Depletion of HuR in murine skeletal muscle enhances exercise endurance and prevents cancer-induced muscle atrophy

作者：Brenda Janice Sánchez, Anne‐Marie K Tremblay, Jean‐Philippe Leduc‐Gaudet, Derek Hall, Erzsébet Nagy Kovács, F. Jennifer, Souad Mubaid, Patricia L. Hallauer, Brittany L. Phillips, Katherine E. Vest, Anita H. Corbett, Dimitris L. Kontoyiannis, Sabah N. A. Hussain, Kenneth E.M. Hastings, Sergio Di Marco, Imed‐Eddine Gallouzi · 发表于：Nature Communications · 年份：2019 · DOI：10.1038/s41467-019-12186-6 · 被引用次数：46 · 研究领域：Muscle Physiology and Disorders、Adipose Tissue and Metabolism、RNA Research and Splicing

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.