[en] Facioscapulohumeral muscular dystrophy (FSHD) is characterised by descending skeletal muscle weakness and wasting. FSHD is caused by mis-expression of the transcription factor DUX4, which is linked to oxidative stress, a condition especially detrimental to skeletal muscle with its high metabolic activity and energy demands. Oxidative damage characterises FSHD and recent work suggests metabolic dysfunction and perturbed hypoxia signalling as novel pathomechanisms. However, redox biology of FSHD remains poorly understood, and integrating the complex dynamics of DUX4-induced metabolic changes is lacking. Here we pinpoint the kinetic involvement of altered mitochondrial ROS metabolism and impaired mitochondrial function in aetiology of oxidative stress in FSHD. Transcriptomic analysis in FSHD muscle biopsies reveals strong enrichment for pathways involved in mitochondrial complex I assembly, nitrogen metabolism, oxidative stress response and hypoxia signalling. We found elevated mitochondrial ROS (mitoROS) levels correlate with increases in steady-state mitochondrial membrane potential in FSHD myogenic cells. DUX4 triggers mitochondrial membrane polarisation prior to oxidative stress generation and apoptosis through mitoROS, and affects mitochondrial health through lipid peroxidation. We identify complex I as the primary target for DUX4-induced mitochondrial dysfunction, with strong correlation between complex I-linked respiration and cellular oxygenation/hypoxia signalling activity in environmental hypoxia. Thus, FSHD myogenesis is uniquely susceptible to hypoxia-induced oxidative stress as a consequence of metabolic mis-adaptation. Importantly, mitochondria-targeted antioxidants rescue FSHD pathology more effectively than conventional antioxidants, highlighting the central involvement of disturbed mitochondrial ROS metabolism. This work provides a pathomechanistic model by which DUX4-induced changes in oxidative metabolism impair muscle function in FSHD, amplified when metabolic adaptation to varying O2 tension is required.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Heher, Philipp; Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London, UK. Electronic address: philipp.heher@kcl.ac.uk
Ganassi, Massimo; Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London, UK
Weidinger, Adelheid ; Ludwig Boltzmann Institute for Traumatology. The Research Center in Cooperation with AUVA, Vienna, Austria, Austrian Cluster for Tissue Regeneration, Vienna, Austria
Engquist, Elise N; Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London, UK
Pruller, Johanna ; Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London, UK
Nguyen, Thuy Hàng ; Université de Mons - UMONS > Faculté de Médecine et de Pharmacie > Service de Physiologie et réadaptation respiratoire
Tassin, Alexandra ; Université de Mons - UMONS > Faculté de Médecine et de Pharmacie > Service de Physiologie et réadaptation respiratoire
Decleves, Anne-Emilie ; Université de Mons - UMONS > Faculté de Médecine et de Pharmacie > Service de Biochimie métabolique et moléculaire
Mamchaoui, Kamel; Institut de Myologie, Sorbonne University, INSERM UMRS974, Paris, France
Banerji, Christopher R S; Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London, UK
Grillari, Johannes ; Ludwig Boltzmann Institute for Traumatology. The Research Center in Cooperation with AUVA, Vienna, Austria, Austrian Cluster for Tissue Regeneration, Vienna, Austria, Institute for Molecular Biotechnology, University of Natural Resources and Life Sciences, Vienna, Austria
Kozlov, Andrey V; Ludwig Boltzmann Institute for Traumatology. The Research Center in Cooperation with AUVA, Vienna, Austria, Austrian Cluster for Tissue Regeneration, Vienna, Austria
Zammit, Peter S; Randall Centre for Cell and Molecular Biophysics, King's College London, Guy's Campus, London, UK. Electronic address: peter.zammit@kcl.ac.uk
R550 - Institut des Sciences et Technologies de la Santé
Funding text :
PH was mainly funded by the Medical Research Council ( MR/P023215/1 ) and then by an Erwin Schroedinger post-doctoral fellowship awarded by the Austrian Science Fund ( FWF, J4435-B ), supported by Friends of FSH Research (Project 936,270 ) and the FSHD Society ( FSHD-Fall2020-3308289076 ). MG was supported by the Medical Research Council ( MR/S002472/1 ), EE was funded by Wellcome Trust PhD Studentship ( WT 222352/Z/21/Z ), as was JP ( WT 203949/Z/16/Z ) initially and then Muscular Dystrophy UK ( 19GRO-PG12-0493 ). THN was supported by the FRIA grant of the Fonds de la Recherche Scientifique (FRS-FNRS) and by the Association Les Amis F.S.H. (Amis FSH) .
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