Disintegration of the NuRD Complex in Primary Human Muscle Stem Cells in Critical Illness Myopathy

Joanna Schneider; Devakumar Sundaravinayagam; Alexander Blume; Andreas Marg; Stefanie Grunwald; Eric Metzler; Helena Escobar; Stefanie Müthel; Haicui Wang; Tobias Wollersheim; Steffen Weber-Carstens; Altuna Akalin; Michela Di Virgilio; Baris Tursun; Simone Spuler

doi:10.3390/ijms24032772

Disintegration of the NuRD Complex in Primary Human Muscle Stem Cells in Critical Illness Myopathy

Int J Mol Sci. 2023 Feb 1;24(3):2772. doi: 10.3390/ijms24032772.

Authors

Joanna Schneider^{1

2

3}, Devakumar Sundaravinayagam⁴, Alexander Blume⁵, Andreas Marg¹, Stefanie Grunwald¹, Eric Metzler¹, Helena Escobar¹, Stefanie Müthel^{1

5}, Haicui Wang¹, Tobias Wollersheim^{3

6}, Steffen Weber-Carstens⁶, Altuna Akalin⁵, Michela Di Virgilio⁴, Baris Tursun⁵, Simone Spuler¹

Affiliations

¹ Muscle Research Unit, Experimental and Clinical Research Center, A Joint Cooperation of the Charité Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Society, Lindenberger Weg 80, 13125 Berlin, Germany.
² Charité Universitätsmedizin Berlin, Department of Pediatric Neurology, 13353 Berlin, Germany.
³ Berlin Institute of Health-Universitätsmedizin Berlin, 10117 Berlin, Germany.
⁴ Laboratory of DNA Repair and Maintenance of Genome Stability, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13092 Berlin, Germany.
⁵ Berlin Institute of Medical Systems Biology (BIMSB), Max Delbruck Center for Molecular Medicine in the Helmholtz Association, 10115 Berlin, Germany.
⁶ Charité Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine, 13353 Berlin, Germany.

Abstract

Critical illness myopathy (CIM) is an acquired, devastating, multifactorial muscle-wasting disease with incomplete recovery. The impact on hospital costs and permanent loss of quality of life is enormous. Incomplete recovery might imply that the function of muscle stem cells (MuSC) is impaired. We tested whether epigenetic alterations could be in part responsible. We characterized human muscle stem cells (MuSC) isolated from early CIM and analyzed epigenetic alterations (CIM n = 15, controls n = 21) by RNA-Seq, immunofluorescence, analysis of DNA repair, and ATAC-Seq. CIM-MuSC were transplanted into immunodeficient NOG mice to assess their regenerative potential. CIM-MuSC exhibited significant growth deficits, reduced ability to differentiate into myotubes, and impaired DNA repair. The chromatin structure was damaged, as characterized by alterations in mRNA of histone 1, depletion or dislocation of core proteins of nucleosome remodeling and deacetylase complex, and loosening of multiple nucleosome-spanning sites. Functionally, CIM-MuSC had a defect in building new muscle fibers. Further, MuSC obtained from the electrically stimulated muscle of CIM patients was very similar to control MuSC, indicating the impact of muscle contraction in the onset of CIM. CIM not only affects working skeletal muscle but has a lasting and severe epigenetic impact on MuSC.

Keywords: critical illness; epigenetic; histone 1; muscle stem cell.

MeSH terms

Animals
Critical Illness
Humans
Mi-2 Nucleosome Remodeling and Deacetylase Complex* / metabolism
Mice
Muscle, Skeletal / metabolism
Muscular Diseases* / metabolism
Quality of Life
Stem Cells

Substances

Mi-2 Nucleosome Remodeling and Deacetylase Complex

Grants and funding

Our research was supported by the German Research Foundation (DFG KFO192/2), the Berlin Institute of Health (BIH), and the Charité. Schneider and Wollersheim are participants in the BIH-Charité Clinician Scientist Program funded by the Charité Universitätsmedizin Berlin and the Berlin Institute of Health. The authors have no financial relationships relevant to this article to disclose.