Abstract
The transcription factor NFAT5 is a key regulator in protection from hypertonic stress in the renal medulla but its role in skeletal muscle has not been examined. Since hypertonic stress occurs during hyperglycemic crisis in patients with diabetes, we sought to evaluate the effects of sustained (1–2 days) and elevated glucose (25–50 mM) on endogenous NFAT5 activity and Ca2+ signaling in skeletal muscle fibers in culture. Exposure to high glucose increased NFAT5 nuclear translocation and its expression. NFAT-driven luciferase assays demonstrated an increase in transcriptional activity in fibers exposed to sustained high glucose. These effects were insensitive to the inhibition of calcineurin A, but were sensitive to both p38α MAPK and PIKK inhibition. Elevated glucose also upregulated the expression of aldose reductase and sodium/myo-inositol transporter. Ca2+ imaging techniques revealed larger and abnormal double Ca2+ transients upon a single 1 ms field stimulus in the majority of fibers challenged with elevated glucose. The transverse tubule morphology was also disrupted in fibers exposed to high glucose. In conclusion, elevated extracellular glucose resulted in increased NFAT5 expression and transcriptional activity and caused osmoregulatory responses in parallel with abnormal Ca2+ signaling in skeletal muscle. These changes may play a role in the pathophysiology of acute hyperglycemic episodes.
Published Version
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