TY - JOUR

T1 - NEB mutations disrupt the super-relaxed state of myosin and remodel the muscle metabolic proteome in nemaline myopathy

AU - Ranu, Natasha

AU - Laitila, Jenni

AU - Dugdale, Hannah F.

AU - Mariano, Jennifer

AU - Kolb, Justin S.

AU - Wallgren-Pettersson, Carina

AU - Witting, Nanna

AU - Vissing, John

AU - Vilchez, Juan Jesus

AU - Fiorillo, Chiara

AU - Zanoteli, Edmar

AU - Auranen, Mari

AU - Jokela, Manu

AU - Tasca, Giorgio

AU - Claeys, Kristl G.

AU - Voermans, Nicol C.

AU - Palmio, Johanna

AU - Huovinen, Sanna

AU - Moggio, Maurizio

AU - Beck, Thomas Nyegaard

AU - Kontrogianni-Konstantopoulos, Aikaterini

AU - Granzier, Henk

AU - Ochala, Julien

N1 - Publisher Copyright: © 2022, The Author(s).

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - Metabolism

KW - Myosin

KW - Nebulin

KW - Nemaline myopathy

KW - Skeletal muscle

U2 - 10.1186/s40478-022-01491-9

DO - 10.1186/s40478-022-01491-9

M3 - Journal article

C2 - 36528760

AN - SCOPUS:85144220055

VL - 10

JO - Acta neuropathologica communications

JF - Acta neuropathologica communications

SN - 2051-5960

M1 - 185

ER -