observed in patients with mutations in KBTBD13. Our data reveal that proper regulation of Cullin-3 activity and ACTN1 levels is essential for normal muscle and neuromuscular junction development. While ACTN1 is naturally downregulated during myogenesis, its overexpression in C2C12 myoblasts triggered defects in fusion, myogenesis, and acetylcholine receptor clustering — features that we characterized in Cullin-3–deficient mice. Taken together, our data highlight the importance of Cullin-3–mediated degradation of ACTN1 for muscle development, and indicate what is to our knowledge new pathomechanism for the etiology of myopathies seen in Cullin-3–knockout mice and patients with nemaline myopathy.

Authors

Jordan Blondelle, Kavya Tallapaka, Jane T. Seto, Majid Ghassemian, Madison Clark, Jenni M. Laitila, Adam Bournazos, Jeffrey D. Singer, Stephan Lange

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Figure 1

Deletion of Cullin-3 in skeletal muscles affects the ubiquitin-proteasome system.

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Deletion of Cullin-3 in skeletal muscles affects the ubiquitin-proteasom...
(A) Immunoblot analysis showing loss of Cullin-3 (Cul3) protein only in skeletal muscle (Sk. muscle) of E18.5 skm-KO mice. (B) Quantification of Cullin-3 protein levels in E18.5 skeletal muscles (n = 3 for each genotype). *P < 0.05 by 2-tailed t test. ctl, control. (C) Immunoblot analysis showing a decrease in NEDD8-associated proteins in E18.5 skeletal muscles of skm-KO mice. (D) Quantification of 80-kDa NEDD8-associated protein levels in E18.5 skeletal muscles (n = 3 for each genotype). **P < 0.01 by 2-tailed t test. (E) Immunoblot analysis showing a decrease in low molecular weights of K48-ubiquitin–associated proteins [Ubiq. (K48)] and no change in p62 expression levels in skeletal muscles of E18.5 skm-KO mice.

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