Abstract
The master posttranscriptional regulator HuR promotes muscle fiber formation in cultured muscle cells. However, its impact on muscle physiology and function in vivo is still unclear. Here, we show that muscle-specific HuR knockout (muHuR-KO) mice have high exercise endurance that is associated with enhanced oxygen consumption and carbon dioxide production. muHuR-KO mice exhibit a significant increase in the proportion of oxidative type I fibers in several skeletal muscles. HuR mediates these effects by collaborating with the mRNA decay factor KSRP to destabilize the PGC-1α mRNA. The type I fiber-enriched phenotype of muHuR-KO mice protects against cancer cachexia-induced muscle loss. Therefore, our study uncovers that under normal conditions HuR modulates muscle fiber type specification by promoting the formation of glycolytic type II fibers. We also provide a proof-of-principle that HuR expression can be targeted therapeutically in skeletal muscles to combat cancer-induced muscle wasting.
Highlights
The master posttranscriptional regulator HuR promotes muscle fiber formation in cultured muscle cells
Knockout of HuR was confirmed by genotyping with PCR primers and by western blot (WB) analysis in several hindlimb skeletal muscles, including the quadricep, gastrocnemius, tibialis anterior (TA), soleus, peroneus, and extensor digitorum longus (EDL) (Fig. 1d–f)
We demonstrate that, in vivo, the RNA-binding proteins (RBPs) HuR plays an important role in muscle physiology as well as in deciding muscle fate under disease conditions. muHuR-KO mice show a significant increase in exercise endurance, a phenotype that is explained in part by an enrichment of type I fibers
Summary
The master posttranscriptional regulator HuR promotes muscle fiber formation in cultured muscle cells. Factors regulating fiber type in muscle could represent ideal drug targets for treating cachexia and other muscle wasting diseases It is well-established that factors such as the transcription factor peroxisome-proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and the deacetylase Sirtuin 1 (Sirt1), modulate the fiber-type composition of skeletal muscles. In response to a stimulus such as voluntary exercise, the activation of Sirt[1] leads to the deacetylation of PGC-1α This in turn, upregulates the expression of NRFs (nuclear respiratory factors) and Tfam (mitochondria transcription factor A), which are key players in mitochondrial biogenesis and oxidative metabolism in muscles[1,4,6,7]. At later steps of myogenesis, HuR stabilizes the mRNAs encoding promoters of muscle fiber formation such as MyoD, Myogenin, and p21, only when muscle cells begin their fusion to form fibers (myotubes)[10]
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