Activation of osmolyte pathways in inflammatory myopathy and Duchenne muscular dystrophy points to osmoregulation as a contributing pathogenic mechanism.
Alongside well-known nuclear factor κB (NFκB) and its associated cytokine networks, nuclear factor of activated T cells 5 (NFAT5), the master regulator of cellular osmoprotective programs, comes forward as an inflammatory regulator. To gain insight into its yet unexplored role in muscle disease, we studied the expression of NFAT5 target proteins involved in osmolyte accumulation: aldose reductase (AR), taurine transporter (TauT), and sodium myo-inositol co-transporter (SMIT). We analyzed idiopathic inflammatory myopathy and Duchenne muscular dystrophy muscle biopsies and myotubes in culture, using immunohistochemistry, immunofluorescence, and western blotting. We report that the level of constitutive AR was upregulated in patients, most strongly so in Duchenne muscular dystrophy. TauT and SMIT expression levels were induced in patients' muscle fibers, mostly representing regenerating and atrophic fibers. In dermatomyositis, strong staining for AR, TauT, and SMIT in atrophic perifascicular fibers was accompanied by staining for other molecular NFAT5 targets, including chaperones, chemokines, and inducible nitric oxide synthase. In these fibers, NFAT5 and NFκB p65 staining coincided, linking both transcription factors with this important pathogenic hallmark. In sporadic inclusion body myositis, SMIT localized to inclusions inside muscle fibers. In addition, SMIT was expressed by a substantial subset of muscle-infiltrating macrophages and T cells in patient biopsies. Our results indicate that osmolyte pathways may contribute to normal muscle functioning, and that activation of AR, TauT, and SMIT in muscle inflammation possibly contributes to the tissue's failing program of damage control.
Department of Neurology, Neuromuscular Reference Center, Ghent University Hospital, Ghent, Belgium.
Boel
0000-0001-9403-4401
B
De Paepe
Department of Ultrastructural Neuropathology, Born-Bunge Institute, Antwerp University Hospital, Wilrijk, Belgium.
Jean-Jacques
JJ
Martin
Department of Neurology, Neuromuscular Reference Center, Ghent University Hospital, Ghent, Belgium.
Sandrine
S
Herbelet
Department of Neurology, Neuromuscular Unit, Hospital Sant Joan de DeuBarcelona, Esplugues de Llobregat, Spain.
Cecilia
C
Jimenez-Mallebrera
Department of Pediatrics, Hospital Sant Joan de Deu Barcelona, Esplugues de Llobregat, Spain.
Estibaliz
E
Iglesias
Department of Pathology and Biobank, Hospital Sant Joan de Deu Barcelona, Esplugues de Llobregat, Spain.
Cristina
C
Jou
Institute for Neuropathology, RWTH Aachen University Hospital, Aachen, Germany.
Joachim
J
Weis
Department of Neurology, Neuromuscular Reference Center, Ghent University Hospital, Ghent, Belgium.
Jan L
JL
De Bleecker
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000449:Aldehyde Reductase / Q000378:metabolism; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003882:Dermatomyositis / Q000378:metabolism; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000209:etiology* / Q000276:immunology / Q000378:metabolism*; D009220:Myositis / Q000209:etiology* / Q000276:immunology / Q000378:metabolism*; D064587:Osmoregulation; D017285:Polymyositis / Q000378:metabolism; D027981:Symporters / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D055815:Young Adult; D000099247:Taurine Transporters
D000449:Aldehyde Reductase; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D027981:Symporters; D051996:Transcription Factor RelA; D014157:Transcription Factors; D000099247:Taurine Transporters; C118125:NFAT5 protein, human; C498143:RELA protein, human; C073884:SLC5A3 protein, human