Activation of osmolyte pathways in inflammatory myopathy and Duchenne muscular dystrophy points to osmoregulation as a contributing pathogenic mechanism

Abstract

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.

Myo-Inositol Transporter SLC5A3 Associates with Degenerative Changes and Inflammation in Sporadic Inclusion Body Myositis

“…We reported earlier that the osmolyte system becomes activated in myositis tissues [10] and in vitro in muscle cells exposed to pro-inflammatory cytokines [11]. In the present study we elaborate on the involvement of the MI transporter SLC5A3 in the degenerative and inflammatory changes associated with IBM.…”

Can Human Embryonic Stem Cell-Derived Stromal Cells Serve a Starting Material for Myoblasts?

“…In addition, the proliferation capability and genetic stability of the ESC-derived mesenchymal stromal cells open up significant new possibilities in regenerative medicine. ESCs can be a promising cellular source for cell-based therapy to treat Duchenne muscular dystrophy, a lethal human disease for which no effective treatment currently exists [11, 12]. …”

“…As therapeutic cellular products, myoblasts and mesenchymal stromal cells are considered the most suitable. In this study, we generated mesenchymal stromal cells from ESCs for the production of cellular therapy products to treat patients with genetic muscular disorders [11, 12]. We developed a novel protocol to manufacture mesenchymal stromal cells from ESCs with certified materials that had been analyzed for viruses.…”

Can human embryonic stem cell-derived stromal cells serve a starting material for myoblasts?

“…Implantation of myoblasts induced from ESC-derived mesenchymal stromal cells into patients with genetic muscular disorders is indeed an ideal strategy, from the viewpoint of industry-based, sustainable supply of large quantities of affordable, quality-controlled cells. It is unlikely that it is possible to prepare unaffected somatic cells in sufficient quantity, necessitating the use of stem cells from suitable, cost-effective allogeneic sources, such as for which no effective treatment currently exists (Assereto et al, 2016;De Paepe et al, 2016).…”

“…As a therapeutic cellular products, myoblasts and mesenchymal stromal cells are considered most suitable. In this study, we generated mesenchymal stromal cells 4 from ESCs for the production of cellular therapy products to treat patients with genetic muscular disorders (Assereto et al, 2016;De Paepe et al, 2016). We developed a novel protocol to manufacture mesenchymal stromal cells from ESCs with certified materials that had been analyzed for viruses.…”