Rev-erb-α controls skeletal muscle calcium homeostasis through myoregulin repression: implications in Duchenne Muscular Dystrophy

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 Rev-erb-α regulates skeletal muscle SR calcium homeostasis. Our data demonstrate that Rev-erbα invalidation in mice impairs SERCA-dependent SR calcium uptake. Rev-erb-α acts on calcium homeostasis by repressing the SERCA inhibitor Myoregulin, through direct binding to its promoter. Restoration of Myoregulin counteracts the effects of REV-ERB-α overexpression on SR calcium content. Interestingly, myoblasts from Duchenne myopathy patients display downregulated REV-ERBα expression, whereas pharmacological Rev-erb activation ameliorates SR calcium homeostasis, and improves muscle structure and function in dystrophic mdx/Utr+/- mice. Our findings demonstrate that Rev-erb-α regulates muscle SR calcium homeostasis, pointing to its therapeutic interest for mitigating myopathy.

[1]  O. Froy,et al.  REV-ERBα activates the mTOR signaling pathway and promotes myotubes differentiation. , 2020, Biology of the cell.

[2]  M. Wood,et al.  Combined Treatment with Peptide-Conjugated Phosphorodiamidate Morpholino Oligomer-PPMO and AAV-U7 Rescues the Severe DMD Phenotype in Mice , 2020, Molecular therapy. Methods & clinical development.

[3]  S. Lancel,et al.  The nuclear receptor FXR inhibits Glucagon-Like Peptide-1 secretion in response to microbiota-derived Short-Chain Fatty Acids , 2020, Scientific Reports.

[4]  M. Lazar,et al.  SR9009 has REV-ERB–independent effects on cell proliferation and metabolism , 2019, Proceedings of the National Academy of Sciences.

[5]  Alicia Mayeuf-Louchart,et al.  MuscleJ: a high-content analysis method to study skeletal muscle with a new Fiji tool , 2018, Skeletal Muscle.

[6]  L. Solt,et al.  Distinct roles for REV-ERBα and REV-ERBβ in oxidative capacity and mitochondrial biogenesis in skeletal muscle , 2018, PloS one.

[7]  J. Eeckhoute,et al.  Nuclear Receptor Subfamily 1 Group D Member 1 Regulates Circadian Activity of NLRP3 Inflammasome to Reduce the Severity of Fulminant Hepatitis in Mice. , 2017, Gastroenterology.

[8]  S. Lancel,et al.  Rev-erb-α regulates atrophy-related genes to control skeletal muscle mass , 2017, Scientific Reports.

[9]  John M. Shelton,et al.  Widespread control of calcium signaling by a family of SERCA-inhibiting micropeptides , 2016, Science Signaling.

[10]  S. Noguchi,et al.  Calcium Dyshomeostasis in Tubular Aggregate Myopathy , 2016, International journal of molecular sciences.

[11]  U. Giovanella,et al.  Inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ signaling mediates delayed myogenesis in Duchenne muscular dystrophy fetal muscle , 2016, Development.

[12]  J. Cavaillon,et al.  Comparative Study of Injury Models for Studying Muscle Regeneration in Mice , 2016, PloS one.

[13]  M. Lazar,et al.  Discrete functions of nuclear receptor Rev-erbα couple metabolism to the clock , 2015, Science.

[14]  J. Molkentin,et al.  SERCA1 overexpression minimizes skeletal muscle damage in dystrophic mouse models. , 2015, American journal of physiology. Cell physiology.

[15]  John M. Shelton,et al.  A Micropeptide Encoded by a Putative Long Noncoding RNA Regulates Muscle Performance , 2015, Cell.

[16]  A. López de Munain,et al.  Dysregulation of calcium homeostasis in muscular dystrophies , 2014, Expert Reviews in Molecular Medicine.

[17]  Douglas J. Kojetin,et al.  REV-ERB and ROR nuclear receptors as drug targets , 2014, Nature Reviews Drug Discovery.

[18]  J. Eeckhoute,et al.  Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy , 2013, Nature Medicine.

[19]  Kay E. Davies,et al.  Hsp72 preserves muscle function and slows progression of severe muscular dystrophy , 2012, Nature.

[20]  M. Michalak,et al.  Calreticulin, a multi-process calcium-buffering chaperone of the endoplasmic reticulum. , 2009, The Biochemical journal.

[21]  S. Baylor,et al.  Comparison of the myoplasmic calcium transient elicited by an action potential in intact fibres of mdx and normal mice , 2008, The Journal of physiology.

[22]  D. Claflin,et al.  Direct observation of failing fibers in muscles of dystrophic mice provides mechanistic insight into muscular dystrophy. , 2008, American journal of physiology. Cell physiology.

[23]  Onn Brandman,et al.  STIM2 Is a Feedback Regulator that Stabilizes Basal Cytosolic and Endoplasmic Reticulum Ca2+ Levels , 2007, Cell.

[24]  M. Falempin,et al.  Compared effects of hindlimb unloading versus terrestrial deafferentation on muscular properties of the rat soleus , 2003, Experimental Neurology.

[25]  M. E. Kargacin,et al.  The sarcoplasmic reticulum calcium pump is functionally altered in dystrophic muscle. , 1996, Biochimica et biophysica acta.

[26]  M. Lazar,et al.  direct repeat . represses transcription as a dimer on a novel The monomer-binding orphan receptor RevErb , 1995 .

[27]  C. Cognard,et al.  Changes in cytosolic resting ionized calcium level and in calcium transients during in vitro development of normal and Duchenne muscular dystrophy cultured skeletal muscle measured by laser cytofluorimetry using indo-1. , 1993, Cell calcium.

[28]  J. Lytton,et al.  Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps. , 1991, The Journal of biological chemistry.