JB is supported by a Muscular Dystrophy Association grant (MDA 515518) and Philippe Foundation grant. Work in the laboratory of SL is supported by an NIH R01 grant (HL128457). MC was supported by the American Heart Association (17UFEL33520004). The work at the mass spectrometry core at UCSD is supported by NIH grants (S10 OD016234, S10 OD021724). We thank the UCSD Microscopy Core and Jennifer Santini, supported by an NIH National Institute of Neurological Disorders and Stroke (NINDS) P30 grant (NS047101).
Muscles -- Molecular aspects, Muscles -- Physiology, Neuromuscular diseases -- Animal models, Ubiquitin
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.
© 2019 American Society for Clinical Investigation
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Published as: Blondelle, J., Tallapaka, K., Seto, J. T., Ghassemian, M., Clark, M., Laitila, J. M., ... & Lange, S. (2019). Cullin-3–dependent deregulation of ACTN1 represents a pathogenic mechanism in nemaline myopathy. JCI insight, 4(10).