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

• Authors: Grace Pavlath, Emory University; Brenda Janice Sanchez, McGill University; Anne-Marie K. Tremblay, McGill University; Jean-Philippe Leduc-Gaudet, McGill University; Derek T. Hall, McGill University; Erzsebet Kovacs, McGill University; Jennifer F. Ma, McGill University; Souad Mubaid, McGill University; Patricia L. Hallauer, McGill University; Brittany L. Phillips, Emory University; Katherine E. Vest, University of Cincinnati; Anita Corbett, Emory University; Dimitris L. Kontoyiannis, Institute of Fundamental Biomedical Research; Sabah N. A. Hussain, McGill University; Kenneth E. M. Hastings, McGill University; Sergio Di Marco, McGill University; Imed-Eddine Gallouzi, McGill University
• Journal Title: Nature Communications
• Volume: Volume 10, Number 1
• Publisher: Nature Research (part of Springer Nature): Fully open access journals | 2019-09-13, Pages 4171-4171
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s41467-019-12186-6
• Subjects: Biology, General; Chemistry, Biochemistry
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; FIBER-TYPE SPECIFICITY; MESSENGER-RNA; MOLECULAR REGULATION; GENE MYF-5; PROTEIN; PGC-1-ALPHA; METABOLISM; MYOD; PHOSPHORYLATION; INACTIVATION

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.