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NEB mutations disrupt the super-relaxed state of myosin and remodel the muscle metabolic proteome in nemaline myopathy

Lookup NU author(s): Professor Giorgio TascaORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022, The Author(s). Nemaline myopathy (NM) is one of the most common non-dystrophic genetic muscle disorders. NM is often associated with mutations in the NEB gene. Even though the exact NEB-NM pathophysiological mechanisms remain unclear, histological analyses of patients’ muscle biopsies often reveal unexplained accumulation of glycogen and abnormally shaped mitochondria. Hence, the aim of the present study was to define the exact molecular and cellular cascade of events that would lead to potential changes in muscle energetics in NEB-NM. For that, we applied a wide range of biophysical and cell biology assays on skeletal muscle fibres from NM patients as well as untargeted proteomics analyses on isolated myofibres from a muscle-specific nebulin‐deficient mouse model. Unexpectedly, we found that the myosin stabilizing conformational state, known as super-relaxed state, was significantly impaired, inducing an increase in the energy (ATP) consumption of resting muscle fibres from NEB-NM patients when compared with controls or with other forms of genetic/rare, acquired NM. This destabilization of the myosin super-relaxed state had dynamic consequences as we observed a remodeling of the metabolic proteome in muscle fibres from nebulin‐deficient mice. Altogether, our findings explain some of the hitherto obscure hallmarks of NM, including the appearance of abnormal energy proteins and suggest potential beneficial effects of drugs targeting myosin activity/conformations for NEB-NM.

Publication metadata

Author(s): Ranu N, Laitila J, Dugdale HF, Mariano J, Kolb JS, Wallgren-Pettersson C, Witting N, Vissing J, Vilchez JJ, Fiorillo C, Zanoteli E, Auranen M, Jokela M, Tasca G, Claeys KG, Voermans NC, Palmio J, Huovinen S, Moggio M, Beck TN, Kontrogianni-Konstantopoulos A, Granzier H, Ochala J

Publication type: Article

Publication status: Published

Journal: Acta Neuropathologica Communications

Year: 2022

Volume: 10

Issue: 1

Online publication date: 17/12/2022

Acceptance date: 08/12/2022

Date deposited: 22/02/2023

ISSN (electronic): 2051-5960

Publisher: BioMed Central Ltd


DOI: 10.1186/s40478-022-01491-9

PubMed id: 36528760


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