Taurine (2-aminoethanesulfonic acid) is required for ensuring proper muscle functioning. Knockout of the taurine transporter in mice results in low taurine concentrations in the muscle and associates with myofiber necrosis and diminished exercise capacity. Interestingly, regulation of taurine and its transporter is altered in the mdx mouse, a model for Duchenne Muscular Dystrophy (DMD). DMD is a genetic disorder characterized by progressive muscle degeneration and weakness due to the absence of dystrophin from the muscle membrane, causing destabilization and contraction-induced muscle cell damage. This review explores the physiological role of taurine in skeletal muscle and the consequences of a disturbed balance in DMD. Its potential as a supportive treatment for DMD is also discussed. In addition to genetic correction, that is currently under development as a curative treatment, taurine supplementation has the potential to reduce muscle inflammation and improve muscle strength in patients.

Myo-inositol exerts many cellular functions, which include osmo-protection, membrane functioning, and secondary messaging. Its Na⁺/myo-inositol co-transporter SLC5A3 is expressed in muscle tissue and further accumulates in myositis. In this study we focused on the peculiar subgroup of sporadic inclusion body myositis (IBM), in which auto-inflammatory responses and degenerative changes co-exist. A cohort of nine patients was selected with clinically confirmed IBM, in which SLC5A3 protein was immune-localized to the different tissue constituents using immunofluorescence, and expression levels were evaluated using Western blotting. In normal muscle tissue, SLC5A3 expression was restricted to blood vessels and occasional low levels on muscle fiber membranes. In IBM tissues, SLC5A3 staining was markedly increased, with discontinuous staining of the muscle fiber membranes, and accumulation of SLC5A3 near inclusions and on the rims of vacuoles. A subset of muscle-infiltrating auto-aggressive immune cells was SLC5A3 positive, of which most were T-cells and M1 lineage macrophages. We conclude that SLC5A3 is overexpressed in IBM muscle, where it associates with protein aggregation and inflammatory infiltration. Based on our results, functional studies could be initiated to explore the possibilities of therapeutic osmolyte pathway intervention for preventing protein aggregation in muscle cells.

Duchenne Muscular Dystrophy (DMD) is a debilitating muscle disorder that condemns patients to year-long dependency on glucocorticoids. Chronic glucocorticoid use elicits many unfavourable side-effects without offering satisfying clinical improvement, thus, the search for alternative treatments to alleviate muscle inflammation persists. Taurine, an osmolyte with anti-inflammatory effects, mitigated pathological features in the mdx mouse model for DMD but interfered with murine development. In this study, ectoine is evaluated as an alternative for taurine in vitro in CCL-136 cells and in vivo in the mdx mouse. Pre-treating CCL-136 cells with 0.1 mM taurine and 0.1 mM ectoine prior to exposure with 300 U/mL IFN-γ and 20 ng/mL IL-1β partially attenuated cell death, whilst 100 mM taurine reduced MHC-I protein levels. In vivo, histopathological features of the tibialis anterior in mdx mice were mitigated by ectoine, but not by taurine. Osmolyte treatment significantly reduced mRNA levels of inflammatory disease biomarkers, respectively, CCL2 and SPP1 in ectoine-treated mdx mice, and CCL2, HSPA1A, TNF-α and IL-1β in taurine-treated mdx mice. Functional performance was not improved by osmolyte treatment. Furthermore, ectoine-treated mdx mice exhibited reduced body weight. Our results confirmed beneficial effects of taurine in mdx mice and, for the first time, demonstrated similar and differential effects of ectoine.

In Duchenne muscular dystrophy (DMD), the absence of dystrophin from the dystrophin-associated protein complex (DAPC) causes muscle membrane instability, which leads to myofiber necrosis, hampered regeneration, and chronic inflammation. The resulting disabled DAPC-associated cellular pathways have been described both at the molecular and the therapeutical level, with the Toll-like receptor nuclear factor kappa-light-chain-enhancer of activated B cells pathway (NF-ƘB), Janus kinase/signal transducer and activator of transcription proteins, and the transforming growth factor-β pathways receiving the most attention. In this review, we specifically focus on the protein kinase A/ mitogen-activated protein kinase/nuclear factor of activated T-cells 5/organic osmolytes (PKA-p38MAPK-NFAT5-organic osmolytes) pathway. This pathway plays an important role in osmotic homeostasis essential to normal cell physiology via its regulation of the influx/efflux of organic osmolytes. Besides, NFAT5 plays an essential role in cell survival under hyperosmolar conditions, in skeletal muscle regeneration, and in tissue inflammation, closely interacting with the master regulator of inflammation NF-ƘB. We describe the involvement of the PKA-p38MAPK-NFAT5-organic osmolytes pathway in DMD pathophysiology and provide a clear overview of which therapeutic molecules could be of potential benefit to DMD patients. We conclude that modulation of the PKA-p38MAPK-NFAT5-organic osmolytes pathway could be developed as supportive treatment for DMD in conjunction with genetic therapy.

Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration. Osmotic stress participates to DMD pathology and altered levels of osmolyte pathway members have been reported. The goal of this study was to gain insight in osmoregulatory changes in the mdx mouse model by examining the expression of osmolyte pathway members, including taurine transporter (TauT), sodium myo-inositol co-transporter (SMIT), betaine GABA transporter (BGT), and aldose reductase (AR) in the skeletal muscles and diaphragm of mdx mice aged 4, 8, 12, and 26 weeks. Necrosis was most prominent in 12 week-old mdx mice, whereas the amount of regenerated fibers increased until week 26 in the tibialis anterior. TauT protein levels were downregulated in the tibialis anterior and gastrocnemius of 4 to 12 week-old mdx mice, but not in 26 week-old mice, whereas TauT levels in the diaphragm remained significantly lower in 26 week-old mdx mice. In contrast, SMIT protein levels were significantly higher in the muscles of mdx mice when compared to controls. Our study revealed differential regulation of osmolyte pathway members in mdx muscle, which points to their complex involvement in DMD pathogenesis going beyond general osmotic stress responses. These results highlight the potential of osmolyte pathway members as a research interest and future therapeutic target in dystrophinopathy.