Key result
Activation of p38 signaling or knockdown of KSRP increased utrophin A expression in skeletal muscle by extending mRNA half-life, suggesting a novel therapeutic approach for Duchenne muscular dystrophy.
Activation of p38 signaling increases utrophin A expression post-transcriptionally, providing proof-of-principle for a novel therapeutic approach in Duchenne muscular dystrophy.
Hypothesis-generating for p38-KSRP modulation in DMD models; human trials needed before clinical consideration.
Several therapeutic approaches are currently being developed for Duchenne muscular dystrophy (DMD) including upregulating the levels of endogenous utrophin A in dystrophic fibers. Here, we examined the role of post-transcriptional mechanisms in controlling utrophin A expression in skeletal muscle. We show that activation of p38 leads to an increase in utrophin A independently of a transcriptional induction. Rather, p38 controls the levels of utrophin A mRNA by extending the half-life of transcripts via AU-rich elements (AREs). This mechanism critically depends on a decrease in the functional availability of KSRP, an RNA-binding protein known to promote decay of ARE-containing transcripts. In vitro and in vivo binding studies revealed that KSRP interacts with specific AREs located within the utrophin A 3' UTR. Electroporation experiments to knockdown KSRP led to an increase in utrophin A in wild-type and mdx mouse muscles. In pre-clinical studies, treatment of mdx mice with heparin, an activator of p38, causes a pronounced increase in utrophin A in diaphragm muscle fibers. Together, these studies identify a pathway that culminates in the post-transcriptional regulation of utrophin A through increases in mRNA stability. Furthermore, our results constitute proof-of-principle showing that pharmacological activation of p38 may prove beneficial as a novel therapeutic approach for DMD.
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Amirouche et al. (2013) studied Duchenne muscular dystrophy (DMD). Activation of p38 signaling (e.g., via heparin) or KSRP knockdown was evaluated on Utrophin A expression levels. Activation of p38 signaling or knockdown of KSRP increased utrophin A expression in skeletal muscle by extending mRNA half-life, suggesting a novel therapeutic approach for Duchenne muscular dystrophy.
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