NR1D1 controls skeletal muscle calcium homeostasis through myoregulin repression

Alexis Boulinguiez (1, 2, 3) , Christian Duhem (1, 2, 3) , Alicia Mayeuf-Louchart (1, 2, 3) , Benoit Pourcet (1, 2, 3) , Yasmine Sebti (1, 2, 3) , Kateryna Kondratska (4) , Valérie Montel (5) , Stéphane Delhaye (1, 2, 3) , Quentin Thorel (1, 2, 3) , Justine Beauchamp (1, 2, 3) , Aurore Hebras (1, 2, 3) , Marion Gimenez (1, 2, 3) , Marie Couvelaere (1, 2, 3) , Mathilde Zecchin (1, 2, 3) , Lise Ferri (1, 2, 3) , Natalia Prevarskaya (4) , Anne Forand (6) , Christel Gentil (6) , Jessica Ohana (6) , France Piétri-Rouxel (6) , Bruno Bastide (5) , Bart Staels (1, 2, 3) , Helene Duez (1, 2, 3) , Steve Lancel (1, 2, 3)

1 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
2 RNMCD - Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011
3 EGID - Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508
4 PHYCELL - Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003
5 URePSSS - Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488
6 Centre de recherche en Myologie – U974 SU-INSERM

The sarcoplasmic reticulum (SR) plays an important role in calcium homeostasis. SR calcium mishandling is described in pathological conditions, such as myopathies. Here, we investigated whether the nuclear receptor subfamily 1 group D member (NR1D1, also called REV-ERBα) regulates skeletal muscle SR calcium homeostasis. Our data demonstrate that NR1D1 deficiency in mice impaired sarco/endoplasmic reticulum calcium ATPase-dependent (SERCA-dependent) SR calcium uptake. NR1D1 acts on calcium homeostasis by repressing the SERCA inhibitor myoregulin through direct binding to its promoter. Restoration of myoregulin counteracted the effects of NR1D1 overexpression on SR calcium content. Interestingly, myoblasts from patients with Duchenne muscular dystrophy displayed lower NR1D1 expression, whereas pharmacological NR1D1 activation ameliorated SR calcium homeostasis and improved muscle structure and function in dystrophic mdx/Utr+/- mice. Our findings demonstrate that NR1D1 regulates muscle SR calcium homeostasis, pointing to its therapeutic potential for mitigating myopathy.

Keywords: Calcium; Cell Biology; Muscle; Muscle Biology

Domains: Life Sciences [q-bio]

Alexis Boulinguiez, Christian Duhem, Alicia Mayeuf-Louchart, Benoit Pourcet, Yasmine Sebti, et al.. NR1D1 controls skeletal muscle calcium homeostasis through myoregulin repression. JCI Insight, 2022, 7 (17), ⟨10.1172/jci.insight.153584⟩. ⟨hal-03828260⟩