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

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt


  • Fulltext

    Forlagets udgivne version, 4,34 MB, PDF-dokument

  • Natasha Ranu
  • Hannah F. Dugdale
  • Jennifer Mariano
  • Justin S. Kolb
  • Carina Wallgren-Pettersson
  • Nanna Witting
  • Juan Jesus Vilchez
  • Chiara Fiorillo
  • Edmar Zanoteli
  • Mari Auranen
  • Manu Jokela
  • Giorgio Tasca
  • Kristl G. Claeys
  • Nicol C. Voermans
  • Johanna Palmio
  • Sanna Huovinen
  • Maurizio Moggio
  • Thomas Nyegaard Beck
  • Aikaterini Kontrogianni-Konstantopoulos
  • Henk Granzier

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.

TidsskriftActa Neuropathologica Communications
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
We thank the Nikon Imaging Centre at King’s College London for the provision of equipment for, and assistance with confocal imaging. We also thank Dr. Steven Lynham and the King’s Proteomics Core Facility for helping with some of the experiments. We finally thank Dr. Philipp Heher and Dr. Ay Lin Kho for assistance with the mouse work associated with piperine studies.

Funding Information:
This work was generously funded by the Novo Nordisk Foundation (NNF-0070539) and Carlsberg Foundation Grant (CF20-0113) to J.O., the Foundation Building Strength For Nemaline Myopathy to J.O. and J.L.

Publisher Copyright:
© 2022, The Author(s).

ID: 330390382